Progressing Nanotechnology To Improve Targeted Cancer Treatment: Overcoming Hurdles in Its Clinical Implementation

Chehelgerdi et al.
Molecular Cancer (2023) 22:169 Molecular Cancer

https://doi.org/10.1186/s12943-023-01865-0
REVIEW Open Access
Progressing nanotechnology to improve

targeted cancer treatment: overcoming hurdles
in its clinical implementation
Mohammad Chehelgerdi1,2* , Matin Chehelgerdi1,2, Omer Qutaiba B. Allela3, Renzon Daniel Cosme Pecho4,
Narayanan Jayasankar5, Devendra Pratap Rao6, Tamilanban Thamaraikani5, Manimaran Vasanthan7,
Patrik Viktor8, Natrayan Lakshmaiya9, Mohamed J. Saadh10, Ayesha Amajd11,12, Mabrouk A. Abo‑Zaid13,
Roxana Yolanda Castillo‑Acobo14, Ahmed H. Ismail13, Ali H. Amin15 and Reza Akhavan‑Sigari16,17
Abstract
The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments
in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques,
which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved
for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze
some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic.
This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting
and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer
detection and treatment in the future, but further research is needed to overcome the current limitations in clinical
translation.
Keywords Nanotechnology, Cancer detection, Cancer treatment, Nanoscale targeting techniques, Protein
engineering, Materials science, Nanocarriers, Medicinal purposes, Human trials
*Correspondence:
Mohammad Chehelgerdi
[email protected]
Full list of author information is available at the end of the article
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Chehelgerdi et al. Molecular Cancer (2023) 22:169 Page 2 of 103
Graphical Abstract
Introduction potentialities offered by nanotechnology to address this

Cancer, an intricate ailment that has long posed for- critical necessity [1].
midable therapeutic challenges, demands novel Nanocarriers stand out as a focal point in the con-
approaches that can surmount the limitations of con- vergence of nanotechnology and cancer treatment.
ventional treatments like chemotherapy and radiation These minute carriers, adept at encapsulating thera-
therapy, which often inflict severe side effects and yield peutic agents such as drugs or genes, present an array
unsatisfactory outcomes [1]. In this landscape of medi- of advantages surpassing the confines of traditional
cal exigency, nanotechnology has emerged as a promis- treatments [3]. Key among these advantages are pin-
ing paradigm for the detection and treatment of cancer. point accuracy in targeting cancer cells, mitigated harm
Nanotechnology harnesses the ability to engineer and to healthy cells, and amplified efficacy of therapeutic
manipulate materials on the nanoscale, typically within payloads [4]. The trajectory of nanocarrier-based can-
the realm of 1 to 100 nm. The unique physicochemical cer cell targeting is manifested through two principal
properties of these diminutive materials confer distinc- avenues: passive targeting and active targeting. Pas-
tive interactions with cells and tissues, thereby paving sive targeting capitalizes on the distinctive attributes of
the way for innovative nanoscale targeting techniques tumor cells, such as their permeable blood vessels, to
that might catalyze transformative shifts in cancer foster accumulation of nanocarriers within the tumor
diagnosis and therapy [2]. The current milieu of cancer microenvironment [2, 4]. Conversely, active target-
therapy underscores the compelling need for ground- ing involves surface modifications of nanocarriers
breaking methodologies, and this paper delves into the with specific targeting ligands that bind to receptors
decorating the surfaces of cancer cells, facilitating pre- significant challenges related to their effective delivery to
cise and enhanced cellular engagement [5]. target cells, including issues such as in vivo decay, limited
Although diverse nanocarriers have traversed pre- uptake by target cells, the need for nuclear penetration,
clinical phases and garnered approvals for human trials, and potential damage to healthy cells. The study high-
a mere fraction have secured authorization for clinical lights the pivotal role of advanced smart nanocarriers,
deployment, particularly those with molecular moie- such as lipids, polymers, spherical nucleic acids, and
ties designed for selective cancer cell interactions [4]. metallic nanoparticles, in overcoming these barriers.
This juncture accentuates the intricacies of transition- These nanocarriers offer a means to efficiently and selec-
ing laboratory discoveries to effective clinical interven- tively deliver nucleic acids to the desired cells and tissues,
tions, underscoring the imperative for further research thereby improving the overall efficacy, reducing toxicity,
to optimize the therapeutic potential of nanocarriers in and enhancing stability of cancer therapeutics in the con-
the context of cancer therapy [6]. The marriage of nano- text of immunotherapy. This research underscores the
technology and cancer treatment holds the promise of potential of nanotechnology as a promising approach in
optimizing the efficacy of therapeutic agents, curbing the ongoing battle against cancer [8]. Table 1 highlights
collateral damage to healthy cells, and elevating patient the various nanocarrier types for cancer therapy and
prognoses [2]. However, navigating this promising terrain their respective properties. Mucosal barriers and non-
is not devoid of hurdles, encompassing the refinement of specific absorption are just a few of the challenges
cost-effective and efficient nanocarriers, assurance of the encountered in employing nanocarriers for cancer ther-
safety profile of these carriers in human settings, and sur- apy. To overcome these obstacles, a combination of
mounting barriers obstructing the translation of labora- rational nanocarrier design and a fundamental under-
tory insights to tangible clinical outcomes [6]. standing of tumor biology is needed [6]. Tumors are
The primary scope of our article is to examine the characterized by a variety of symptoms, but two of the
advancements and challenges in utilizing nanotechnol- most prevalent ones are leaky blood vessels and poor
ogy for targeted cancer therapy. We will specifically lymphatic drainage. Nanocarriers can take advantage of
focus on nanocarriers and compounds that demonstrate these characteristics through the EPR (enhanced perme-
potential for selective tumor targeting. The nanocarri- ability and retention) effect, which allows them to escape
ers covered will encompass liposomes, nanoparticles, into tumor tissues via leaky arteries and distribute drugs
and micelles, among others. As for authorized formula- to the region surrounding the tumor cells [9]. In addition,
tions, we will select those that have undergone clinical the size of the nanocarrier is also important, with parti-
trials or have been approved for clinical use in targeting cles with diameters of 200 nm being found to be more
cancer cells. The criteria for selecting these authorized efficient, although experiments utilizing liposomes of
formulations will include their demonstrated efficacy varying mean sizes imply that the threshold vesicle size
in targeting cancer cells, their safety profile, and their for extravasation into tumors is 400 nm [10]. Although
potential for clinical translation. By providing this clarity, passive targeting methods form the backbone of thera-
our review aims to shed light on the current landscape of peutic practice, they are not without their flaws. One
nanotechnology-based cancer therapies and the criteria major issue is the possibility that not all of the tumor’s
that underlie the selection of promising formulations for cells may be accessible for treatment [6, 10]. This can be
clinical application. due to the inability of certain pharmaceuticals to disperse
well, making it difficult to control the process. The lack of
Methods of passive and active targeting control can lead to multiple-drug resistance (MDR),
Nanocarriers are being increasingly investigated as a where chemotherapy treatments fail because the cancer
promising approach to cancer treatment, but they face is resistant to the drugs [11]. This is facilitated by the
numerous roadblocks on their journey to the targeted overexpression of transporter proteins on the surface of
site [7]. In a recent study by Baker et al., the potential of cancer cells that eliminate drugs from cells [5]. Figure 1
smart nanocarriers in the targeted delivery of therapeutic presents a study on the ability of ligand-installed nano-
nucleic acids for cancer immunotherapy has been carriers to target cancer cells. Active targeting, where
explored. Cancer treatment has seen remarkable progress nanocarriers actively adhere to the cells they are target-
with the advent of immunotherapy, particularly through ing following extravasation, is one way to circumvent the
the use of antibodies targeting immune checkpoints. limitations of passive targeting (Fig. 1A). Ligands, which
However, the field of cancer immunotherapy is evolving, are targeted agents, can be attached to the surface of the
with a growing emphasis on nucleic acid technology, nanocarrier using various conjugation chemistry meth-
including cancer vaccines, adoptive T-cell therapies, and ods. Ligand-receptor interactions enable the nanocarrier
gene regulation. Yet, these promising approaches face to identify and attach to its intended cells [9]. The
Table 1 Comparison of nanocarrier types for cancer therapy
Nanocarrier Size Range Surface Drug Payload Targeting Biodegradability Description Novelty Advantages Disadvantages Limitations/ References
Type Charge Capacity Mechanism Challenges
Liposomes 50–200 nm Neutral Low–High Passive/Active Biodegradable Spherical First-genera‑ Good biocom‑ Short circulation Limited drug [13]
structures tion nanocarri‑ patibility, low time, potential payload capac‑
composed ers for drug immuno‑ drug leakage, ity, challenges
of a lipid delivery, used genicity, ver‑ lack of tumor in scaling
bilayer enclos‑ in clinical satility in drug specificity up produc‑
ing an aque‑ practice loading tion, difficulty
Chehelgerdi et al. Molecular Cancer
ous core and targeting in achieving

controlled drug
release in vivo
Polymeric 10–200 nm Variable Low–High Passive/Active Biodegradable Solid particles Wide range High drug Potential Challenges [14, 15]
nanoparti- made of syn‑ of materials loading toxicity, burst in achieving
cles thetic or natu‑ and formula‑ capacity, release of drug, controlled
(2023) 22:169
ral polymers tions, suitable stable in cir‑ batch-to-batch release, low

for various culation, tun‑ variation, diffi‑ targeting effi‑
administration able surface culty in achiev‑ ciency, limited
routes properties ing targeted biocompat‑
drug delivery ibility of some
to tumors materials
Dendrimers 1–10 nm Variable Low-Moderate Passive/Active Non-biodegrad‑ Branched, Highly High biotoxic‑ Limited blood Limited target‑ [15]
able highly customizable, ity, low bio‑ circulation time, ing efficiency,
branched multivalent degradability, potential renal challenges
or spherical surface chem‑ challenges toxicity, difficulty in achieving
molecules istry, high in scaling in achiev‑ controlled
with defined drug loading up production ing targeted release, poten‑
size and shape capacity drug delivery tial immuno‑
to tumors genicity
Gold nano- 1–100 nm Neutral Low-Moderate Passive/Active Non-biodegrad‑ Spherical Excellent bio‑ Low drug Potential toxicity, Limited bio‑ [16, 17]
particles able or rod-shaped compatibility, loading limited targeting compatibility
particles made high surface capacity, efficiency, diffi‑ of some surface
of gold plasmon limited tumor culty in achiev‑ modifications,
resonance penetration, ing controlled potential
effect, stability challenges drug release immunogenic‑
in biological in scaling in vivo ity
fluids up production
Carbon nano- 1–100 nm Negative Low–High Passive/Active Non-biodegrad‑ Hollow High aspect High toxicity, Limited blood Potential immu‑ [18, 19]
tubes able cylindrical ratio, high limited bio‑ circulation nogenicity, dif‑
structures drug loading compatibility, time, poten‑ ficulty in scaling
made of car‑ capacity, challenges tial clearance up production
bon atoms potential in achieving by the reticu‑
for multi-func‑ controlled loendothelial
tionalization release system, difficulty
in achiev‑
ing targeted
drug delivery
to tumors
Page 4 of 103
Table 1 (continued)
Iron oxide 5–100 nm Negative Low-Moderate Passive/Active Biodegradable Magnetic High targeting Low drug Potential toxicity, Potential immu‑ [20]
nanoparti- particles made specificity, loading limited tumor nogenicity, low
cles of iron oxide potential capacity, lim‑ penetration, dif‑ biocompat‑
for MRI ited blood cir‑ ficulty in scaling ibility of some
imaging culation time, up production surface modifi‑
and magnetic challenges cations
hyperthermia in achieving
controlled
release
Quantum 1–10 nm Negative Low-Moderate Passive/Active Non-biodegrad‑ Semiconduc‑ High bright‑ High toxicity, Limited blood Potential immu‑ [21]
dots able tor nanocrys‑ ness, tun‑ potential circulation nogenicity,
tals able emission for heavy time, poten‑ limited tumor
(2023) 22:169
spectrum, metal tial clearance specificity

potential leaching, by the reticu‑
for mul‑ challenges loendothelial
tiplexed in achieving system, dif‑
imaging targeted drug ficulty in scaling
delivery up production
Silica nano- 10–500 nm Negative Low–High Passive/Active Biodegradable Solid particles High drug Potential Limited biocom‑ Potential immu‑ [22]
particles made of silica loading toxicity, patibility, chal‑ nogenicity,
capacity, good limited blood lenges in achiev‑ limited tumor
stability, tun‑ circulation ing controlled specificity
able surface time, difficulty release
properties in achiev‑
ing targeted
drug delivery
to tumors
Mesoporous 20–200 nm Negative Low–High Passive/Active Biodegradable Porous High surface Potential Limited biocom‑ Potential immu‑ [23]
silica nanoparticles made area, high toxicity, patibility, chal‑ nogenicity,
particles of silica drug loading limited blood lenges in achiev‑ limited tumor
capacity, tun‑ circulation ing targeted specificity
able pore size time, difficulty drug delivery
and surface in achieving to tumors
chemistry controlled
drug release
in vivo
Page 5 of 103
Table 1 (continued)
Lipid-nucleic 50–200 nm Neutral Low-Moderate Active Biodegradable Nanoparticles Suitable Limited drug Potential Limited target‑ [24, 25]
acid nano- made of lipids for nucleic loading immunogenic‑ ing efficiency,
particles and nucleic acid delivery, capacity, ity, limited blood difficulty in scal‑
acids good biocom‑ potential circulation time ing up produc‑
patibility, low instability, tion
toxicity challenges
in achiev‑
ing efficient
delivery
Protein nano- 2–200 nm Variable Low-Moderate Passive/Active Biodegradable Nanoparti‑ Good bio‑ Limited drug Potential immu‑ Limited target‑ [26, 27]
particles cles made compatibility, loading nogenicity, ing efficiency,
of proteins low toxicity, capacity, limited stability, difficulty in scal‑
(2023) 22:169
or peptides potential challenges limited blood ing up produc‑

for targeted in achieving circulation time tion
delivery efficient drug
release in vivo
Inorganic– 10–200 nm Variable Low–High Passive/Active Biodegradable Nanoparti‑ Highly Potential tox‑ Limited biocom‑ Potential immu‑ [28]
organic cles made customizable, icity, limited patibility, diffi‑ nogenicity,
hybrid nano- of a com‑ multifunc‑ blood circula‑ culty in achiev‑ limited tumor
particles bination tional, high tion time, ing efficient specificity
of inorganic drug loading challenges targeting
and organic capacity in achieving
components controlled
drug release
in vivo
Metal– 10–500 nm Variable Low–High Passive/Active Biodegradable Porous crystal‑ Highly Potential tox‑ Limited biocom‑ Potential immu‑ [29]
organic line materials customizable, icity, limited patibility, poten‑ nogenicity,
frameworks made tunable pore blood circula‑ tial for drug limited tumor
of metal ions size and sur‑ tion time, leakage, limited specificity
and organic face chem‑ challenges stability
ligands istry, high in achiev‑
drug loading ing efficient
capacity targeting
Exosomes 30–150 nm Negative Low-Moderate Active Biodegradable Small extracel‑ High bio‑ Limited drug Limited blood Limited target‑ [30]
lular vesicles compatibility, loading circulation time, ing efficiency,
derived potential capacity, difficulty in scal‑ potential
from cells for targeted challenges ing up produc‑ for immune sys‑
delivery, in achiev‑ tion tem recognition
natural carriers ing efficient
of biological targeting,
cargoes potential
for premature
drug release
Page 6 of 103
Table 1 (continued)
Bacterial 10–300 nm Negative Low-Moderate Active Biodegradable Nanoparticles High bio‑ Limited drug Limited blood Limited target‑ [31]
nanoparti- produced compatibility, loading circulation ing efficiency,
cles by bacteria potential capacity, time, difficulty potential
for targeted potential in achieving effi‑ for clearance
delivery, easy for immu‑ cient targeting by the immune
(2023) 22:169
to produce nogenicity, system

limited control
over drug
release
Polymeric 10–100 nm Variable Low-Moderate Passive/Active Biodegradable Spherical High drug Limited blood Limited biocom‑ Potential immu‑ [32]
micelles particles loading circula‑ patibility, diffi‑ nogenicity,
made of block capacity, good tion time, culty in achiev‑ limited tumor
copolymers stability, easy challenges ing controlled specificity
to produce in achiev‑ release
ing efficient
targeting,
potential
for premature
drug release
Page 7 of 103
Fig. 1 A An illustrative diagram depicting the concepts of active and passive targeting in nano-delivery systems for anti-tumor treatment. Passive
targeting relies on the enhanced permeability and retention (EPR) effects, where nanocarriers circulate in the bloodstream, exit into the tumor
tissue through the leaky tumor blood vessels, and accumulate there. On the other hand, nanocarriers modified with targeting ligands can
specifically attach to receptors that are overexpressed on tumor cells, enabling localized drug delivery or internalization via receptor-mediated
endocytosis. Reprint from [33] with a permission from Springer Nature. B A diagrammatic representation of a targeting ligand-conjugated
nanocarrier. Tumor targeting by nanocarriers (A) and ligand-installed nanocarriers B). Reprint from [34] with a permission from Wiley. C The ability
of ligand-installed nanocarriers to target cancer cells. A illustrates the use of phenylboronic-acid-installed DACHPt-loaded polymeric micelles
(PBA-DACHPt/m) for targeting cancer cells that overexpress sialylated epitopes receptors; B shows the cellular uptake of micelles with and without
PBA ligands by B16F10 cancer cells; C displays the tumor accumulation of PBA-DACHPt/m and DACHPt/m; and (D) exhibits the tumor suppression
effect of PBA-DACHPt/m micelles against subcutaneous B16F10 tumor models. Reprint from [34] with a permission from Wiley
nanocarrier system is designed to target tumors, and the contact is far stronger than binding during individual
diagram shows two different mechanisms of tumor tar- interactions [10, 12]. One of the promising ways to
geting: (Fig. 1B-A) nanocarriers that are capable of pas- achieve multivalent binding is through the use of den-
sive targeting, and (Fig. 1B-B) nanocarriers that are drimers, which are highly branched polymers that allow
equipped with ligands for active targeting. In passive tar- for the attachment of multiple targeting molecules. For
geting, nanocarriers accumulate in tumors due to their instance, dendrimer nanocarriers conjugated to any-
small size and the leakiness of tumor blood vessels. In where from three to fifteen folate molecules have shown
active targeting, ligands attached to the surface of the a significant increase in binding affinity when bound to
nanocarriers bind specifically to receptors on the surface immobilized folate-binding proteins, as compared to free
of tumor cells, which results in the accumulation of the folate. Despite these advances, there are still several chal-
nanocarriers in the tumor and increased therapeutic effi- lenges that need to be addressed in the development of
cacy. This nanocarrier system represents an exciting and targeted nanocarriers. One major challenge is the issue of
promising approach to targeted drug delivery, offering heterogeneity, where different regions of a tumor may
the potential for more effective and less toxic cancer have varying levels of expression of the target receptor
treatments. In (Fig. 1C-A), phenylboronic-acid-installed [10, 12]. This can lead to ineffective or non-specific tar-
DACHPt-loaded polymeric micelles (PBA-DACHPt/m) geting, reducing the efficacy of the nanocarrier. Addi-
are used to target cancer cells that overexpress sialylated tionally, the development of drug resistance is a major
epitopes receptors. The cellular uptake of micelles with concern, as cancer cells can quickly adapt and develop
and without PBA ligands by B16F10 cancer cells is shown resistance to new drugs. The use of nanocarriers for tar-
in (Fig. 1C-B). The results demonstrate that PBA- geted cancer therapy is an exciting area of research that
DACHPt/m micelles have a higher uptake rate than those offers significant potential for improving patient out-
without PBA ligands. In (Fig. 1C-C), the tumor accumu- comes. While there are still many challenges to be over-
lation of PBA-DACHPt/m and DACHPt/m is displayed, come, the development of novel nanocarrier designs and
and it is found that PBA-DACHPt/m micelles accumu- improved understanding of tumor biology offer hope for
late more in the tumor tissue than DACHPt/m micelles. the continued advancement of this promising field. With
Finally, in (Fig. 1C-D), the tumor suppression effect of further research and development, it may be possible to
PBA-DACHPt/m micelles against subcutaneous B16F10 create targeted nanocarriers that are highly effective at
tumor models are exhibited, indicating that PBA- delivering drugs to cancer cells, minimizing side effects,
DACHPt/m micelles possess superior tumor suppression and improving the overall efficacy of cancer treatment [9,
ability. These findings suggest that the use of ligand- 12].
installed nanocarriers could potentially improve cancer
therapy by enhancing drug delivery to the tumor site. Distinct categories of targeting agents
Receptor-mediated internalization is generally necessary Targeting agents can be put into three broad categories:
for nanocarriers to transport drugs into the cell. Target proteins (mostly antibodies and their fragments), nucleic
cells must have an overabundance of a surface marker acids (aptamers), and other receptor ligands (peptides,
compared to nontarget cells for maximum specificity, vitamins, and carbohydrates). In 1981, Milstein was the
and targeted efficacy rises in tandem with binding affin- first to publicly discuss using a monoclonal antibody to
ity. However, there is evidence that a "binding-site bar- kill cancer cells. The clinical viability of antibody-based
rier" may prevent nanocarriers from penetrating solid tissue targeting has been shown over the last two dec-
tumors when they have a high binding affinity [9]. While ades, and the FDA has licensed 17 different mAbs. In
nanocarriers show great promise for cancer therapy, 1997, FDA approval of the monoclonal antibody rituxi-
there are still many challenges that need to be addressed. mab (trade name: Rituxan) for the treatment of patients
The design of nanocarriers needs to be optimized to with non-Hodgkin’s lymphoma was granted. Afterwards,
ensure better efficacy and safety in humans, and further a year later, the anti-HER2 monoclonal antibody trastu-
research is needed to develop more efficient and cost- zumab (Herceptin) was approved for use in the treatment
effective nanocarriers [6, 10]. A better understanding of of breast cancer [35]. In a recent groundbreaking study
tumor biology and the development of innovative target- by Ferguson et al., a significant advancement in the field
ing techniques will also be necessary to overcome the of nanomedicine has been achieved, addressing the per-
limitations of passive targeting and maximize the poten- sistent challenge of achieving precise drug delivery to
tial of nanocarriers for cancer treatment. Improving tar- specific target cells and organs. The research introduces a
geting may need a combination of affinity enhancement novel approach called Dual Affinity to RBCs and Target
and multivalent binding effect enhancement (also known Cells (DART), which utilizes nanocarriers conjugated
as avidity) [12]. Collective binding during multivalent with two affinity ligands. One ligand binds to red blood
cells (RBCs), while the other binds to target cells, specifi- this is not the case [38, 39]. With this method, several dif-
cally pulmonary endothelial cells in this study. This inno- ferent antibodies may be generated, each with the ability
vative strategy allows DART nanocarriers to initially bind to bind to the same set of target cells but with different
to RBCs and subsequently transfer to the endothelial cells epitopes (a part of a macromolecule that is recognized by
of the target organ, in this case, the lungs. Remarkably, antibodies; one receptor may have several epitopes that
within minutes of intravascular injection in mice, DART will be recognized by multiple antibodies). One example
nanocarriers achieve an accumulation of nearly 70% of is the development of scFv antibodies with improved
the injected dose in the target organ, a remarkable binding and internalization properties for prostate cancer
improvement compared to previous technologies. cells using a selection process. It is possible to increase
Humanized DART nanocarriers tested in ex vivo per- the efficiency of an antibody by directly conjugating a
fused human lungs replicate this success. Furthermore, medicinal molecule to it for targeted distribution. Cali-
DART demonstrates a six-fold enhancement in the selec- cheamicin, a chemotherapeutic medication, was the first
tivity of drug delivery to target endothelial cells over local formulation approved for use in the clinic that specifi-
phagocytes within the target organ. This groundbreaking cally targets cancer cells [38, 39]. The combination of this
advancement in both organ- and cell-type targeting holds drug (marketed under the trade name Mylotarg) with an
tremendous promise for the localized delivery of drugs, anti-CD33 antibody makes cancer cells a clear target. A
particularly in the context of cancer treatment, where few examples include Zevalin and Bexxar, which use anti-
precise targeting is of paramount importance [36]. In CD20 antibodies to target cancer cells with radioiso-
2004, the anti-VEGF monoclonal antibody bevacizumab topes. While the efficacy of these therapies has been
(Avastin) was approved for use in the treatment of colo- established, certain studies have shown that they may
rectal cancer. It was the first time a disease was treated have deadly adverse effects [40]. Non-specific binding
using an angiogenesis inhibitor. It is estimated that over between the agent of interest and non-target moieties on
200 distinct antibody-or antibody-fragment-based deliv- the cell surface is likely to be to blame for these effects.
ery techniques are now being evaluated in preclinical and When the targeting agent is produced by healthy cells
clinical settings. Antibody engineering has advanced to rather than cancerous ones, it may interact with the tar-
the point where hybrid antibodies may be synthesized; get. An immunoconjugate called BR96-doxorubicin,
these include chimeric mAbs, humanized mAbs (which which consists of an antibody that targets and binds to
have a higher human contribution), and antibody frag- the Lewis-Y antigen (expressed on 75% of all breast
ments [37]. For the sake of targeting, antibodies may be tumors), showed a strong anti-tumor effect in animal
used either in their whole, unaltered form or as subunits. tumor models. To do this, doxorubicin was conjugated to
However, the availability of two binding sites (within a an antibody that recognizes and binds to the Lewis-Y
single antibody) leads to a larger binding avidity, making antigen. Compared to doxorubicin alone, BR96-doxoru-
the use of full monoclonal antibodies preferable. Moreo- bicin showed promising results in these animal models
ver, when immune cells bind to the Fc region of the anti- with much reduced toxicity [38, 39]. However, canines
body, a signaling cascade is initiated that ultimately kills had symptoms consistent with acute enteropathy. Conju-
cancer cells. This particular component is featured in the gate binding to Lewis-Y-related antigens generated by
antibody. The Fc domain of an unmodified mAb, on the untargeted gastrointestinal epithelial cells seems to be to
other hand, may bind to Fc receptors on normal cells like blame for this phenomenon. The Phase II human clinical
macrophages [35, 37]. This may boost the nanocarrier’s research using BR96-doxorubicin immunoconjugates
uptake by the liver and spleen, as well as its immuno- showed modest anti-tumor activity and caused serious
genicity (the ability to induce an immune response). gastrointestinal harm, hence the trial was stopped.
Another advantage of employing full or complete anti- Selecting appropriate targets using genomics and prot-
bodies is that they may be kept stable for long periods of eomics technologies is an essential area of research.
time. Due to their decreased non-specific binding, modi- However, to date, no targets have been uncovered that
fied antibody fragments such as antigen-binding frag- are therapeutically useful. There seems to be more hope
ments (Fab), dimers of antigen-binding fragments in the development of new technologies that may
(F(ab)2), single-chain fragment variables (scFv), and oth- enhance selectivity and targeting efficacy while still mak-
ers are safer for systemic injection. Phage display libraries ing use of current targets [38, 39]. It is possible to create a
that use a high throughput method can be used to rapidly new protein with the desired properties by fusing two or
identify antibodies or their fragments that bind to and more genes, as in the case of fusion proteins. Molecular
internalize cancer cells. Despite the fact that antibody biology techniques may be used to successfully create
fragments such as antigen-binding fragments (Fab) and protein-based ligand mimetics that mimic a receptor’s
dimers of antigen-binding fragments (F(ab) can be used, structure. These mimetics may be developed in the same
way that antibodies can be engineered to attach more nanoparticles may be an effective method of therapy [44].
strongly to their targets [41]. Dimerization of proteins or So, for instance, nanoparticles encapsulating docetaxel
peptides may boost ligand affinity via a process known as (Dtxl) have been administered in vivo with high selectiv-
divalency, which includes the simultaneous binding of a ity and efficacy. This was made feasible by adding an
protein or peptide to an antibody’s two Fc domains. Diva- aptamer to the nanoparticles, which specifically targets
lency is a means through which ligand affinity may be the antigen on the surface of prostate cancer cells [15].
enhanced. For instance, increasing tumor localization in Figure 2-A shows NP transport through gaps between
a mouse tumor model was seen, for instance, when a low- adjacent endothelial cells in dynamic vascular bursts,
affinity scFv (also known as a diabody) was dimerized. In while Fig. 2-B demonstrates NP transport across the
addition, it is possible to improve binding affinity and endothelial cell layer through transcytosis. In Fig. 2-C,
selectivity to cell surface receptors by designing proteins representative images of eruptions occurring near and
that identify a specific conformation of a target receptor without leukocyte cells are presented, using 70 nm Doxil
[42]. The affinity for the target receptor, integrin LFA-1, particles and a BxPC3-GFP dorsal skinfold model. Finally,
was boosted 10,000-fold in a recent in vivo investigation Fig. 2-D shows the colocalization of NPs with endothelial
employing a fusion protein comprised of a scFv antibody cells to form hotspots along the vessel lining in MMT-
fragment to target and deliver small interfering RNA VPyMT and 4T1 tumor models using 50 nm AuNPs con-
(siRNA) to lymphocytes. Using a fusion protein to specif- jugated with Alexa Fluor 647. The scale bars for all panels
ically target and deliver siRNA to lymphocytes yielded are provided, and insets are included where appropriate.
the desired effect. Integrin LFA-1 is generally expressed Common targeting strategies focus on the connections
on peripheral leukocytes in its low-affinity, non-adhesive between growth hormones or vitamins and malignant
form (white blood cells that have not been activated by cells. This is because cancer cells often overexpress nutri-
cancer cells or pathogens that have entered the body) ent receptors in an effort to maintain a steady metabo-
[43]. On the other hand, when the immune system is lism despite their rapid division [45]. Epidermal growth
stimulated, this low-affinity, sticky version of integrin factor (EGF) is able to suppress and reduce tumor expres-
LFA-1 undergoes conformational modifications and sion of the EGF receptor, which is overexpressed in a
becomes the high-affinity, adhesive form. Therefore, variety of tumor cells, including those that cause breast
drugs may be delivered selectively to activated and sticky and tongue cancer. The nutrient folic acid (folie) has also
leukocytes by targeting the high-affinity form of LFA-1 been used for cancer targeting since folate receptors
[43]. In order to target certain conformations, it is feasi- (FRs) are often overexpressed in a range of tumor cells,
ble to create novel classes of targeting chemicals. Affibod- such as ovarian, endometrial, and renal cancer [13, 14].
ies are one example; they are small protein domains that As with that, this one is predicated on the same idea. Due
may be tailored to bind selectively to a wide range of tar- to increased metabolic rates, many tumor cells (including
get proteins in a manner that is sensitive to conforma- those responsible for pancreatic, colon, lung, and bladder
tional changes. Multivalent effects include the use of cancer) express an increased number of Tf receptors
several small proteins that act like antibodies to bind (TfRs). Direct coupling of these targeted agents to nano-
selectively to various receptors. The proteins that have carriers delivering chemotherapies, such as medications,
this structure are called avimers [9]. Cancer markers has been demonstrated to improve intracellular delivery
include the protein carcinoembryonic antigen (CEA). In and treatment effectiveness in animal tumor models. To
order to bind to CEA, scientists have employed nanobod- make matters more complicated, metabolic rate-corre-
ies, which are heavy-chain antibodies that have been cre- lated receptors like folate and Tf are also expressed in
ated to be one tenth of the size of an intact antibody with rapidly proliferating healthy cells, including fibroblasts,
a missing light chain. It is not only antibodies that have epithelial cells, and endothelial cells. When attempting to
benefited from high-throughput methods; aptamers and target these receptors, this presents a challenge [9]. As a
other targeting molecules have also been designed using consequence, the medicine’s effectiveness and toxicity
rational approaches [9]. In vitro-selected aptamers are might suffer from non-specific targeting. Many kinds of
short oligonucleotides (oligonucleotides with just one murine malignancies benefit from increased intracellular
strand of DNA or RNA) (1014–1015). Aptamers are delivery of medications when peptides are utilized as tar-
selected for their broad specificity in terms of the targets geting agents, such as arginine-glycine-aspartic acid
they may bind to, which can vary from intracellular pro- (RGD), which is the ligand of the cell adhesion integrin
teins and transmembrane proteins to soluble proteins v3 on endothelial cells. Nonetheless, RGD binds to integ-
and carbohydrates to small-molecule drugs [11]. Several rins different than those seen on cancer cells, including
aptamers that target specific cancer cell receptors have integrins 51 and 41. Since this is a trait, it may limit its
also been developed. Therefore, aptamer-conjugated usefulness in certain contexts. Heparin sulfate,
Fig. 2 New insights on the transport of nanoparticles (NPs) through endothelial cells using intravital microscopy (IVM). Panel (A) shows NP
transport through gaps between adjacent endothelial cells in dynamic vascular bursts, while panel (B) shows NP transport across the endothelial
cell layer via transcytosis. Panel (C) presents representative images of eruptions occurring near and without leukocyte cells, respectively, using
70 nm Doxil particles and a BxPC3-GFP dorsal skinfold model. Panel (D) demonstrates colocalization of NPs with endothelial cells to form hotspots
along the vessel lining in MMTVPyMT and 4T1 tumor models using 50 nm AuNPs conjugated with Alexa Fluor 647. The scale bars for all panels are
provided, and insets are included where appropriate. Reprint from [47] with a permission from Elsevier
chondroitin sulfate, and hyaluronan (HA) are examples own advantages and limitations, such as low immuno-
of extracellular matrices (ECMs) that are overexpressed genicity or limited penetration of solid tumors. Other
in tumors and might serve as efficient targets for specific approaches include CAR T cells, radioimmunotherapy
ECM receptors. This is in addition to the targetable cell (RIT), small molecule inhibitors, and viral vectors, each
surface antigens. In vivo, liposomes coated with HA stay providing unique advantages in targeting specific cancer
in the body longer and can target tumors that have HA types or overcoming resistance. Furthermore, peptide
receptors [46]. Table 2 provides a comprehensive com- nucleic acids (PNAs), aptamer-drug conjugates (ApDCs),
parison of various cancer targeting agents, highlighting peptide vaccines, and various nanoparticle-based thera-
their respective target antigens, affinity, specificity, bind- pies contribute to the diverse landscape of cancer target-
ing sites, and targeted therapy types. For instance, mono- ing agents, all aiming to optimize efficacy, specificity, and
clonal antibodies (mAbs) targeting CD20 offer a highly safety while minimizing side effects and resistance
specific first-line treatment for non-Hodgkin lymphoma development.
and chronic lymphocytic leukemia, while antibody–drug
conjugates (ADCs) target HER2-positive cancer cells for Proteins as targeting agents
chemotherapy with reduced side effects. Bispecific T cell Various proteins, including antibodies and engineered
engagers (BiTEs) show high potency and lower toxicity proteins, have been harnessed as targeting agents in
compared to CAR T cell therapy, although they are lim- nanotechnology-based cancer therapy [63]. These pro-
ited to CD19-positive cancers. Peptide ligands, aptamers, teins can be designed to recognize specific antigens or
and nanobodies offer alternative strategies, with their receptors overexpressed on cancer cells. For instance,
Table 2 Comparison of cancer targeting agents
Targeting Agent Target Antigen Affinity Specificity Binding Site Targeted Therapy Description Novelty Advantages References
Type Type
Monoclonal anti- CD20 High Specific Epitope on B-cell Immunotherapy First-line treatment Highly specific to tar‑ Target other healthy [48]
bodies (mAbs) surface for non-Hodgkin lym‑ get antigen cells with similar
phoma and chronic antigen, Costly
lymphocytic production
leukemia
Antibody–drug HER2 High Specific Epitope on HER2-posi‑ Chemotherapy Targeted delivery Reduced side effects Limited therapeu‑ [49, 50]
conjugates (ADCs) tive cancer cells of cytotoxic agents compared to tradi‑ tic window, Risk
to HER2-positive tional chemotherapy of resistance devel‑
cancer cells opment
Bispecific T cell CD19 and CD3 High Specific Epitopes on B-cell Immunotherapy Redirect T cells High potency, Lower Limited to CD19- [51]
engagers (BiTEs) and T-cell surfaces to attack CD19-posi‑ toxicity compared positive cancers,
(2023) 22:169
tive B cells to CAR T cell therapy Potential for cytokine

release syndrome
Peptide ligands VEGF receptor Moderate Specific Ligand-binding site Anti-angiogenic Inhibit angiogenesis Low immunogenic‑ Short half-life, Rapid [52]
on VEGF receptor therapy by blocking VEGF ity, Easier to produce clearance
receptor signaling than mAbs
Aptamers PDGF High Specific Binding site on PDGF Anti-angiogenic Inhibit PDGF High binding affinity, Short half-life, Lim‑ [44]
therapy signaling to block Low immunogenic‑ ited in vivo stability
angiogenesis ity, Easier to produce
than mAbs
Nanobodies EGFR High Specific Epitope on EGFR Immunotherapy Target EGFR-positive Small size, High Limited penetration [53]
cancer cells for imag‑ specificity, High of solid tumors, Lim‑
ing and therapy in vivo stability ited capacity for mul‑
tivalent binding
CAR T cells CD19 High Specific Epitope on B-cell Immunotherapy Genetically High efficacy, Risk of severe toxicity [54]
surface engineered T cells Durable response, including cytokine
that express a chi‑ Curative potential release syndrome
meric antigen recep‑ for some hematolog‑ and neurotoxicity,
tor (CAR) for CD19 ical malignancies High cost
Radioimmunother- CD20 High Specific Epitope on B-cell Radiation therapy Combine the speci‑ Selectively target Limited to CD20- [48, 54]
apy (RIT) surface ficity of mAbs and destroy cancer positive cancers, Risk
with the therapeutic cells, Potential of toxicity to normal
potential of ionizing for long-term tissue, Complex pro‑
radiation response duction process
Small molecule BCR-ABL High Specific Active site of BCR-ABL Targeted therapy Inhibit the activity Oral administration, Limited to cancers [49, 50]
inhibitors kinase of cancer-promoting High selectivity, driven by specific
proteins Overcome resistance mutations, Develop‑
to traditional chemo‑ ment of resistance
therapy
Page 13 of 103
Table 2 (continued)
Type Type
Viral vectors HER2 High Specific Epitope on HER2-posi‑ Gene therapy Deliver therapeutic High specificity Limited to HER2- [49, 50]
tive cancer cells genes to HER2-posi‑ and selectivity, positive cancers,
tive cancer cells Potential for long- Potential for toxic‑
term response ity and immune
response
Peptide nucleic KRAS High Specific Target site on KRAS Gene therapy Inhibit the expression High specific‑ Limited to cancers [55]
acids (PNAs) mRNA of cancer-promoting ity, Stable in vivo, driven by specific
genes Overcome resistance mutations, Develop‑
to traditional chemo‑ ment of resistance
therapy
Aptamer-drug con- PSMA High Specific Binding site on PSMA Chemotherapy Targeted delivery Reduced side effects Limited therapeu‑ [44]
jugates (ApDCs) of cytotoxic agents compared to tradi‑ tic window, Risk
(2023) 22:169
to PSMA-positive tional chemotherapy, of resistance devel‑

cancer cells Easier to produce opment
than mAbs
Peptide vaccines MUC1 Moderate Specific Epitope on MUC1- Immunotherapy Activate the immune Induce long-lasting Limited to MUC1- [56]
positive cancer cells system to recognize immune responses, positive cancers,
and attack cancer Low toxicity Limited efficacy
cells in solid tumors
Liposomes Doxorubicin Low Non-specific Passive target‑ Chemotherapy Deliver drugs Easier to produce Limited selectivity, [57]
ing to tumors to tumors than mAbs, Versatile Variable EPR effect
through the enhanced with reduced side drug delivery system in different cancers
permeability and reten‑ effects on healthy
tion (EPR) effect tissues
Gold nanoparticles EGFR Moderate Specific Epitope on EGFR Photothermal Absorb light High biocompat‑ Limited penetration [58]
therapy to generate heat ibility, Versatile drug of solid tumors, Lim‑
and destroy cancer delivery system ited efficacy in deep
cells tissues
Magnetic nanopar- CD44 Low Non-specific Magnetic targeting Chemotherapy Deliver drugs Easier to produce Limited selectivity, [59]
ticles to tumors with external to tumors than mAbs, Minimal Limited efficacy
magnetic fields with reduced side systemic exposure in deep tissues
effects on healthy
tissues
RNA interference Survivin High Specific Target site on survivin Gene therapy Inhibit the expression High specificity, Limited to cancers [60]
(RNAi) mRNA of cancer-promoting Overcome resistance
genes to traditional chemo‑
therapy
Page 14 of 103
Table 2 (continued)
Type Type
Aptamer-conju- Nucleolin High Specific Binding site on nucleo‑ Chemotherapy Targeted delivery High specificity, Limited to nucleolin- [44]
gated nanoparticles lin of drugs to nucleolin- Reduced side effects positive cancers, Lim‑
positive cancer cells compared to tradi‑ ited in vivo stability
tional chemotherapy,
Easier to produce
than mAbs
Antibody-nanopar- CD20 High Specific Epitope on B-cell Immunotherapy Targeted delivery Increased tumor Limited to CD20- [61]
ticle conjugates surface of nanoparticles penetration positive cancers, Risk
to CD20-positive can‑ and retention, High of immunogenicity
cer cells for imaging selectivity
and therapy
(2023) 22:169
Tumor-penetrating iRGD Moderate Specific Binding site on integ‑ Chemotherapy Enhance the pen‑ High specificity, Limited efficacy [43]
peptides rins and neuropilin-1 etration and accu‑ Overcome barriers in deep tissues,
mulation of drugs to drug delivery Potential for off-
in tumors in solid tumors target effects
Nanobody-drug EGFR High Specific Epitope on EGFR Chemotherapy Targeted delivery Small size, High Limited to EGFR-pos‑ [44]
conjugates of cytotoxic agents specificity, Reduced itive cancers, Limited
to EGFR-positive side effects com‑ capacity for multiva‑
cancer cells pared to traditional lent binding
chemotherapy
Dual-targeting CD3 and CD20 High Specific Epitopes on B-cell Immunotherapy Redirect T cells Increased efficacy, Limited to CD20- [61]
antibodies and T-cell surfaces to attack CD20-posi‑ Overcome resistance positive cancers,
tive B cells to monoclonal Potential for cytokine
antibodies release syndrome
Protein cages Ferritin Low Non-specific Passive target‑ Drug delivery Deliver drugs Easier to produce Limited selectivity, [28]
ing to tumors to tumors than mAbs, Biocom‑ Variable EPR effect
through the EPR effect with reduced side patible in different cancers
effects on healthy
tissues
Aptamer-siRNA VEGF High Specific Binding site on VEGF Gene therapy Inhibit VEGF expres‑ High specificity, Limited to VEGF- [44]
conjugates sion to block angio‑ Overcome delivery driven cancers, Vari‑
genesis challenges able in vivo stability
Therapeutic anti- CTLA-4 High Specific Epitope on CTLA-4 Immunotherapy Block inhibitory sig‑ High specificity, Risk of toxicity, Lim‑ [61]
bodies nals to activate T cells Durable response, ited efficacy in solid
against cancer cells Synergistic with PD-1 tumors
blockade
Bifunctional fusion IL-2 and CD25 High Specific Epitopes on T-cell Immunotherapy Stimulate T-cell pro‑ Increased efficacy, Limited to IL-2-re‑ [62]
proteins and cancer cell liferation and activa‑ Reduced toxicity sponsive cancers,
surfaces tion against cancer compared to sys‑ Limited efficacy
cells temic IL-2 in solid tumors
Page 15 of 103
monoclonal antibodies can be conjugated to nanoparti- biological environments and efficient delivery systems
cles to enhance their tumor-targeting capabilities [64]. must be overcome for optimal clinical use [76]. Small
Additionally, protein engineering techniques, such as organic molecules represent a diverse group of targeting
phage display and recombinant DNA technology, have agents that can interact with specific signaling pathways
enabled the development of novel proteins with high involved in cancer progression. They offer the advantage
specificity for cancer-associated targets [65]. Monoclo- of diverse chemical structures and drug-like properties,
nal antibodies, derived from hybridoma cells or through which can be leveraged for cancer therapy [74]. However,
recombinant technology, have been extensively uti- optimizing their specificity and selectivity while ensuring
lized to recognize specific antigens or receptors that are stability and delivery to the tumor site remains a focus of
overexpressed on the surface of cancer cells. These anti- ongoing research. Fusion proteins combine the functions
bodies can be conjugated to nanoparticles, enhancing of targeting and therapeutic molecules, offering dual-
their ability to deliver therapeutic agents directly to the action targeted therapy [76]. Created through recombi-
tumor site [66]. The key advantage of monoclonal anti- nant DNA technology, these proteins enhance treatment
bodies lies in their high specificity, making them ideal efficacy while reducing side effects. Their design and pro-
for targeting specific cancer biomarkers. However, they duction can be complex, necessitating careful considera-
face challenges related to limited tissue penetration and tion in clinical applications [67].
potential immunogenicity, which need to be carefully
considered in their clinical application [67]. Engineered Nucleic acids as targeting agents
proteins, created through recombinant DNA technol- Nucleic acids, specifically aptamers and siRNAs (small
ogy, offer a customizable approach to cancer targeting. interfering RNAs), have emerged as promising targeting
These proteins can be designed to bind selectively to agents in the field of cancer therapy [77]. Aptamers are
cancer-associated markers, providing a versatile plat- single-stranded DNA or RNA molecules with the unique
form for both targeted therapy and diagnostic imaging capability to fold into specific three-dimensional struc-
[68]. Engineered proteins have the advantage of reduced tures. This structural versatility enables them to selec-
immunogenicity compared to traditional antibodies. tively bind to cancer-specific cell surface biomarkers,
However, their production can be complex and costly, making them attractive candidates for targeted therapy
necessitating further optimization to streamline their [70]. Aptamers offer several advantages, including high
manufacturing process [69]. Aptamers, another class of specificity for their target biomarkers, low immuno-
targeting agents, are single-stranded DNA or RNA mol- genicity, and the potential for multi-targeting to address
ecules with unique three-dimensional structures that heterogeneous cancer populations [78]. However, the
enable them to bind tightly to cancer-specific biomark- challenges associated with aptamer development, such
ers. In vitro selection processes yield aptamers with as the selection and optimization of aptamers for spe-
high specificity, making them valuable tools for targeted cific targets, as well as ensuring their stability in biologi-
drug delivery and imaging. Their reduced immunogenic- cal environments, remain areas of active research. On
ity compared to antibodies is an attractive feature [70]. the other hand, siRNAs are short double-stranded RNA
However, ensuring their stability in biological environ- molecules designed to silence specific genes involved in
ments remains a challenge, requiring ongoing research cancer cell growth and survival. They hold significant
efforts [71]. Small interfering RNAs (siRNAs) represent a promise for personalized cancer therapy by allowing
different approach to targeting cancer cells at the genetic precise control over gene expression [79]. SiRNAs can
level [72]. SiRNAs, synthesized chemically or produced be incorporated into nanocarriers for targeted delivery
through recombinant technology, can silence genes to cancer cells, offering the advantage of selective gene
responsible for cancer cell growth and survival. This silencing. This approach can be particularly valuable for
precision in gene regulation offers the potential for gene cancers driven by specific genetic mutations or overex-
therapy and the inhibition of cancer-related genes [73]. pression of oncogenes [77]. However, efficient intracel-
While siRNAs provide a powerful tool, efficient delivery lular delivery of siRNAs remains a challenge, as does
and the risk of off-target effects are issues that need to be minimizing off-target effects that can potentially disrupt
addressed [74]. Peptide ligands, often synthesized chemi- normal cellular processes [80]. Examples of nucleic acids
cally or produced through recombinant methods, bind to in cancer therapy include the use of aptamers targeting
specific cell surface receptors, contributing to targeted specific cancer-associated biomarkers. For instance, the
cancer therapy and improved cell penetration. Their cus- PSMA aptamer has been employed for prostate cancer
tomizable nature makes them versatile targeting agents, targeting, while the MUC1 aptamer has shown promise
and they hold promise for multi-targeting strategies in breast cancer targeting [81, 82]. In the case of siRNAs,
[75]. Nevertheless, challenges related to their stability in researchers have explored their potential in targeting
critical genes in cancer, such as the use of siRNAs against tissue-specific accumulation, play a crucial role in deter-
the BCR-ABL fusion gene in chronic myeloid leukemia mining their biodistribution. Tumor microenvironment
and siRNAs targeting KRAS mutations in pancreatic can- factors, such as tumor perfusion, extracellular matrix, pH
cer. These nucleic acid-based targeting agents represent gradients, and cellular uptake, also impact the delivery and
innovative approaches to cancer therapy, offering the effectiveness of nanocarriers. Lastly, the administration
potential for enhanced specificity and reduced off-target route, encompassing intravenous, intratumoral, oral, local,
effects [79]. However, addressing challenges related to and active targeting methods, significantly affects the bio-
aptamer and siRNA development, intracellular delivery, distribution of nanocarriers within the body. Nanocarriers
and safety will be crucial for realizing their full therapeu- are a versatile and innovative approach to drug delivery
tic potential in clinical settings. Researchers continue to with distinct characteristics and advantages. Their
work on optimizing these strategies and advancing the nanoscale size, controlled release kinetics, biocompatibil-
field of nucleic acid-based cancer therapeutics [82, 83]. ity, targeted drug delivery capabilities, and long-term sta-
bility make them a promising choice for enhancing the
Availability of nanocarriers, section precision and effectiveness of drug therapy in various
Nanocarriers are substances between one and one hun- medical applications [80]. Controlled release kinetics is
dred nanometers in size, and they may carry a wide variety another key feature of nanocarriers. These systems provide
of drugs and imaging agents. They may be employed for precise control over the rate and duration of drug release,
targeting thanks to the high ligand density that can be making them ideal for sustained drug delivery. For exam-
established on their surfaces according to their huge sur- ple, nanocarriers based on polymers like PLGA
face area in relation to their volume [84]. In a recent study (Poly(lactic-co-glycolic acid)) can offer prolonged drug
conducted by Sultan et al., significant progress has been release, which is essential for maintaining therapeutic drug
made in the development of targeted delivery formulations levels in the body over extended periods. Biocompatibility
for combating cancer. Specifically, the study focused on the is a vital advantage of nanocarriers. These systems are
characterization of cisplatin-loaded chitosan nanoparticles designed to be non-toxic and to minimize adverse effects
(CCNP) and cisplatin-loaded chitosan nanoparticles sur- on the body. This characteristic reduces the risk of immune
face-linked to rituximab (mAbCCNP). These formulations responses and makes nanocarriers a safe option for drug
exhibited notable physicochemical properties, with CCNP delivery [78]. Lipid-based nanocarriers, for instance, have
having a zetapotential (ZP) value of 30.50 ± 5.64 mV and a demonstrated high biocompatibility, making them suitable
particle size of 308.10 ± 1.10 nm, while mAbCCNP had a for various pharmaceutical applications [86]. Targeted
ZP value of 26.90 ± 9.09 mV and a slightly larger particle drug delivery is a hallmark feature of nanocarriers. They
size of 349.40 ± 3.20 nm. Importantly, both CCNP and have the unique ability to deliver drugs specifically to tar-
mAbCCNP demonstrated controlled release kinetics of geted cells or tissues, enhancing drug efficacy and reduc-
cisplatin, suggesting their potential as effective delivery ing toxicity to healthy tissues [80]. Antibody–drug
systems. In vitro cytotoxicity studies on MCF-7 ATCC conjugates, a type of nanocarrier, exemplify this feature, as
human breast cancer cells revealed that CCNP exhibited they are designed to selectively target cancer cells, thereby
significant cytotoxicity with an IC50 of 4.085 ± 0.065 µg/ improving the precision of cancer therapy. Long-term sta-
mL, while mAbCCNP, designed for targeted delivery, did bility is also a benefit of nanocarriers. These systems can
not induce any cytotoxic effects. Although the results indi- extend the shelf-life of drugs and maintain drug stability
cated that CCNP was more successful due to rituximab’s over time. For instance, polymeric micelles, a type of nano-
lack of specificity against MCF-7 ATCC human breast carrier, have demonstrated excellent stability, ensuring that
cancer cells, this study underscores the promising role of pharmaceutical agents remain effective even after pro-
nanocarriers in cancer treatment, offering a potential ave- longed storage [86]. Table 3 highlights the various factors
nue for more effective and targeted therapy [85]. Nanocar- affecting nanocarrier biodistribution, which can be catego-
riers may also be used to increase the local concentration rized into nanocarrier properties, physiological factors,
of the medication by transporting the medicine in the blood circulation time, tumor microenvironment, and
nanocarrier and releasing it slowly once the nanocarrier administration route. Figure 3 displays the results of an
has linked to its target. Nanocarrier properties such as in vivo biodistribution study of nanocarriers. The study
size, shape, surface charge, surface functionalization, drug utilized DiD-loaded formulations, and images were
payload, biodegradability, and shape stability directly influ- obtained from mice with 4T1 tumors at various times after
ence the interaction with physiological factors like blood administration. The red circles in the images indicate the
flow rate, lymphatic drainage, plasma protein corona, and tumor sites. Furthermore, the study involved ex vivo imag-
renal function. The blood circulation time of nanocarriers, ing of isolated tumors and organs from the mice 24 h after
including half-life and clearance rate, protein binding, and administration. The semiquantification of fluorescence
Table 3 Factors affecting nanocarrier biodistribution

Nanocarrier Properties Physiological Factors Blood Circulation Time Tumor Administration Route References
Microenvironment
Size and shape Blood flow rate and vessel Half-life and clearance Tumor perfusion and oxy‑ Intravenous, intratumoral, [105]
permeability rate genation intraperitoneal, etc
Surface charge and Lymphatic drainage Protein binding Extracellular matrix Oral, nasal, pulmonary, [106]
coating and lymph node accu‑ and opsonization and cell adhesion mol‑ transdermal, etc
mulation ecules
Surface functionaliza- Plasma protein corona Blood–brain barrier pH and redox gradients Local, regional, systemic, [106]
tion and immune system penetration etc
response
Drug payload and Renal and hepatic func‑ Tissue-specific accumula‑ Cellular uptake and traf‑ Active targeting, passive [106, 107]
release mechanism tion tion and clearance ficking targeting, etc
Biodegradability and Interstitial fluid pressure Cellular metabolism Tumor heterogeneity Single dose, repeated [56, 108]
toxicity and flow and excretion and evolution dose, etc
Shape stability Inflammatory response Vascular permeability Stromal cells and immune Direct injection, inhala‑ [109]
and cytokine release and leakiness cells tion, etc
Aggregation and Oxygen and carbon Extravasation and intersti‑ Hypoxia and acidity Local hyperthermia, [84]
stability dioxide transport tial diffusion phototherapy, etc
Magnetism and target- Enzyme activity Receptor density Angiogenesis and lym‑ Ultrasound, magnetic, etc [110]
ing and expression and internalization phangiogenesis
Encapsulation and Protease activity and inhi‑ Immune checkpoint Immunosuppression Combination, alternat‑ [109]
surface modification bition expression and regulation and immunostimulation ing, etc
Controlled release and Nutrient and oxygen Apoptosis and necrosis Resistance and tolerance Adjuvant therapy, radia‑ [45]
activation deprivation tion, etc
intensity was conducted, revealing significant differences (doxorubicin, camptothecin, paclitaxel, and platinate) and
(P < 0.05, P < 0.01, P < 0.001) among the three formulations. four polymers (N-(2-hydroxylpropyl) methacrylamide
Finally, the distribution of Free DiD, DiD@BNP, and DiD@ (HPMA)copolymer, poly-L-glutamic acid, poly(ethylene
MBNP was examined in the frozen sections of tumors, glycol) (PEG), and Dextran) [36]. Despite several new
with blue indicating the cell nucleus, red indicating DiD, pharmacological targets and cutting-edge chemicals, the
and green indicating CD31. The scale bars used in the use of polymers in the creation of nanoparticle-based drug
images are 100 mm. Overall, the results of this study pro- carriers has been the subject of the vast majority of
vide valuable insights into the biodistribution of nanocar- research. Adsorption of anticancer drugs to polyalkylcy-
riers, which can inform the development of more effective anoacrylate nanoparticles has been recorded as far back as
therapeutic interventions for cancer treatment. Nanocarri- 1979. This utilization dates back to when these particles
ers include a wide variety of different structures, including were first developed for use in the treatment of cancer. The
polymerconjugates, polymeric nanoparticles, lipid-based article was among the first to detail their use in cancer
carriers like liposomes and micelles, dendrimers, carbon treatment [15]. Experiments on tissue distribution and
nanotubes, and gold nanoparticles (including nanoshells efficacy using a tumor model were conducted after Cou-
and nanocages). Medication delivery, imaging, photother- vreur et al. revealed the release mechanism of the medica-
mal ablation of malignancies, radiation sensitizers, apop- tions from the polymer in calf serum. This finding allowed
tosis detection, and sentinel lymph node mapping are just for the development of doxorubicin-loaded nanoparticles,
some of the many uses for these nanocarriers that have which were tested in the middle of the 1980s [2, 3]. To
been studied [87]. The use of these conjugates is very help- encapsulate pharmaceuticals without chemical alteration,
ful for focusing on tumor blood vessels. Anti-endothelial polymeric nanoparticles may be made from either syn-
immunoconjugates, fusion proteins, and caplostatin, the thetic polymers like poly(lactic acid) (PLA) and poly(lactic
first polymer-angiogenesis inhibitor conjugate, are all co-glycolic acid) or from natural polymers like chitosan
examples of these molecules.Chemically conjugated poly- and collagen. Nanoparticles may originate from either syn-
mers containing medicines are typically considered to be thetic or natural polymers [89]. The drugs may be released
new chemical entities (NCEs) [88]. This is due to the fact gradually over time by a variety of mechanisms, including
that their pharmacokinetic characteristics vary greatly surface or bulk erosion, diffusion through the polymer
from those of the original drug. Polymer-drugconjugates matrix, swelling followed by diffusion, and environmental
have been developed primarily using just four medicines response. Several types of multifunctional polymeric
Fig. 3 The results of the in vivo biodistribution of nanocarriers. The study involved the use of DiD-loaded formulations, and the images obtained
from 4T1 tumor-bearing mice were taken at different times post-administration. The red circles in the images indicate the tumor sites. Additionally,
ex vivo imaging of isolated tumors and organs from the mice was performed 24 h after administration. The semiquantification of fluorescence
intensity was also done, and the results showed statistically significant differences (P < 0.05, P < 0.01, P < 0.001) among the three formulations.
Finally, the fluorescent distribution of Free DiD, DiD@BNP, and DiD@MBNP in the frozen sections of tumors was analyzed, with blue indicating
the cell nucleus, red indicating DiD, and green indicating CD31. The scale bars used in the images are 100 mm. Reprint from [111] with a permission
from Elsevier
nanoparticles are already being evaluated in both pre-clin- carriers may be easily modified by incorporating agents
ical and clinical settings [6]. The usage of polymer-based into the lipid membrane or modifying the surface chemis-
nanocarriers raises concerns due to polymers’ inherent try [90]. There are several approaches to achieving this
structural heterogeneity, which is shown, for example, in a goal. Some examples of amphiphile-based particles include
high polydispersity index (the ratio of the weight-and- micelles, liposomes, and polymersomes. One or more con-
number-average molecular weight, Mw/Mn) [15]. How- centric lipid bilayers enclose an inner aqueous phase to
ever, there have been isolated cases of polymeric form spherical structures known as liposomes [57]. These
nanoparticles exhibiting a nearly homogeneous size distri- structures are self-closing and sphere-shaped. Today, regu-
bution. Lipid-based carriers have several desired biological latory authorities have provided their stamp of approval to
properties, including universal biocompatibility, biodegra- enable liposomes to include a broad array of chemothera-
dability, drug isolation from the environment, and the peutics. Polymersomes are made up of synthetic polymer
capacity to entrap hydrophilic and hydrophobic drugs. The amphiphiles, most of which are PLA-based copolymers.
size, charge, and surface functionality of lipid-based Although their design is similar to that of liposomes,
polymersomes are not comprised of lipids [57]. On the circulation [93, 94]. Clinical investigations have revealed
other hand, similar to the situation with polymer thera- that liposomal systems accumulate preferentially in
pies, there are presently no treatments that have been clin- tumors, and the toxicity of the cargo they transport is
ically authorized that entail active cellular targeting for much reduced as a result of the EPR effect. A liposome
lipid-based carriers [57]. Pharmaceutical carriers for that circulates for a long time may lead to the drug being
water-insoluble medications have been successfully imple- released in an undesirable region, a phenomenon known
mented via the use of micelles, which are self-assembling as extravasation [95]. Most patients who receive PEGylated
closed lipid monolayers with a hydrophobic core and a liposomal doxorubicin report experiencing palmar-plantar
hydrophilic shell [91]. Hydrophilic micelles are encased in erythrodysesthesia (PPE), also called the hand-foot condi-
a hydrophobic core. They belong to the class of amphiphi- tion. Dosage and administration schedule adjustments
lic colloids, which are able to self-assemble from amphiph- may help patients who have PPE, a dermatologic toxicity
ilic or surface-active chemicals (surfactants) under certain reaction. PPE is a side effect that may happen after receiv-
circumstances (such as concentration and temperature) ing high dosages of many types of chemotherapy at once
[91]. Clinical trials are now being conducted on polymeric [95]. Additional challenges with liposome application in
micelles like NK911, a block copolymer comprising PEG clinical settings include the high production cost of
and poly (aspartic acid). NK911 was studied as a possible liposomes, the quick oxidation of certain phospholipids,
treatment for advanced pancreatic cancer; it consists of a and the lack of controlled-release characteristics in encap-
bound doxorubicin fraction (45%) and a free drug [32]. A sulated medications. Using a "polymercore/lipid shell" (a
micelle NK105, which contains the drug paclitaxel, has combination of polymers and phospholipids) as a delivery
also been investigated as a possible carrier for the treat- agent may allow for the synchronized release of two dis-
ment of cancers of the pancreas, colon, and stomach. The tinct drugs [96]. Once the nanoparticle has been localized
challenges that arise from utilizing lipid-based nanocarri- to the tumor site through the EPR effect, it will begin to
ers are indicative of those that arise when using other produce both an anti-angiogenesis agent from its outer
focused nanocarriers, such as polymeric nanoparticles phospholipid shell and a chemotherapeutic substance
[61]. For instance, the reticuloendothelial defense system from its inner polymeric nanoparticle in response to local
efficiently clears the bloodstream of injected particles hypoxia [97]. Reduced toxicity and improved anti-meta-
regardless of the particles’ composition [29]. The non-spe- static effects were shown in two different mouse tumor
cific absorption by the mononuclear phagocytic system models using this approach, demonstrating the value of a
(MPS) and the instability of the carrier, which may result mechanism-based design for targeted nanocarriers [96].
in burst drug release, are further challenges that need to be Organic nanoparticles include dendrimers, viral capsids,
addressed before these carriers may be employed in clini- and nanostructures produced from biological building
cal settings [92]. Because of their extensive background, materials like proteins, Abraxane, an albumin-bound
liposomal carriers are a good example of the challenges paclitaxel nanoparticle formulation, was approved by the
and solutions that have been explored throughout the FDA in 2005 as a second-line therapeutic option for
development of nanocarriers [93]. By stabilizing and patients with metastatic breast cancer [98]. Abraxane was
shielding micelles and liposomes against opsonization, the created as an answer to the insoluble problems seen with
process by which plasma protein deposition signals paclitaxel. As a result of its use, dangerous solvents like
Kupffer cells in the liver to remove the carriers from circu- Cremophor EL (polyoxyethylated castor oil) are no longer
lation, PEG, for example, has been demonstrated to extend required for the delivery of Taxol. Creating dendrimers
the duration a chemical spends in circulation [94]. How- from scratch is a cutting-edge topic in polymer chemistry
ever, two examples of liposomes used in clinical settings [95]. Dendrimers are manmade macromolecules with a
are the PEG-free Daunosome and Myocet, which have a branching, tree-like structure. For several reasons, includ-
diameter of 80–90 nm. Even though not as much as ing their small size (5 nm), high water solubility, well-
PEGylated liposomes like Doxil and Caelyx, these defined chemical structures, biocompatibility, and rapid
liposomes have been shown to have longer circulation clearance from the blood through the kidneys, polyami-
times [94]. In addition to the need for rapid clearance, the doamine dendrimers have been shown to have potential
rapid burst release of the chemotherapeutic drugs from for use in biomedical applications [99]. Dendrimer-metho-
the liposomes presents a challenge. For instance, doxoru- trexate conjugates delivered in vivo by multivalent target-
bicin may have been encapsulated in the liposomal aque- ing have been shown to reduce tumor development by a
ous phase with an ammonium sulfate gradient to avoid factor of ten. This may be compared to the shrinkage of
this phenomenon [93]. This method results in the stable tumors that occurs when free systemic methotrexate is
trapping of the medication, with little leakage of the drug administered at the same molar concentration. This find-
during circulation; this holds true even after prolonged ing prompted other preliminary studies, and many
different dendrimers are being looked at as potential can- break down and aren’t small enough for the body to get rid
cer therapies. Additional resources provide a comprehen- of them easily [102].
sive overview of these dendrimers [99]. Despite their
potential advantages, large-scale production of dendrimers Multidrug resistance and its consequences
is complicated by their higher price tag compared to other Nanoprecipitation and self-assembly techniques, on
nanoparticles and the necessity for many iterations during the other hand, offer medium-scale manufacturing with
the synthesis process [100]. Metal nanoparticles make up moderate cost and quality control. Large-scale produc-
the bulk of inorganic nanoparticles and may be produced tion is achievable through methods such as spray dry-
with near-perfect monodispersity [29]. Inorganic materials ing and solvent casting, although they may compromise
have been the focus of many studies for applications quality control and flexibility [112–114]. Innovations
including magnetic resonance imaging and high-resolu- like flash nanoprecipitation and hydrodynamic focus-
tion superconducting quantum interference devices. Fur- ing microfluidics yield high-quality nanoparticles with
thermore, inorganic particles may be functionalized to excellent control and flexibility, while hot melt extru-
include specific chemicals and pharmaceuticals. Some sion caters to large-scale production with high quality
specialized kinds of inorganic nanoparticles, such as control. Each manufacturing method has its specific
nanoshells and gold nanoparticles, have just lately been applications, and researchers must carefully weigh the
manufactured [29]. The same carrier might be used for factors of scale, cost, quality control, yield, and flex-
both imaging and therapy in nanoshells on the order of ibility when selecting the most suitable technique for
100–200 nm in size. They have a silica core and a metal their needs. Table 4 presents a comparison of various
exterior. Nanoshells’ optical resonances can be adjusted to nanocarrier manufacturing techniques, each with its
absorb or scatter electromagnetic radiation across a wide unique set of advantages and drawbacks. Emulsion and
range of frequencies [23]. The near-infrared region microfluidics methods, for example, boast high qual-
(820 nm, 4 W cm-2) of the electromagnetic spectrum ity control and flexibility but are limited to small-scale
allows for the most efficient transmission of light through production. Pharmaceuticals can also be delivered to
tissue [23]. Absorbing nanoshells may be used in treat- cells via targeted nanocarriers that are absorbed by
ments that rely on hyperthermia. Nanoshells would be the cells rather than through diffusion. This technique
used to absorb radiation and heat the surrounding cancer has the potential to allow selected carriers to circum-
tissue in these types of therapies [101]. The enhanced con- vent the action of multiple drug resistance transport-
trast that scattering nanoshells provide makes them a use- ers (MDRtransporters), which are integral membrane
ful tool for imaging applications. The new cancer proteins. MDRtransporters are implicated in the efflux
treatment uses infrared (NIR) light absorption by of many chemotherapeutic agents from cancer cells. An
nanoshells as its basis. Tumors implanted in mice are killed increased concentration of enzymes that may neutral-
selectively thanks to the rapid local heating triggered by ize chemotherapy drugs has been related to the complex
this therapy [101]. In tissues heated past the point of ther- molecular basis of cancer medicine resistance [115]. The
mal damage, coagulation, cell shrinkage, and loss of discovery of this fact is due to the study of the molecular
nuclear staining were observed [93]. Despite being treated basis of cancer medication resistance. However, most of
at the same temperature, control tissues showed no signs the time, this occurs due to an overexpression of MDR
of damage. Similar methods use gold nanocages, which are transporters, which actively pump chemotherapeutic
even smaller than nanoshells (less than 50 nm) [90, 102]. drugs out of the cell and reduce the quantity of drug
These gold nanocages may be engineered to generate heat present inside the cell to levels below the deadly thresh-
in response to NIR light. As a result, they may be beneficial old [102]. In a recent study conducted by Maliyakkal
for hyperthermia-based therapies. In contrast to et al., a promising approach to enhance the efficacy of
nanoshells and nanocages, pure gold nanoparticles may be cisplatin in the treatment of glioblastoma multiforme
easily manufactured and controlled [103, 104]. Non-spe- (GBM) was investigated. Cisplatin is a potent antican-
cific interactions that generate toxicity in healthy tissues cer drug commonly used for GBM therapy; however, its
may limit the usefulness of many types of nanoparticles. clinical effectiveness has been hampered by low thera-
However, the use of inorganic particles for photo-ablation peutic ratios, toxicity, and multidrug resistance (MDR)
greatly reduces the amount of non-specific toxicity that issues. To address these limitations, the researchers
may occur due to light’s localized nature [90, 102]. How- developed a novel system utilizing cisplatin-loaded pol-
ever, for systemic targeting of particular cancer cells, inor- ymeric nanoplatforms (CSP-NPs) designed for active
ganic particles may not provide any benefits over other targeting within GBM. These CSP-NPs were character-
forms of nanoparticles. Inorganic particles that build up in ized extensively and demonstrated a smooth surface,
the body can cause long-term harm because they don’t appropriate particle size, zeta potential, polydispersity
Table 4 Comparison of nanocarrier manufacturing techniques

Manufacturing Method Scale Cost Quality Control Yield Flexibility References
Emulsion Small Low High Low High [117]

Nanoprecipitation Medium Moderate Moderate Moderate High [118]
Microfluidics Small High High High High [118]
Electrospinning Small High High High Low [118]
Self-Assembly Medium High Low High Moderate [119]
Spray Drying Large Moderate Low High Low [120]
Solvent Casting Large Moderate High Moderate Moderate [120]
Superparamagnetic Iron Oxide Nanoparticle Synthesis by Small Low High High Low [121]
Co-precipitation
Microemulsion Method for Solid Lipid Nanoparticle Synthesis Small Moderate High Moderate High [57]
Flash NanoPrecipitation for Polymer Nanoparticle Synthesis Medium High High High High [122]
Hydrodynamic Focusing Microfluidics for Liposome Synthesis Small High High High High [123]
Electrospray for Protein Nanoparticle Synthesis Small High High Low High [100]
Ultrasonic Atomization for Polymeric Micelle Synthesis Medium Moderate Moderate Moderate Moderate [123]
Hot Melt Extrusion for Lipid Nanoparticle Synthesis Large High High High Moderate [57]
Flash Nanocomplexation for RNA Nanoparticle Synthesis Medium High Moderate High High [100]
• Manufacturing Method: Different nanocarrier manufacturing methods used in the industry
• Scale: The manufacturing scale range of each method, categorized as small, medium, and large
• Cost: The estimated cost range of manufacturing nanocarriers by each method, categorized as low, moderate, and high
• Quality Control: The level of quality control required for each method, categorized as low, moderate, and high
• Yield: The expected nanocarrier yield by each method, categorized as low, moderate, and high
• Flexibility: The degree of flexibility offered by each manufacturing method in terms of nanocarrier properties and customizability, categorized as low, moderate, and
high
index, drug entrapment efficiency, and drug content. same function of clearing chemotherapeutic drugs from
Importantly, CSP-NPs exhibited an initial burst effect the body’s cells. Multiple studies have shown that MDR
followed by sustained drug release, resulting in dose transporters may be avoided with the use of nanocar-
and time-dependent cytotoxicity and apoptosis induc- riers. SP1049C is a doxorubicin-containing non-ionic
tion in human GBM cells. Furthermore, these nanocar- (sometimes called a pluronic or poloxamer) block-
riers significantly enhanced the uptake and intracellular copolymer. It consists of a hydrophobic body and a
accumulation of anticancer drugs while also reversing hydrophilic extension [13]. SP1049C is now being evalu-
the activity of MDR transporters (ABCB1 and ABCG2) ated in clinical trials for its potential to reverse p-glyco-
in GBM cells. This research highlights the potential of protein-mediated drug resistance in a mouse model of
nanocarriers as a promising strategy to overcome the leukemia. Cell uptake of doxorubicin-loaded liposomes
limitations of current chemotherapy approaches in the through the foliate receptor was shown to be unaffected
treatment of GBM, offering a more effective and spe- by P-glycoprotein (Pgp)-mediated drug efflux in an
cific therapeutic option [116]. Medication-resistant cells MDR cell line. This contrasts with the absorption of free
that strongly express MDR transporters will survive doxorubicin. These results may be attributed to folic
chemotherapy treatment because they are more sensi- acid receptors [57]. In resistant human myelogenous
tive to the effects of the drug. It’s because not all can- leukemia cell lines, cytotoxicity was increased when
cer cells express the MDR transporters. It is possible vincristine-loaded lipid nanoparticles were coupled to
that chemotherapy will not be effective against recur- an anti-Pgp monoclonal antibody (MRK-16). The Pgp-
ring cancers since the tumor population is dominated mediated efflux of vincristine is inhibited by MRK-16,
by drug-resistant cells. The MDR transporters that which causes this reaction. The goal was to undo the
have gotten the greatest interest from scientists include effects of MDR. Possible answers to the issue of MDR
P-glycoprotein (also known as MDR1 or ABCB1), the have been looked at, and these include polymer thera-
multidrug resistance-related proteins (MRPs), of which peutics, polymeric nanoparticles, lipid nanocapsules,
MRP1 (or ABCC1) has been investigated the most, and micelles. These tests have been done in cell cultures
and the breast cancer resistance protein (ABCG2) [5]. or in animal models of cancer. Targeted nanocarriers for
Though structurally diverse, these proteins all have the selective drug delivery and multidrug resistance pump
inhibitors may be able to solve some of the problems nanotechnology development is the use of immunother-
caused by resistant tumors [48]. apy in combination with nanocarriers. Immunotherapy
is a type of cancer treatment that stimulates the body’s
Cancer therapy using nanomaterials immune system to attack cancer cells [127]. By combin-
Cancer is a devastating disease that affects millions of ing immunotherapy with nanocarriers, it is possible to
people worldwide. Traditional cancer therapies such as increase the efficacy of the treatment and reduce toxicity
chemotherapy and radiation therapy have significant to healthy cells. Another promising area of research is the
limitations, including non-specific targeting and high development of nanotechnology-based diagnostic tools
toxicity to healthy cells. The development of nanotech- for cancer detection. Figure 4 depicts the schematic of
nology has offered new approaches for cancer detection cancer immunotherapy using NLG919@DEAP-DPPA-1
and treatment. Nanotechnology refers to the science of nanoparticles. The multifunctional peptide showcased its
manipulating materials at the nanoscale, typically in the antitumor mechanism in the tumor microenvironment.
range of 1–100 nm [124, 125]. The small size of nanoma- The figure also displays transmission electron micros-
terials allows them to interact with cells and tissues in copy images of the nanoparticles under various pH con-
unique ways, enabling them to be used for targeted drug ditions, with or without recombinant human MMP-2
delivery and cancer therapy. Nanocarriers, which are tiny (rhMMP-2). Additionally, the treatment efficacy of pep-
particles that can be loaded with therapeutic agents, are tide nanoparticles and the measurement of CD8 + T cells
a key area of research in the field of nanotechnology for in melanoma-bearing mice are presented. The scale bars
cancer treatment [61]. One of the challenges in the devel- for the TEM images are 100 nm, providing a clear visual
opment of nanocarriers for cancer therapy is the ability representation of the nanoparticles. Nanoscale sensors
to target cancer cells specifically, while avoiding healthy and probes can be used to detect cancer cells in blood
cells. Passive targeting methods, such as the enhanced samples or to visualize tumors in the body, enabling
permeability and retention (EPR) effect, take advantage early diagnosis and treatment. Despite the many advan-
of the unique characteristics of tumor cells, such as their tages of using nanotechnology in cancer therapy, there
leaky blood vessels and poor lymphatic drainage [126]. In are still challenges that need to be addressed [61]. These
contrast, active targeting involves modifying the surface challenges include the development of more efficient and
of the nanocarrier with specific targeting molecules that cost-effective nanocarriers, ensuring the safety of nano-
bind to receptors on cancer cells, enabling them to be carriers in humans, and improving the understanding of
more effectively targeted. Nanotechnology has been used tumor biology. The development of new and innovative
in various forms for cancer therapy, including polymeric nanocarriers and the continued improvement of targeted
nanoparticles, monoclonal nanoparticle antibodies, drug delivery systems will be essential to the future of
lipid-based nanomaterials, nanoemulsions, dendrimers, cancer therapy and the continued development of nano-
and nano-scale carbon materials [126]. These materials technology [127]. The development of nanotechnology
have been used to improve drug delivery to cancer cells, has offered a promising new approach to cancer detec-
reduce toxicity to healthy cells, and improve patient out- tion and treatment. With further research and develop-
comes. Liposomes, for instance, show sustained release ment, it may be possible to create targeted nanocarriers
of doxorubicin through a pH gradient mechanism in that are highly effective at delivering drugs to cancer cells,
acidic environments, maintaining stability. Polymeric minimizing side effects, and improving the overall effi-
nanoparticles offer controlled diffusion of paclitaxel in cacy of cancer treatment. The use of nanotechnology in
neutral pH conditions, remaining stable throughout the cancer therapy has the potential to revolutionize the field
process. Dendrimers, on the other hand, release metho- of oncology and offer renewed hope to patients with this
trexate through swelling in a pulsatile manner under devastating disease [128]. Figure 5 highlights the critical
basic conditions, though they are unstable. Nanoemul- role of mechanical strength and multivalency of nanoma-
sions demonstrate pulsatile partitioning of docetaxel terials in shaping cancer immunotherapy outcomes. The
in acidic environments, while gold nanoparticles can stiffness of polymeric nanoparticles plays a pivotal role in
release curcumin through a photothermal-triggered determining lysosome stability, which directly influences
mechanism under neutral pH conditions. These nano- inflammasome activation, a crucial step in cancer immu-
carriers exhibit various release rates, pH sensitivities, notherapy. Flexible nanomaterials exhibit better adapt-
and stabilities, contributing to their diverse applications ability and lateral movement, optimizing antigen loading
in drug delivery systems. Table 5 outlines various nano- and targeting lymph nodes more efficiently. Furthermore,
carrier drug release kinetics, which have been studied to nanoparticles with multiple binding sites can significantly
optimize the delivery of different drug types. One of the enhance immune signaling or attract immune cells to the
most promising areas of research in cancer therapy and tumor environment. Uniform multiple binding sites on
Table 5 Nanocarrier drug release kinetics

Nanocarrier Type Drug Type Release Mechanism Release Rate pH Sensitivity Stability References
Liposomes Doxorubicin pH Gradient Sustained Acidic Stable [13]

Polymeric nanoparticles Paclitaxel Diffusion Controlled Neutral Stable [90, 102]
Dendrimers Methotrexate Swelling Pulsatile Basic Unstable [99]
Nanoemulsions Docetaxel Partitioning Pulsatile Acidic Stable [117]
Gold nanoparticles Curcumin Photothermal Triggered Neutral Stable [90, 102]
Iron oxide nanoparticles Doxorubicin Magnetic field Sustained Neutral Stable [121]
Lipid-based Paclitaxel Diffusion Sustained Acidic Stable [57]
Polymer-lipid hybrid Cisplatin Hydrolysis Burst Neutral Unstable [57]
Carbon-based Cisplatin Adsorption Triggered Neutral Unstable [90, 102]
Gold nanorods Doxorubicin Photothermal Pulsatile Neutral Stable [90, 102]
Silica nanoparticles Curcumin pH-Responsive Sustained Neutral Stable [88]
Polymer nanoparticles Paclitaxel Erosion Sustained Neutral Stable [90, 102]
Liposomes Curcumin Gradient Sustained Neutral Stable [13]
Gold nanoparticles Doxorubicin Photothermal Pulsatile Neutral Stable [90, 102]
Polymeric micelles Docetaxel Solubilization Controlled Neutral Stable [91]
Carbon nanotubes Cisplatin Diffusion Sustained Neutral Unstable [90, 102]
Metal–organic frameworks Methotrexate Degradation Sustained Basic Unstable [101]
Polymeric nanoparticles Doxorubicin Degradation Sustained Neutral Stable [90, 102]
Liposomes Methotrexate pH Gradient Controlled Acidic Stable [13]
Dendrimers Paclitaxel Swelling Controlled Neutral Unstable [99]
Nanoemulsions Curcumin Partitioning Sustained Neutral Stable [117]
Liposomes Doxorubicin pH Gradient Sustained Acidic Stable [13]
Polymeric nanoparticles Paclitaxel Diffusion Controlled Neutral Stable [90, 102]
Dendrimers Methotrexate Swelling Pulsatile Basic Unstable [99]
Nanoemulsions Docetaxel Partitioning Pulsatile Acidic Stable [117]
Gold nanoparticles Curcumin Photothermal Triggered Neutral Stable [117]
Iron oxide nanoparticles Doxorubicin Magnetic field Sustained Neutral Stable [121]
Lipid-based Paclitaxel Diffusion Sustained Acidic Stable [57]
Polymer-lipid hybrid Cisplatin Hydrolysis Burst Neutral Unstable [57]
Carbon-based Cisplatin Adsorption Triggered Neutral Unstable [90, 102]
Gold nanorods Doxorubicin Photothermal Pulsatile Neutral Stable [58]
Silica nanoparticles Curcumin pH-Responsive Sustained Neutral Stable [88]
these nanoparticles improve T cell immune recognition opportunities for drug functionalization on their surface
by inhibiting immune checkpoints. On the other hand, or within their interior. Although organic nanoparticles
nanoparticles featuring varied multiple binding sites fos- are less stable than inorganic nanoparticles, they still
ter interactions between cancer cells and immune cells, offer several advantages in cancer therapy. Hybrid nan-
ultimately leading to tumor-specific immune responses. oparticles, which are a combination of both inorganic
The nanoparticles are classified as either inorganic or and organic nanoparticles, offer improved biocompat-
organic. Inorganic nanoparticles, which include metal- ibility and stability, making them an excellent choice for
lic, silica, carbon, and quantum dots, are highly stable cancer therapy. Figure 6 illustrates the use of chemically
and possess unique electronical and optical properties, modified nanoparticles in cancer therapy. Figure 7-A
which make them useful for cancer imaging and thera- illustrates different types of nanocarriers that can be uti-
nostics. However, the solid cores of inorganic nanopar- lized to target cancer cells. These delivery agents typically
ticles may lead to the rapid degradation of conjugated comprise of three main components: a nanocarrier, a
therapeutic molecules within the body. Organic nanopar- targeting moiety, and a cargo, which may include chem-
ticles, such as lipid-based and macromolecular assem- otherapeutic drugs. The figure depicts various potential
blies, offer good biocompatibility and provide numerous delivery agents, along with a schematic representation
Fig. 4 The schematic of cancer immunotherapy using NLG919@DEAP-DPPA-1 nanoparticles. The multifunctional peptide demonstrates its
antitumor mechanism in the tumor microenvironment. Transmission electron microscopy images of nanoparticles under various pH conditions,
with or without recombinant human MMP-2 (rhMMP-2), are shown. The treatment efficacy of peptide nanoparticles and the measurement
of CD8 + T cells in melanoma-bearing mice are also presented. The scale bars for the TEM images are 100 nm. Reprint from [129] with a permission
from Springer Nature
of the drug conjugation and entrapment processes. Cer- surface after their formation. Bioconjugation is a strategy
tain nanocarriers, including polymer-drug conjugates, that uses biological recognition and binding mechanisms
dendrimers, and particulate carriers, can directly bind to attach the targeting ligands to the nanocarriers. Finally,
chemotherapeutic drugs. In contrast, other nanocarriers physical attachment involves non-covalent interactions
trap the drugs within them. The diverse range of delivery between the targeting ligands and the nanocarriers, such
agents shown in the figure offers an array of possibilities as electrostatic interactions and hydrophobic interac-
for targeted cancer therapy, highlighting the potential for tions. The selection of an appropriate strategy depends
nanocarrier-based drug delivery systems in the treatment on the specific application and the properties of the
of cancer. Preconjugation involves the conjugation of tar- nanocarriers and targeting ligands. Figure 7-B illustrates
geting ligands to the surface of nanocarriers before their the different methods used for installing targeting ligands
assembly. Postconjugation, on the other hand, involves onto nanocarriers, which are categorized into four
the attachment of targeting ligands to the nanocarrier groups: preconjugation, postconjugation, bioconjugation,
Fig. 5 The impact of mechanical strength and multivalency of nanomaterials on cancer immunotherapy outcomes. a, the stiffness of polymeric
nanoparticles influences the stability of lysosomes, which is related to inflammasome activation in cancer immunotherapy. The flexibility of these
nanomaterials governs their adaptability and lateral movement, which in turn affects their ability to load antigens and target lymph nodes. b,
Nanoparticles with multiple binding sites can trigger immune signaling or promote the attraction of immune cells within the tumor environment.
Nanoparticles with uniform multiple binding sites improve T cell immune recognition by inhibiting immune checkpoints. In contrast, nanoparticles
with varied multiple binding sites facilitate interactions between cancer cells and immune cells, resulting in tumor-specific immune responses.
Reprint from [130] with a permission from Springer Nature
and physical attachment. Table 6 presents an overview of encapsulate hydrophobic drugs and improve their solu-
various nanocarriers utilized in clinical trials for cancer bility, enhancing drug bioavailability [135]. However,
therapy. their stability can be a concern, leading to premature
The use of nanocarriers in drug delivery has revolu- drug release [98]. Clinical trials have reported minor side
tionized the field of medicine by providing targeted and effects, such as infusion-related reactions, but overall,
controlled release of therapeutic agents. This critical anal- lipid nanoparticles have demonstrated remarkable poten-
ysis aims to shed light on various approved nanocarriers, tial in delivering a range of therapeutics [136]. Polymeric
evaluating their effectiveness, limitations, and poten- micelles, formed from amphiphilic block copolymers,
tial side effects based on clinical trial data [133]. Under- offer promising drug delivery platforms. They enhance
standing the practical implications of these formulations the solubility of poorly water-soluble drugs, improving
is crucial for optimizing drug delivery strategies [134]. their bioavailability [137]. However, their stability and
Lipid nanoparticles, including liposomes and lipid-based drug-loading capacity can be limiting factors, and clini-
nanocarriers, have gained widespread acceptance due cal trials have reported challenges in maintaining thera-
to their biocompatibility and versatility. They effectively peutic concentrations [138]. Additionally, the long-term
Fig. 6 Chemically modified nanoparticles intended for use in cancer therapy. These nanoparticles can be classified as either inorganic or organic.
Inorganic nanoparticles, such as metallic, silica, carbon, and quantum dots, are highly stable and possess electronical and optical properties
that make them useful for cancer imaging and theragnostic. However, their solid cores may lead to the rapid degradation of conjugated
therapeutic molecules in vivo. Organic nanoparticles, on the other hand, such as lipid-based and macromolecular assemblies, are less stable
but have good biocompatibility and provide multiple opportunities for drug functionalization either on their surface or within their interior. Hybrid
nanoparticles are a combination of both inorganic and organic nanoparticles and offer improved biocompatibility and stability. Reprint from [131]
with a permission from Springer Nature
safety profile of some polymers remains under investiga- They enhance drug stability and can accumulate in tumor
tion [100]. Gold nanoparticles and gold nanorods have tissues through the enhanced permeability and retention
shown promise in photothermal therapy and imaging effect [142]. Clinical trials have reported relatively few
applications. While they offer precise control over drug adverse effects, but there is ongoing research to optimize
release through external stimuli, their clinical utility their efficacy [143]. PLGA nanoparticles have been exten-
has been limited due to concerns about toxicity [139]. sively studied for their controlled drug release capabili-
Clinical trials have raised questions about the long-term ties. They offer biodegradability and can be tailored for
impact of gold nanoparticles on the body and the poten- various drug types [89]. However, their effectiveness can
tial for immune responses [140]. Mesoporous silica nano- be compromised by rapid drug release or poor drug load-
particles offer a unique drug delivery platform with high ing. Clinical trials have identified potential challenges in
drug-loading capacity and tunable release kinetics [23]. achieving consistent therapeutic outcomes [144]. Carbon
However, their relatively large size may limit their abil- nanotubes have shown promise in drug delivery, but con-
ity to target specific tissues or cells. Clinical trials have cerns regarding their biocompatibility and toxicity have
provided valuable insights into their safety and have iden- limited their clinical translation [145]. Clinical trials have
tified potential side effects, such as gastrointestinal dis- revealed safety concerns, particularly in long-term expo-
turbances [141]. Albumin-bound nanoparticles have been sure scenarios [146]. Iron oxide nanoparticles, including
developed to improve the delivery of hydrophobic drugs. magnetic nanoparticles, have been explored for targeted
Fig. 7 A Different types of nanocarriers that can be used for targeting cancer. The main components of these delivery agents usually consist
of a nanocarrier, a targeting moiety that is connected to the nanocarrier, and a cargo, which can be the desired chemotherapeutic drugs. The
diagram shows a range of possible delivery agents, and a schematic representation of the drug conjugation and entrapment processes. In some
cases, the chemotherapeutic drugs can be bound to the nanocarrier, such as in polymer-drug conjugates, dendrimers, and some particulate
carriers, while in other cases they can be trapped inside the nanocarrier. Reprint from [132] with a permission from Springer Nature. B The various
approaches for installing targeting ligands onto nanocarriers. The strategies are divided into four categories: preconjugation (A), postconjugation
(B), bioconjugation (C), and physical attachment (D). Reprint from [34] with a permission from Wiley
drug delivery and imaging [147]. While they offer precise enhancing drug delivery efficiency [152]. Clinical trials
control over drug release, there are concerns about their have reported favorable safety profiles, but their efficacy
potential toxicity, especially with long-term use. Clinical in specific therapeutic applications may vary [153]. Cal-
trials have highlighted the need for comprehensive safety cium phosphate-coated iron oxide nanoparticles provide
assessments [148]. Quantum dots have unique optical a versatile platform for imaging and drug delivery. How-
properties, making them valuable for imaging and diag- ever, their clinical translation may be hindered by con-
nostics [149]. However, concerns about their potential cerns about long-term toxicity and potential side effects
toxicity, particularly due to heavy metal components, [154]. Self-assembling peptide nanofibers offer a unique
have raised questions about their clinical use. Lipid- approach for drug delivery and tissue engineering. Clini-
polymer hybrid nanoparticles represent a promising cal trials have demonstrated their biocompatibility, but
approach by combining the advantages of both lipid and further research is needed to assess their long-term
polymeric nanocarriers [150]. They offer improved stabil- effects [155]. Lipid-polymer-metal hybrid nanoparticles
ity and drug-loading capacity, making them suitable for a combine the properties of lipids, polymers, and metals
wide range of drugs. However, clinical trials are needed for multifunctional drug delivery systems. Clinical trials
to assess their long-term safety and potential side effects. are essential to evaluate their safety and effectiveness in
Calcium phosphate nanoparticles have shown potential complex therapeutic applications [156]. Gold nanopar-
in gene delivery and vaccine formulations. They offer ticles have found applications in drug delivery, imaging,
biocompatibility and controlled release properties. How- and therapy. Clinical trials have identified potential tox-
ever, clinical trials have highlighted challenges in achiev- icity issues, especially with larger particles, emphasiz-
ing efficient transfection and potential immunogenicity ing the importance of rigorous safety assessments [157].
concerns [151]. Liposome-encapsulated nanoparticles Magnetic nanoparticles have shown potential in drug
combine the advantages of liposomes and nanoparticles, targeting and imaging. Clinical trials have reported some
Table 6 Clinical trials of nanocarriers for cancer therapy
Study Title Types of Cancer Interventions Phase Outcome Pateints Sex NCT Number
Paclitaxel Albumin-Stabilized Breast Cancer Biological: bevacizumab, Drug: Phase 2 6-month Progression-free Survival 50 All NCT00662129
Nanoparticle Formulation, gemcitabine hydrochloride, Drug: (PFS) Rate, Overall Survival Time,
Gemcitabine, and Bevacizumab paclitaxel albumin-stabilized PFS Time
in Treating Patients With Meta- nanoparticle formulation
static Breast Cancer
ABI-007 (Nab-Paclitaxel) and Breast Cancer Drug: Gemcitabine, Drug: Phase 2 Proportion of Patients With Con‑ 50 Female NCT00110084
Gemcitabine in Treating Women Paclitaxel protein-bound parti‑ firmed Responses, Progression-

With Metastatic Breast Cancer cles for injectable suspension free Survival, Overall Survival,
(albumin-bound) and Adverse Event
Nanoparticle Albumin-Bound Breast Cancer Drug: nab paclitaxel, Drug: Cyclo‑ Phase 2 Number of Participants Who 63 All NCT00629499
(Nab) Paclitaxel/Cyclophos- phosphamide, Drug: Trastuzumab Remained Alive Without Evidence
phamide in Early-Stage Breast of Recurrence as a Measure
(2023) 22:169
Cancer of Tolerability of Adjuvant Nab

Paclitaxel, Disease-free Survival,
Overall Survival
S0800, Nab-Paclitaxel, Doxoru- Breast Cancer Biological: bevacizumab, Bio‑ Phase 2 Number of Patients With 215 Female NCT00856492
bicin, Cyclophosphamide, and logical: pegfilgrastim, Drug: cyclo‑ Pathological Complete Response
Pegfilgrastim With or With- phosphamide, and 2 more… Rate, Overall Survival, Event-free
out Bevacizumab in Treating Survival, and Number of Adverse
Women With Inflammatory or Events That Are Possibly, Probably
Locally Advanced Breast Cancer or Definitely Related to Study
Drug
Carboplatin, Paclitaxel, and Breast Cancer Biological: bevacizumab, Drug: Phase 2 Progression-free Survival, 32 All NCT00654836
Bevacizumab in Treating Carboplatin, Drug: ABI-007 Response Rate at End of Treat‑
Patients With Locally Recurrent ment, Overall Survival
or Metastatic Breast Cancer
Carboplatin and Paclitaxel Lung Cancer Drug: carboplatin, Drug: erlotinib Phase 2 Overall Survival at 12 Months, 78 All NCT00553462
Albumin-Stabilized Nanopar- hydrochloride, Drug: paclitaxel Response Rate, Progression-free
ticle Formulation Followed by albumin-stabilized nanoparticle Survival
Radiation Therapy and Erlotinib formulation, Radiation: radiation
in Treating Patients With Stage therapy
III Non-Small Cell Lung Cancer
That Cannot Be Removed By
Surgery
Paclitaxel Albumin-Stabilized Lung Cancer Drug: carboplatin, Drug: paclitaxel Phase 2 Overall Response Rate Defined 63 All NCT00729612
Nanoparticle Formulation and albumin-stabilized nanoparticle as Complete or Partial Response
Carboplatin in Treating Patients formulation, Genetic: protein as Assessed by RECIST Version 1.0
With Stage IIIB, Stage IV, or expression analysis, and 3 more… Criteria, Progression Free Survival,
Recurrent Non-Small Cell Lung Overall Survival, and Incidence
Cancer and Intensity of Adverse Events
Graded According to NCI CTCAE
v. 3.0
Page 29 of 103
Table 6 (continued)
Phase II NCT (Neoadjuvant Breast Cancer Drug: bevacizumab, Drug: carbo‑ Phase 2 Number of Patients With Patho‑ 33 Female NCT00675259
Chemotherapy) w/ Weekly platin, Drug: nab-paclitaxel, and 2 logic Complete Response (pCR),
Abraxane in Combination With more… Side Effects of Weekly Nab-
Carboplatin & Bevacizumab in paclitaxel, Carboplatin and Beva‑
Breast Cancer cizumab, Evaluation of Dynamic
Contrast-enhanced Magnetic
Resonance Imaging in Assess‑
ing pCR at Baseline and After 2

Cycles of Neoadjuvant Therapy,
and Overall Expression of LZTS1
Before and After Neoadjuvant
Therapy as Assessed by Immuno‑
histochemistry
(2023) 22:169
Paclitaxel Albumin-Stabilized Recurrent Non-Small Cell Lung Other: Laboratory Biomarker Phase 2 Overall Response Rate (Complete 26 All NCT01620190
Nanoparticle Formulation in Carcinoma, Stage IV Non-Small Analysis, Drug: Paclitaxel Albumin- and Partial Response) Defined
Treating Patients With Previ- Cell Lung Cancer Stabilized Nanoparticle Formula‑ by RECIST 1.1 Criteria, Overall
ously Treated Advanced Non- tion Percentage of Patients Experienc‑
small Cell Lung Cancer ing Toxicity Within a Clinically
Significant Category Defined
as Neutropenia, Neutropenic
Fever, or Neuropathy, Overall
Survival
Abraxane Therapy in Patients Pancreatic Cancer Drug: Abraxane Phase 2 Overall Survival Rate at 6 Months, 20 All NCT00691054
With Pancreatic Cancer Who Number of Participants Showing
Failed First-Line Gemcitabine Complete or Partial Response,
Therapy Number of Participants Showing
Stable Disease
Phase 1/2 Study of ABI-009 in Non-muscle Invasive Bladder Drug: ABI-009, Drug: Gemcitabine Phase 1, Phase 2 Phase 1: Dose Limiting Toxici‑ 21 All NCT02009332
Nonmuscle Invasive Bladder Cancer (NMIBC) ties (DLT) Following Intravesical
Cancer Administration of ABI-009, Phase 2:
Number of Participants Achieving
a Complete Response Following
Intravesical Administration of ABI-
009 and Gemcitabine, Phase 1:
Number of Participants Achieving
a Complete Response Follow‑
ing Intravesical Administration
of ABI-009
Page 30 of 103
Table 6 (continued)
Doxorubicin Hydrochloride, Estrogen Receptor-positive Breast Drug: doxorubicin hydrochloride, Phase 2 Disease-free Survival Following 60 Female NCT00407888
Cyclophosphamide, and Fil- Cancer, HER2-positive Breast Drug: cyclophosphamide, Biologi‑ a Dose-intensive Weekly Regimen
grastim Followed By Paclitaxel Cancer, and 6 more… cal: filgrastim, and 4 more… of Adriamycin + Oral Cyclophos‑
Albumin-Stabilized Nanoparti- phamide Augmented With G-CSF
cle Formulation With or Without Support Followed by Abraxane
Trastuzumab in Treating and Herceptin, Delivered Dose
Patients With Breast Cancer Pre- Intensity of the Regimen, Toxicity
viously Treated With Surgery Associated With This Regimen

Phase II Study With Abraxane, Breast Cancer Drug: Abraxane, Drug: Bevaci‑ Phase 2 Best Clinical Response Expressed 41 Female NCT00479674
Bevacizumab and Carboplatin zumab, Drug: Carboplatin as Percentage of Participants
in Triple Negative Metastatic Treated With Combination
Breast Cancer Regimen of Weekly Abraxane®
and Carboplatin Plus Biweekly
(2023) 22:169
Bevacizumab to Treat Women

With Stage IV or Inoperable Stage
III "Triple Negative" Metastatic
Breast Cancer, Median Proportion
Progression-free as Estimated
by Kaplan–Meier Methods, To
Evaluate Sequential Plasma
Samples for Presence of Selected
Angiogenic Markers
Nab-Paclitaxel and Bevaci- Estrogen Receptor-negative Breast Drug: paclitaxel albumin-stabilized Phase 2 Progression-free Survival (PFS), 59 Female NCT00733408
zumab Followed By Bevaci- Cancer, HER2-negative Breast nanoparticle formulation, Biologi‑ Overall Survival, Percentage of Par‑
zumab and Erlotinib in Meta- Cancer, and 3 more… cal: bevacizumab, Drug: erlotinib ticipants With Response
static Breast Cancer hydrochloride
Sargramostim and Paclitaxel Brenner Tumor, Fallopian Tube Biological: sargramostim, Drug: Phase 2 Time to Progression, Response 21 All NCT00466960
Albumin-Stabilized Nanopar- Cancer, Ovarian Clear Cell Cystad‑ paclitaxel albumin-stabilized Rate, Correlation Between
ticle Formulation in Treating enocarcinoma, and 9 more… nanoparticle formulation, Other: Circulating Monocytes and Time
Patients With Advanced Ovarian laboratory biomarker analysis, to Progression
Cancer, Fallopian Tube Cancer, and 2 more…
or Primary Peritoneal Cancer
That Did Not Respond to Previ-
ous Chemotherapy
Paclitaxel Albumin-Stabilized Metastatic Pancreatic Adeno‑ Drug: AZD1775, Drug: Gemcit‑ Phase 1, Phase 2 Number of Participants With 8 All NCT02194829
Nanoparticle Formulation and carcinoma, Stage III Pancreatic abine, Drug: Nab-paclitaxel Dose Limiting Toxicities (DLT), To
Gemcitabine Hydrochloride Cancer AJCC v6 and v7, Stage IV Determine the Pharmacokinetics
With or Without WEE1 Inhibitor Pancreatic Cancer AJCC v6 and v7, of AZD1775 in Combination With
AZD1775 in Treating Patients and 1 more… Nab-paclitaxel and Gemcitabine,
With Previously Untreated Progression-free Survival
Pancreatic Cancer That Is Meta-
static or Cannot Be Removed by
Surgery
Page 31 of 103
Table 6 (continued)
Paclitaxel, Nab-paclitaxel, or Estrogen Receptor Negative, Biological: Bevacizumab, Drug: Phase 3 Progression Free Survival, Objec‑ 799 All NCT00785291
Ixabepilone With or Without Estrogen Receptor Positive, HER2/ Ixabepilone, Other: Laboratory tive Tumor Response Rate, Time
Bevacizumab in Treating Neu Negative, and 6 more… Biomarker Analysis, and 3 more… to Treatment Failure
Patients With Stage IIIC or Stage
IV Breast Cancer
Paclitaxel Albumin-Stabilized Fallopian Tube Carcinoma, Primary Drug: Paclitaxel Albumin-Stabi‑ Phase 2 Tumor Response, Frequency 51 Female NCT00499252
Nanoparticle Formulation in Peritoneal Carcinoma, Recurrent lized Nanoparticle Formulation and Severity of Observed Adverse
Treating Patients With Recurrent Ovarian Carcinoma Effects, Progression-free Survival,
or Persistent Ovarian Epithelial Overall Survival
Cancer, Fallopian Tube Cancer,
or Primary Peritoneal Cancer
Study of Albumin-bound Pacli- Breast Cancer Drug: Albumin-bound pacli‑ Phase 2 Percentage of Participants Who 32 Female NCT00093145
taxel (Abraxane) in Combination taxel, Drug: Carboplatin, Drug: Achieved an Objective Confirmed
(2023) 22:169
With Carboplatin and Herceptin Herceptin® Complete or Partial Overall

in Patients With Advanced Response, Percentage of Partici‑
Breast Cancer pants With a Total Response, Time
to Disease Progression
A Phase I/II Clinical Trial of Vid- Advanced or Metastatic Solid Drug: Azacitidine (Vidaza), Drug: Phase 1, Phase 2 Phase I: Percentage of Participants 30 All NCT00748553
aza With Abraxane in Patients Tumors, Advanced or Metastatic Nab-paclitaxel (Abraxane) Responding to Treatment, Phase
With Advanced/Metastatic Solid Breast Cancer II: Percentage of Participants
Tumors and Breast Cancer With Objective Response Rate
(ORR) Measured Using RECIST 1.0
Criteria, Number of Participants
With ER + Status, Progression-free
Survival
A Phase 2 Study of Non-Small Cell Lung Cancer Drug: CRLX101, Other: Best Sup‑ Phase 2 To Compare Overall Sur‑ 157 All NCT01380769
CRLX101(NLG207) in Patients portive Care vival of Patients Treated With
With Advanced Non-Small Cell CRLX101 + BSC to Those Patients
Lung Cancer Treated With BSC Only, Assess
Objective Response Rate (ORR)
of CRLX101 + BSC Compared
to BSC Only
Nab-Paclitaxel, Cisplatin, and Head and Neck Cancer Biological: Cetuximab, Drug: Phase 1, Phase 2 Phase I Maximum Tolerated Dose 37 All NCT00851877
Cetuximab With Concurrent Cisplatin, Drug: Nab-Paclitaxel, of Nab-Paclitaxel, Phase II 2-year
Radiation Therapy for Locally Radiation: intensity-modulated Progression-free Survival, Phase
Advanced Head and Neck radiation therapy II 2-year Local Control, Phase II
Cancer 2-year Overall Survival
Page 32 of 103
Table 6 (continued)
Pre-Operative Staging of Pan- Pancreatic Cancer Drug: Superparamagnetic Iron Phase 4 To Determine the Sensitivity High 35 All NCT00920023
creatic Cancer Using Superpara- Oxide Magnetic Resonance Resolution Magnetic Resonance
magnetic Iron Oxide Magnetic Imaging Imaging With Lymphotrophic
Resonance Imaging (SPIO MRI) Superparamagnetic Nanoparti‑
cles to Identify Small and Oth‑
erwise Undetectable Lymph
Node Metastases., To Determine
the Specificity of High Resolution

Magnetic Resonance Imaging
With Lymphotrophic Superpara‑
magnetic Nanoparticles to Identify
Small and Otherwise Undetect‑
able Lymph Node Metastases
(2023) 22:169
Gemcitabine Hydrochloride, Stage III Intrahepatic Cholan‑ Drug: Cisplatin, Drug: Gemcitabine Phase 2 Median Progression Free Survival 62 All NCT02392637
Cisplatin, and Nab-Paclitaxel giocarcinoma AJCC v7, Stage IIIA Hydrochloride, Other: Laboratory (PFS), Median Overall Survival (OS),
in Treating Patients With Gallbladder Cancer AJCC v7, Stage Biomarker Analysis, Drug: Nab- Number of Participants With Treat‑
Advanced or Metastatic Biliary IIIB Gallbladder Cancer AJCC v7, paclitaxel ment Response Rate
Cancers and 6 more…
Phase II Lapatinib Plus Nab- Neoplasms, Breast Drug: Lapatinib/nab-Paclitaxel Phase 2 Overall Tumor Response (OR), 60 Female NCT00709761
Paclitaxel As First And Second Overall Survival (OS), Duration
Line Therapy In her2 + MBC of Response (DOR)
A Phase III Study of NK105 in Breast Cancer Nos Metastatic Drug: NK105, Drug: Paclitaxel Phase 3 Progression Free Survival, Overall 436 Female NCT01644890
Patients With Breast Cancer Recurrent Survival, Overall Response Rate,
S1505: Combination Chemo- Pancreatic Adenocarcinoma, Drug: Fluorouracil, Drug: Gem‑ Phase 2 Overall Survival (OS), Number 147 All NCT02562716
therapy or Gemcitabine Resectable Pancreatic Carcinoma citabine Hydrochloride, Drug: of Patients With Grade 3 Through
Hydrochloride and Paclitaxel Irinotecan Hydrochloride, and 3 Grade 5 Adverse Events That Are
Albumin-Stabilized Nanoparti- more… Related to Study Drug, Number
cle Formulation Before Surgery of Patients Going to Surgery
in Treating Patients With for Resection After Preoperative
Pancreatic Cancer That Can Be Chemotherapy
Removed by Surgery
Induction Chemotherapy With Head and Neck Neoplasms Drug: paclitaxel albumin-stabilized Phase 2 Percentage of Participants With 30 All NCT01566435
ACF Followed by Chemoradia- nanoparticle formulation, Drug: Complete Response (CR) by Clini‑
tion Therapy for Adv. Head & Cisplatin, Drug: Fluorouracil, and 3 cal Exam at Primary Tumor Site,
Neck Cancer more… Percentage of Participants With
Partial Response (PR) at Primary
Tumor Site, Number of Par‑
ticipants Per Anatomic Tumor
Response by CT Scan
Page 33 of 103
Table 6 (continued)
(2023) 22:169
Topical Imiquimod and Abrax- Male Breast Cancer, Recurrent Drug: imiquimod, Drug: Abraxane, Phase 2 Anti-tumor Effects of Imiquimod 15 All NCT00821964
ane in Treating Patients With Breast Cancer, Skin Metastases, Other: laboratory biomarker analy‑ as Assessed by Modified World
Advanced Breast Cancer and 1 more… sis, and 2 more… Health Organization (WHO)
Criteria, Safety and Systemic
Toxicity as Assessed by a Review
of Medical History, Physical Exam,
Systems, Performance Status,
and Clinical Labs (CBC and CMP),
Pathologic Response by Immu‑
nohistochemical (IHC)as Assessed
by Skin Punch Biopsy of the Target
Lesion
Phase 1 Trial of PAN-301–1 (SNS- Prostate Cancer Biological: PAN-301–1 Phase 1 Safety Assessed by Development 18 All NCT00262916
301) in Cancer Patients of Adverse Events and Dose-
limiting Toxicity to Determine
Maximum Tolerated Dose, Safety
Assessed by Administration Site
Reactions, Abnormal Laboratory
Values and/or Clinically Significant
Changes in Physical Examinations
Page 34 of 103
concerns about their potential impact on the immune polymeric nanoparticles (PNPs), monoclonal antibody
system and long-term biocompatibility [158]. Silica nanoparticles (mAbNPs), extracellular vesicles (EVs),
nanoparticles have been explored for their drug delivery and PNPs have all been the subject of much study (NPs).
capabilities. Clinical trials have reported some safety con- PNPs are colloidal macromolecules between ten and one
cerns related to their size and surface properties, high- thousand nanometers in size [57, 58]. PNPs serve as drug
lighting the need for careful design and optimization transporters, delivering chemotherapy chemicals directly
[159]. Polymeric nanoparticles with surface modifica- to tumor locations before gradually releasing them.
tion offer tailored drug delivery solutions. Clinical trials When medications are enclosed inside nanoparticles or
have revealed promising outcomes in specific applica- connected to the surfaces of nanoparticles, a nanocap-
tions, but their safety and efficacy may vary depend- sule or nanosphere is formed [48]. Nanoparticle building
ing on the modification and drug being delivered [160]. blocks have experienced multiple evolutions throughout
Graphene oxide nanoparticles and carbon quantum dots time. Early efforts to create nanoparticles relied on the
have shown potential in drug delivery and imaging. How- use of nonbiodegradable polymers such as polymethyl
ever, concerns about their biocompatibility and potential methacrylate (PMMA), polyacrylamide, polystyrene,
toxicity have limited their clinical adoption [161]. Nano- and polyacrylates [167]. To reduce toxicity and prolong
gels represent a versatile platform for drug delivery, with inflammation, it is important to eliminate any polymeric
tunable properties. Clinical trials are necessary to assess nanoparticles generated from these substances as soon as
their safety and effectiveness in different therapeutic con- feasible [88]. The difficulties in degrading, excreting, or
texts [162, 163]. Cationic liposomes and chitosan nano- physically removing these polymer-based nanoparticles
particles offer unique advantages for gene and nucleic from tissues, which had previously posed a health risk,
acid delivery. Clinical trials have demonstrated their have been addressed [84]. These nanoparticles accumu-
safety and efficacy, but further optimization is needed for lated because they were so difficult to remove. Because
broader clinical applications [164]. Dendrimer-encapsu- of advances in biodegradable polymer manufacture, tox-
lated nanoparticles and micelle-encapsulated nanoparti- icity has been decreased, while drug release kinetic pat-
cles provide controlled drug release capabilities. Clinical terns have been enhanced, and biocompatibility has been
trials are essential to evaluate their safety and effective- widened [168]. Table 7 outlines the biocompatibility of
ness in specific drug delivery scenarios [165]. various nanocarrier materials, which play a crucial role
in drug delivery systems. Figure 8 depicts the various
mechanisms by which nanocarriers can deliver drugs to
Various nano‑formulations: revolutionizing drug tumours.
delivery The diagram shows polymeric nanoparticles repre-
Nanotechnology has ushered in a new era in science sented as circles that can passively target the tumour tis-
and medicine, bringing forth innovative solutions to sue by extravasating through the tumour vasculature and
longstanding challenges across various domains, with ineffective lymphatic drainage (ePr effect). In addition to
drug delivery standing out prominently [166]. Through passive targeting, the diagram illustrates active cellular
the precise manipulation of materials at the nanoscale, targeting by functionalizing the surface of the nanopar-
nanotechnology has sparked considerable interest for ticles with ligands that promote cell-specific recognition
its potential to revolutionize drug delivery. Nano-for- and binding. The inset in the diagram shows that the
mulations hold the promise of significantly improving nanoparticles can release their contents in close proxim-
the bioavailability, efficacy, and safety of drugs [59]. By ity to the target cells, attach to the cell membrane and act
exploiting the unique properties of nanoparticles, such as an extracellular sustained-release drug depot, or inter-
as their high surface area and tunable characteristics, nalize into the cell. Natural polymers, including chitosan,
scientists and researchers have developed novel drug alginate, gelatin, and albumin, as well as synthetic poly-
delivery systems that can target specific cells or tissues, mers like polylactic acid (PLA), poly(lactic-co-glycolic
reduce side effects, and enhance therapeutic outcomes. acid), poly(amino acids), and poly(-caprolactone) (PCL),
This breakthrough in nanotechnology not only opens are all examples of such polymers [168]. These recently
new avenues for personalized medicine but also holds the produced polymeric nanoparticles provide special advan-
potential to transform the way we approach healthcare tages according to their architecture and characteristics.
and treatment strategies in the future [20]. PNPs are a practical method for making unstable phar-
maceuticals more stable [20]. Chemical medicines may
be given orally or intravenously with PNPs, and they
Polymeric nanoparticles
have a higher loading capacity than free pharmaceuti-
The term "nanoparticle" is used to describe any particle
cals. It has been shown that adding dexamethasone or
with a size on the nanometer scale. Metal nanoparticles,
Table 7 Biocompatibility of nanocarrier materials
Nanocarrier Biocompatibility Cytotoxicity Immunogenicity Hemocompatibility Clearance Description Novelty Advantages References
Material Score Pathway
Liposomes High Low Low Low RES Phospholipid First generation Biodegradable, [13]
bilayer vesicles nanocarriers versatile, well-
with aqueous core established
Polymeric Nano- Medium to High Variable Variable Variable RES, Renal, Nanoparticles Tailorable size Potential toxicity, [90, 102]
particles or Lymphatic composed of syn‑ and surface prop‑ batch-to-batch
thetic or natural erties, good drug variability

polymers payload capacity
Gold Nanopar- Low to Medium Low to Moderate Low Low to Moderate RES or Renal Nanoparticles Good biocompat‑ Potential [58]
ticles made of gold ibility, versatile for accumulation
with surface coat‑ in organs, poor
ings biodegradability
(2023) 22:169
Carbon Nano- Low to Medium Variable Variable Variable RES, Pulmonary, Cylindrical High drug pay‑ Potential toxicity, [169]
tubes or Renal carbon structures load capacity, tun‑ poor biodegrada‑
with high aspect able properties bility
ratio
Magnetic Nano- Low to Medium Variable Variable Variable RES or Renal Nanoparticles Good targeting Potential [59]
particles with magnetic ability, potential for accumulation
properties for imaging in organs, poor
biodegradability
Calcium Phos- High Low Low Low RES or Renal Nanoparticles Good biocompat‑ Limited drug [124, 125]
phate Nanopar- composed of cal‑ ibility, potential payload capacity,
ticles cium and phos‑ for bone-targeted potential for pre‑
phate therapy cipitation
Protein-Based High Low Low Low RES or Renal Nanocarriers com‑ High biocompat‑ Limited stability, [170]
Nanocarriers posed of proteins ibility, potential high production
for targeted cost
therapy
DNA Nanocar- Medium Low Low Low Renal or Hepatic Nanocarriers Potential for gene Limited drug [171]
riers made of DNA therapy, good bio‑ payload capac‑
or DNA-based degradability ity, potential
materials for immunogenic‑
ity
Lipid Nanopar- High Low Low Low RES or Renal Nanoparticles Versatile, easy Limited drug [99]
ticles composed to produce, good payload capacity,
of lipids stability potential for lipid
accumulation
Iron Oxide Nano- Low to Medium Low Low Low to Moderate RES or Renal Nanoparticles Good targeting Potential [121]
particles with magnetic ability, potential for accumulation
properties for imaging in organs, poor
biodegradability
Silica Nanopar- Low to Medium Variable Variable Variable RES or Renal Nanoparticles High drug Potential for toxic‑ [88]
ticles composed of silica payload capacity, ity, poor biodegra‑
good stability dability
Page 36 of 103
Table 7 (continued)
Polyethylene High Low Low Low Renal or Hepatic Nanoparticles Good biocom‑ Potential for insta‑ [172]
Glycol Nanopar- with PEG coatings patibility, long bility, potential
ticles circulation time for immune
response
Albumin Nano- High Low Low Low RES or Renal Nanoparticles Good biocompat‑ Limited drug [27]
particles composed ibility, potential payload capacity,

of albumin for targeted potential for insta‑
therapy bility
Polysaccharide High Low Low Low RES or Renal Nanoparticles Good biocompat‑ Limited drug [173]
Nanoparticles composed ibility, potential payload capac‑
of polysaccharides for targeted ity, potential
therapy for batch-to-batch
(2023) 22:169
variability
Graphene Oxide Low to Medium Variable Variable Variable RES, Pulmonary, Nanoparticles High drug Potential for toxic‑ [174]
Nanoparticles or Renal composed of gra‑ payload capacity, ity, poor biodegra‑
phene oxide good stability dability
Chitosan Nano- High Low Low to Moderate Low Renal or Hepatic Nanoparticles Good biocompat‑ Potential [84]
particles composed of chi‑ ibility, potential for aggregation,
tosan for targeted limited drug pay‑
therapy load capacity
Quantum Dots Low to Medium Low to Moderate Low to Moderate Low to Moderate RES or Renal Nanoparticles Good imaging Potential for toxic‑ [21, 103, 104]
made of semicon‑ properties, poten‑ ity, poor biodegra‑
ducting materials tial for targeted dability
therapy
DNA Origami Medium Low Low Low Renal or Hepatic Nanocarriers Potential for tar‑ Limited stabil‑ [175]
Nanoparticles made of DNA geted therapy ity, potential
and folded and gene delivery for immunogenic‑
into specific ity
shapes
Metal–Organic Medium to High Variable Variable Variable RES or Renal Nanocarriers com‑ Tailorable proper‑ Potential for tox‑ [101]
Frameworks posed of metal ties, potential icity, limited
ions and organic for drug delivery biodegradability
ligands and imaging
Self-Assembling High Low Low Low RES or Renal Peptides Good biocompat‑ Limited drug [87]
Peptides that self-assemble ibility, potential payload capacity,
into nanocarriers for targeted potential for insta‑
therapy bility
Lipid-Polymer High Low Low Low RES or Renal Nanoparticles Tailorable size Potential for insta‑ [57]
Hybrid Nanopar- composed and surface prop‑ bility, potential
ticles of lipids and poly‑ erties, good drug for lipid accumu‑
mers payload capacity lation
Page 37 of 103
(2023) 22:169
Table 7 (continued)
Carbon Quan- Low to Medium Low Low Low RES or Renal Nanoparticles Good imag‑ Potential for toxic‑ [176]
tum Dots composed of car‑ ing properties, ity, poor biodegra‑
bon materials potential for drug dability
delivery
Page 38 of 103
Fig. 8 Various ways in which nanocarriers can transport drugs to tumors, using polymeric nanoparticles as a representative example. To achieve
passive tissue targeting, the nanoparticles extravasate through the tumor vasculature due to increased permeability and inefficient lymphatic
drainage (ePr effect). Active cellular targeting can be accomplished by modifying the surface of the nanoparticles with ligands that promote
recognition and binding to specific cells. Nanoparticles can then either (i) release their contents in close proximity to the target cells; (ii) adhere
to the cell membrane and serve as an extracellular sustained-release drug reservoir; or (iii) become internalized by the cell. Reprint from [132]
tocopheryl succinate to cisplatin-loaded PNPs may mit- nanoparticles are made up of different materials and
igate the ototoxicity that results from cisplatin usage in possess unique physical and chemical attributes, such
chemotherapy [20]. This property protects drugs against as size, shape, surface properties, and flexibility. Fur-
degradation, which lessens the chance of their adverse thermore, these nanoparticles can be customized with a
effects on non-target tissues. Medication distribution, for variety of ligands to target specific tumors. The diverse
instance, often employs one of two methods: active tar- properties of these nanoparticles influence the biologi-
geting or passive targeting [44]. Overactive angiogenesis cal mechanisms involved in their delivery to tumors, such
gives an advantage that is objectively known as EPR when as their interactions with serum proteins, their distribu-
there is a robust extracellular matrix present, making it tion throughout the body, their penetration through the
more difficult for drugs to reach the tissue [125]. Growing tumor’s blood vessels and tissues, their targeting of tumor
tumors have high energy and oxygen needs. Meanwhile, cells, and their intracellular movement. Moreover, the
tumor-induced angiogenesis generates many immature nanoparticles can be engineered to control the release of
vasculatures, which obstruct lymphatic drainage [13]. their contents, enhancing their efficacy in treating can-
This leakage in the blood vessel wall makes it possible cer. However, the particle size of the drug is crucial since
for chemical drugs to reach tumors. Figure 9 highlights regular particles cannot enter malignant cells unless they
the importance of the characteristics of nanoparticles in are very small. However, because of impaired lymphatic
their ability to be delivered systemically to tumors. These drainage, nanoparticles and their associated chemical
Fig. 9 The characteristics of nanoparticles impact their ability to be delivered systemically to tumors. Nanoparticles are composed of various
materials and possess different physical and chemical attributes, such as size, shape, surface properties, and flexibility, and can be modified
with diverse ligands to target tumors. These properties influence the biological mechanisms involved in delivering nanoparticles to tumors,
including interactions with serum proteins, circulation in the bloodstream, distribution throughout the body, penetration through the tumor’s
blood vessels and tissues, targeting of tumor cells, and intracellular movement. Additionally, nanoparticles can be engineered to control the release
of their contents. Reprint from [177] with a permission from Springer Nature
medication carriers may rapidly permeate targeted areas differently than traditional chemical treatments, poly-
and concentrate there [105]. meric nanoparticles may carry a wide variety of chemi-
The high surface-to-volume ratio of PNPs is similar cals to specific areas [88]. Anticancer medicines, small
to that of nanoscale particles, making it easy to attach interfering RNAs (siRNA), radionuclides, and ultrasonic
targeting polymers to the particle’s surface [13]. Bioa- wave-reactive polymeric nanoparticles are all examples
vailability may be improved by coating polymers with pol- of such compounds. Fluorescent polymeric nanoparticles
ysorbates since this makes use of the surfactant activity have been shown to be valuable tools in the area of ther-
of polysorbates by solubilizing and fluidizing endothelial agnostics. The phrase "theragnostic" refers to a procedure
cell membranes [10, 12]. By having a coating on their sur- that combines "diagnosis" and "treatment" in the same
face, PNPs are better able to interact with the endothelial sentence. Fluorescent polymeric nanoparticles (FNPs)
cells that make up the blood–brain barrier (BBB), facili- have recently come to the forefront as a promising new
tating their endocytosis. Because new nanocarriers work therapeutic material. Complex nanomaterial structures
might be designed to serve dual diagnostic and therapeu- mice with MCF-7 tumor xenografts. The in vivo fluores-
tic purposes [142]. Fluorescent protein networks (FNPs) cence images show that the Dox/Ce6 nanoparticles pro-
are typically constructed from biocompatible biopoly- duced a much stronger fluorescence signal in the tumor
mers, inorganic quantum dots, organic dyes, and fluores- tissue compared to the free Ce6 solution. The ex vivo
cent proteins [49]. To improve nanomedicine’s efficacy fluorescence images also reveal that the nanoparticles
against cancer, drugs might be loaded through bonds or have accumulated significantly in the tumor tissue and
hydrophobic contacts in fluorescence tests. Not only is not in other organs. This co-assembly of the drug and
this in addition to imaging for tumors, but it is an inte- the photosensitizer could potentially improve the moni-
gral part of it. Delivering siRNA more efficiently in vivo toring of tumor response to treatment and thus improve
has been shown using cyclodextrin polymer (CDP)-based cancer management. To further facilitate the controlled
nanoparticles. Research has revealed that adamantane- release of chemical treatments, ultrasound may be used
polyethylene glycol (AD-PEG) modified with transferrin as a planned trigger. This is possible because ultrasonic
and adamantane-PEG-transferrin (AD-PEG-Tf ) are both can generate a heat effect, which may finally cause the
effective in vivo nucleic acid delivery vehicles [49]. Nano- nanoparticles to fracture [15]. Because ultrasound has a
particles might be used to encapsulate radionuclides like heating impact, it allows for this to happen. There is evi-
I125 by a technique called electrophilic aromatic sub- dence that certain polymeric nanoparticles undergo haz-
stitution, which leads to high radiochemical yields. This ardous breakdown and toxic monomer aggregation, so
easy procedure might be used to keep the radioactive additional study is needed to improve the manufacturing
substance in the core where it is most stable [178, 179]. of these nanoparticles and their chemical characteristics
Dey created an 11 nm-diameter, self-assembling peptide/ [110].
protein nanoparticle. This nanoparticle performed well Lymphatic drainage refers to the natural clearance
in terms of biocompatibility and in vivo stability, suggest- mechanism of the lymphatic system, responsible for
ing it might be useful for drug delivery in cancer therapy draining interstitial fluid and foreign particles from tis-
[57]. Figure 10 illustrates the use of hydrogel as a means sues [181]. In the context of nanomedicine delivery, lym-
to control drug delivery. The process of preparing and phatic drainage plays a critical role. It leads to the rapid
releasing drugs from Salecan/PMAA semi-IPN hydro- clearance of nanoparticles from the injection site, reduc-
gels is shown in (Fig. 10-A). In (Fig. 10-B), the in vitro ing their retention and bioavailability at the target site.
behavior of Dox release from the semi-IPN sample under This can be particularly problematic for nanomedicines
two different pH values is depicted. The images obtained designed for targeted drug delivery or immunotherapy
using fluorescent microscopy of A549 and HepG2 cells in lymph nodes [182]. Additionally, if nanomedicines
after 4 h of incubation with 6 μg/mL free Dox solutions enter the systemic circulation due to lymphatic drain-
and the extract liquid of Dox-loaded hydrogel are shown age, there’s an increased risk of systemic toxicity and
in (Fig. 10-C). Lastly, real-time fluorescence images of side effects associated with these therapeutic agents
FITC-labeled PMAA nanohydrogels in ICR mice are pre- [183]. Vessel wall leakage, or the permeability of blood
sented in (Fig. 10-D). The use of hydrogels as a vehicle vessel walls, has a significant impact on the distribution
for controlling drug delivery is a promising method that of nanomedicines in the body [184]. The enhanced per-
can improve the efficacy and safety of drug therapies by meability and retention (EPR) effect, a result of vessel
providing controlled and sustained release of drugs at wall leakage in tumor vasculature, can be harnessed for
specific sites. Recently, ultrasound-sensitive polymeric the targeted delivery of nanomedicines to cancerous tis-
nanoparticles have emerged as a useful tool for cancer sues. This effect allows nanomedicines to accumulate in
diagnosis and treatment. Applications for ultrasound- tumor tissues, improving treatment efficacy for cancer
interactive nanoparticles have multiplied [89]. Ultra- patients [185]. However, vessel wall leakage in normal
sound is employed in the synthesis of NPs to improve vasculature can also lead to non-specific drug delivery
their distribution efficiency; this, in turn, reduces the to healthy tissues, increasing the risk of off-target effects
likelihood of adverse effects from the increased ability to [184]. The extent of vessel wall leakage can vary based on
overcome barriers to cancer therapy. These include the factors like inflammation, disease state, and the formu-
nuclear membrane, interstitium, interstitial fluid, and lation of the nanomedicine. Researchers and scientists
the endothelium that lines blood vessels and tissue [15]. have developed various strategies to mitigate the impact
Figure 11 shows a new method for improving tumor size of lymphatic drainage and vessel wall leakage on nano-
imaging during treatment. The approach involves the medicine delivery. These strategies include engineer-
co-assembly of a drug called DOX and a photosensitizer ing nanoparticles with surface modifications that help
named Ce6 to form carrier-free nanoparticles. The nano- evade lymphatic drainage, thus prolonging their circu-
particles were tested in vivo and ex vivo on Balb/c nude lation time and improving targeting. Utilizing targeting
Fig. 10 The use of hydrogel as a vehicle for controlling drug delivery. A the process of preparing and releasing drugs from Salecan/PMAA semi-IPN
hydrogels; B the in vitro behavior of Dox release from the semi-IPN sample under two different pH values; C images obtained using fluorescent
microscopy of A549 and HepG2 cells after 4 h of incubation with 6 μg/mL free Dox solutions and the extract liquid of Dox-loaded hydrogel; and (D)
real-time fluorescence images of FITC-labeled PMAA nanohydrogels in ICR mice. Reprint from [180] with a permission from Springer Nature
ligands for active uptake by specific cells or tissues is prolong circulation by reducing lymphatic drainage, thus
another approach, enhancing precision and reducing enhancing retention at the target site. Antibody–drug
off-target effects [183]. Nanocarrier design plays a role conjugates (ADCs) in targeted cancer therapy dem-
in exploiting the EPR effect while minimizing non-spe- onstrate specific cell targeting, minimizing off-target
cific leakage. Additionally, developing drug formula- effects [184]. Liposomal amphotericin B (AmBisome)
tions with controlled release profiles can help sustain for fungal infections showcases controlled release, which
therapeutic effects and reduce systemic toxicity. Several not only ensures sustained therapeutic effects but also
case studies exemplify the impact of lymphatic drain- minimizes systemic toxicity. These case studies illustrate
age and vessel wall leakage on nanomedicine delivery. how different nanomedicine formulations and strategies
Liposomal doxorubicin (Doxil), for instance, effectively can be tailored to optimize drug delivery based on the
utilizes the EPR effect to target tumor tissues in cancer interplay between lymphatic drainage and vessel wall
therapy [185]. PEGylated nanoparticles are designed to leakage [183].
Fig. 11 The co-assembly of a drug and a photosensitizer to improve tumor size imaging during treatment. A A diagram illustrating the creation
of carrier-free nanoparticles (NPs) through the co-assembly of DOX and Ce6. B In vivo fluorescence images of free Ce6 solution and Dox/
Ce6 nanoparticles (NPs) are presented. The black circles indicate the tumor tissue. C Representative ex vivo fluorescence images of the tumor
and organs from Balb/c nude mice xenografted with MCF-7 tumor, 24 h after injection, are displayed. Reprint from [180] with a permission
The advancement of nanotechnology in cancer ther- minimizing the harm to healthy tissues [188]. The impact
apy represents a remarkable leap forward in the quest of nanotechnology in cancer therapy is already being felt
to combat this devastating disease [64]. The use of in the realm of clinical translation [186]. While there have
nanoscale materials and engineered carriers has intro- been numerous exciting developments in the laboratory,
duced a level of precision and specificity that was pre- translating these findings to the clinic remains a complex
viously unimaginable in cancer treatment [126]. One of challenge [63]. Regulatory approvals, safety assessments,
the key qualities of nanotechnology in this context is its and scalability are among the hurdles that researchers
ability to target cancer cells with unprecedented accuracy and pharmaceutical companies must overcome [186].
[186]. By designing nanoparticles or nanocarriers that Nevertheless, several nanocarriers and formulations have
can selectively seek out and bind to cancerous cells while successfully made their way into clinical trials and, in
sparing healthy tissue, nanotechnology offers a highly some cases, received authorization for clinical use [187].
targeted approach to therapy. This selectivity minimizes These early successes demonstrate the tangible impact
the collateral damage associated with conventional of nanotechnology in cancer therapy, offering patients
treatments like chemotherapy, reducing side effects and new hope and treatment options. As researchers con-
improving the overall quality of life for cancer patients tinue to refine and expand upon these technologies, the
[63]. Furthermore, nanotechnology has the potential future holds even greater promise for harnessing nano-
to enhance the delivery of therapeutic agents to tumor technology’s full potential in the fight against cancer. In
sites. These nanocarriers can carry a variety of payloads, addition to improving the precision and effectiveness of
including chemotherapy drugs, antibodies, or nucleic cancer treatment, nanotechnology is also contributing
acids, and release them specifically within the tumor to advancements in cancer diagnosis and monitoring
microenvironment. This not only increases the effective- [64]. Nanoscale materials can be engineered to detect
ness of the treatment but also reduces the systemic expo- specific biomarkers or tumor-associated molecules at
sure to toxic agents, mitigating adverse effects [187]. The incredibly low concentrations. This capability has paved
ability to encapsulate and deliver drugs precisely where the way for highly sensitive diagnostic tests and imag-
they are needed within the body has the potential to sig- ing techniques that can detect cancer at its earliest stages
nificantly improve the efficacy of cancer therapies while when treatment is often most successful [187]. These
diagnostic tools not only aid in early detection but also Monoclonal nanoparticle antibodies
allow for real-time monitoring of a patient’s response to Figure 12 illustrates the various types of targeting mole-
therapy, enabling healthcare providers to make timely cules that can be used in medicine, including monoclo-
adjustments to treatment plans [186]. Furthermore, the nal antibodies, non-antibody ligands, and aptamers.
interdisciplinary nature of nanotechnology has fostered Enzymatic cleavage or molecular biology techniques can
collaborations between experts in various fields, such be used to create antibody fragments such as F(ab’)2,
as chemistry, biology, physics, and engineering [187]. Fab’, scFv, and bivalent scFv (Diabody). Non-antibody
This interdisciplinary approach has accelerated progress ligands can include vitamins, carbohydrates, peptides,
in cancer research and led to innovative solutions that and other proteins, while aptamers can be composed of
would not have been possible without nanotechnology. either DNA or RNA. The panel also shows how affinity
It has also spurred the development of novel theranos- and selectivity can be improved through ligand dimeri-
tic approaches, where diagnostics and therapy are com- zation or by screening for conformational-sensitive tar-
bined into a single nanoscale system, offering a holistic geting agents such as affibodies, avimers, nanobodies, as
approach to cancer care [63]. Despite these promising well as intact antibodies and their fragments. These
developments, challenges in clinical translation persist techniques can help to create more effective and precise
[186]. Issues related to the long-term safety and biocom- targeting agents for use in medical treatments. There
patibility of nanomaterials, as well as concerns about have been some promising recent advancements in the
potential unforeseen side effects, must be thoroughly realm of mAb nanoparticles. Due to their specific target-
addressed [64]. Additionally, the cost of manufacturing ing ability and anti-tumor efficacy, monoclonal antibod-
and scaling up nanocarrier production can be prohibi- ies (mAbs) are widely utilized in the area of targeted
tive. Regulatory agencies around the world are working treatment [189]. The use of mAbs in the creation of
to establish clear guidelines for the approval of nanotech- novel anti-tumor nanoplatforms has also been a driving
nology-based cancer therapies, but the process remains force in the field in recent years. Improved specificity
complex [186]. and reduced toxicity may be obtained by directing the
Fig. 12 Different types of targeting agents and strategies to enhance their affinity and selectivity in two parts. Part a shows various targeting
molecules, such as monoclonal antibodies or fragments, non-antibody ligands, and aptamers. Antibody fragments, such as F(ab’)2 and Fab’, are
generated by enzymatic cleavage, while molecular biology techniques produce Fab’, scFv, and bivalent scFv (diabody) fragments. The antibody
structure comprises the variable heavy chain (vH), variable light chain (vL), constant heavy chain (CH), and constant light chain (CL). Non-antibody
ligands consist of vitamins, carbohydrates, peptides, and other proteins. Aptamers can be made up of DNA or RNA. Part b outlines methods
to enhance affinity and selectivity, such as ligand dimerization or screening for conformation-sensitive targeting agents like affibodies, avimers,
and nanobodies. Ligand dimerization involves linking two ligands together, which increases binding affinity. Conformation-sensitive targeting
agents are proteins that recognize specific three-dimensional structures and differentiate between closely related molecules. Intact antibodies
and their fragments are also useful for enhancing affinity and selectivity. Reprint from [132] with a permission from Springer Nature
drug combination toward antigens that are differentially cytotoxicity was seen in the control of human breast epi-
expressed between malignant and healthy cells [189]. An thelial cells when using the NP complex [35]. Numerous
antibody–drug conjugate (ADC) is a method of boosting studies are currently being conducted on trastuzumab
the effectiveness of anticancer medications in treatment. nanoparticles (NPs) based on the ADC mechanism as
Cytotoxic medicines are attached to mAbs [49, 50]. potential nanoplatforms in the treatment of cancer
Patients with breast cancer and an overexpression of [189]. Two HER2-positive cell lines and one HER2-nega-
human epidermal growth factor receptor 2 are often tive cell line were given the novel NP, PTX, and trastu-
administered the monoclonal antibody Herceptin (or zumab, respectively. The results were promising: the NP
trastuzumab) (HER2) [190]. The use of trastuzumab complex showed better anti-tumor efficacy than PTX or
(Tmab) in the ADC system has been studied, and the trastuzumab [49, 50]. Figure 13-A provides an overview
findings imply increased therapy efficacy compared to of the structural development of mAbs and highlights
utilizing Tmab alone [49, 50]. Using paclitaxel (PTX) as their various functions, which can range from antago-
the core medication and trastuzumab as the surface nism to signaling, mediated by specific regions within
modification, Abedin et al. developed an antibody–drug the mAb structure. The structure of an immunoglobulin
nanoparticle [189]. This kind of nanoparticle proved G (IgG) mAb is schematically represented in Fig. 13-A-a.
effective in its targeting of breast cancer cells. Better It consists of a Fab region and an Fc region. The Fab
anti-tumor activity was shown with the NP complex region contains variable (V) regions that bind to specific
compared to either PTX or trastuzumab alone, and less targets, and it has undergone modifications in the
Fig. 13 A The evolution and characteristics of monoclonal antibodies (mAbs) in terms of their structure and function. The different types
of mAbs that have been developed over time, starting from murine mAbs and progressing to chimeric mAbs, humanized mAbs, and fully human
mAbs. Reprint from [191] with a permission from Lancet Publishing Group. B Various strategies employed in monoclonal antibody (mAb) cancer
therapeutics. Various strategies employed in monoclonal antibody (mAb) cancer therapeutics include targeting specific cancer cell surface
antigens, blocking signaling pathways crucial for tumor growth, enhancing the immune system’s ability to recognize and destroy cancer cells,
and conjugating mAbs with toxins to deliver targeted cytotoxic effects. These diverse approaches have contributed to the success of mAb therapies
in treating cancer. Reprint from [192] with a permission from Springer Nature. C The mechanisms of action of monoclonal antibodies (mAbs)
that specifically target cancer cells. These mAbs exert their antitumor effects through various means, which are commonly studied in laboratory
settings. However, determining the individual contributions of these mechanisms to the clinical responses observed during mAb therapy
is challenging. Reprint from [192] with a permission from Springer Nature
development of mAbs. Murine mAbs initially had fully other arm (Fig. 13-B-f ) (e.g., linatumomab). Another
murine V regions, while chimeric mAbs had murine V approach involves a gene therapy technique where DNA
regions grafted onto human constant (C) regions. for a mAb variable region fused to signaling peptides is
Humanized mAbs retained a human Ig scaffold, with transferred to T cells, thereby creating chimeric antigen
only the complementarity-determining regions (CDRs) receptor (CAR) T cells (Fig. 13-B-g) that specifically tar-
derived from murine origin. Finally, fully human mAbs get tumors. In the figure, several key molecules are
were generated, indicating that their entire structure is labeled, including CD3, CTLA4, PD1, PDL1, VEGF, and
derived from human components. The Fc region of a VEGFR, which play important roles in these therapeutic
mAb includes the hinge and constant heavy-chain strategies [192]. Figure 13-C illustrates the mechanisms
domains (CH2 and CH3) and serves various functions by which monoclonal antibodies (mAbs) that target can-
such as complement fixation or binding to Fc receptors. cer cells exert their anti-tumor effects. One mechanism
The nomenclature of mAbs reflects their type, with indi- involves the ability of mAbs to facilitate antibody-
cators like ’xi’ for chimeric mAbs (e.g., rituximab). Fig- dependent cellular cytotoxicity (ADCC) by engaging
ure 13-A-b of the figure highlights the functions of immune effector cells expressing immunoreceptor tyros-
mAbs, which are influenced by specific CDRs within the ine-based activation motifs (ITAMs). Examples of such
Fab region. Some mAbs can bind to ligands or receptors, cells include natural killer (NK) cells, monocytes, mac-
preventing their stimulation and exhibiting antagonism. rophages, and granulocytes. Upon binding to cancer
Examples of ligand-binding mAbs are infliximab and cells, the mAbs can trigger ADCC, leading to the
omalizumab, while receptor-binding mAbs include destruction of the target cells. Additionally, the fixation
natalizumab and daclizumab. On the other hand, certain of complement, a component of the immune system, can
mAbs can induce signal transduction by binding to enhance the process by promoting opsonization (coating
receptors. TGN1412, a CD28 superagonist, is an exam- of the target cell) and facilitating phagocytosis and lysis
ple of a mAb that activates T-cells without the need for by monocytes and granulocytes. Complement-mediated
T-cell receptor ligation. The Fc region of mAbs controls cytotoxicity (CMC) can directly induce target cell death
additional functions, such as complement-dependent through the formation of a membrane attack complex
cytotoxicity (CDC), antibody-dependent cell-mediated (MAC) (Fig. 13-C-a). Another mechanism employed by
cytotoxicity (ADCC), and antibody-dependent cellular mAbs involves their direct effects on target cells. They
phagocytosis. CDC involves cell lysis through comple- can block the binding of activating ligands responsible
ment activation, while ADCC involves the binding of for the survival of cancer cells. By doing so, mAbs pre-
mAbs to Fc receptors, leading to cell lysis. Furthermore, vent the activation signal from reaching the cancer cells,
the binding of mAbs to the neonatal Fc receptor influ- inhibiting their growth and survival. Additionally, mAbs
ences their transport across cell barriers and affects their can inhibit receptor dimerization, which is necessary for
half-life [191]. Figure 13-B illustrates various monoclo- activation, thereby blocking the activation signal. Fur-
nal antibody-based therapeutic strategies for cancer thermore, mAbs can induce an apoptotic signal in can-
treatment. The immunoglobulin G (IgG) molecules can cer cells by crosslinking specific receptors. This receptor
bind to cancer cells (Fig. 13-B-a) and trigger immune crosslinking can be enhanced when mAbs are bound to
effector cells to carry out antibody-dependent cellular Fc receptor-expressing cells. The Fc receptor-binding
cytotoxicity (ADCC). They can also induce complement- promotes the clustering of mAbs and enhances the
mediated cytotoxicity (CMC) or directly induce the apoptotic signal. Immunoglobulin G (IgG) is the sub-
death of cancer cells through signaling pathways (e.g., class of antibodies commonly used in this context
herceptin and rituximab). In addition, IgG mAbs can (Fig. 13-C-B) [192].
hinder angiogenesis (Fig. 13-B-b) (e.g., bevacizumab) or
block inhibitory signals (part c), resulting in a stronger T Membrane‑bound packets are found outside of cells
cell response against tumors (e.g., ipilimumab and Bilayer phospholipids make up EVs,. The vast majority of
nivolumab). Radioimmunoconjugates (part d) (e.g., 131I extracellular vacuoles can be classified into three broad
tositumomab and ibritumomab tiuxetan) deliver radioi- groups: exosomes, microvesicles, and apoptotic bodies
sotopes to cancer cells, while antibody–drug conjugates (EVs). Exosomes are 40–200 nm nano-scale particles.
(Fig. 13-B-e) (e.g., brentuximab vedotin and trastuzumab EVs are involved in long-distance communication and
emtansine) deliver potent toxic drugs to cancer cells. have the capacity to transport protein, RNA, and DNA
The variable regions of mAbs are also utilized to redirect in their bodies [96]. Exosome NPs are natural carriers
immune effector cells towards cancer cells using bispe- that may be used with known anti-tumor compositions
cific mAbs that recognize cancer cells with one arm and and procedures. This is owing to the fact that the mem-
activating antigens on immune effector cells with the brane of exosomes includes lipids and chemicals that are
comparable to those present in the cells from whence in the field of nanomedicine, have been harnessed to
they originated [15]. This enables exosome NPs to avoid target and deliver therapeutic payloads to these tumor
immune monitoring and integrate seamlessly with tar- cell exosomes. By encapsulating drugs or genetic mate-
get cells. In order to be successful in treating cancer, rial within nanocarriers, researchers can achieve precise
gene therapy requires the use of DNA and RNA. In gene and efficient drug delivery to cancer cells [198]. Addi-
therapy, various alternative ways are being researched tionally, membrane-bound packets, akin to exosomes
[30]. These include reactivating mutated proto-onco- but originating from different cellular sources, can also
genes like p53, inhibitor of growth 4 (ING4), and phos- be found outside of cells and are under investigation
phatase and tensin homolog (PTEN), as well as gene for their potential in therapeutic applications. Under-
editing with the clustered regularly interspaced short standing the intricate interactions between tumor cell
palindromic repeats (CRISPR)-associated proteins (Cas) exosomes, nanocarriers, and membrane-bound packets
system, which inhibits the activity of key oncogenes. offers promising avenues for developing innovative can-
Some of these small RNAs, such as siRNAs and micro- cer treatments [199].
RNAs, may trigger RNAi (RNA interference) (miRNAs)
[193]. Multiple physiological and pathological processes Lipid‑based nanomaterials
include RNA interference (RNAi). Research using siRNA The three primary types of lipid carriers that have
to target oncogenic mRNAs is currently being assessed. been the focus of recent studies and clinical trials are
Gene therapy is another way that may be used to deliver liposomes, solid lipid nanoparticles (SLNs), and nano-
a transgene or a cell death-inducing gene to cancer cells structured lipid carriers. Figure 14 illustrates the cur-
[194, 195]. Exosomes have been successfully used as rent advancements in the field of delivering genetic drugs
nanoparticle platforms for the delivery of nucleic acids, using self-assembled nanoparticles made from lipid and
tiny chemicals, and proteins [30]. Human breast cancer polymer materials. The study of lipid-based nanomate-
cells were treated with doxorubicin-loaded exosomes by rials is growing, with a particular focus on these three
the group of Hadla et al. (exoDOX). The findings demon- areas (NLCs) [57]. It wasn’t until 1965 that liposomes
strated that exoDOX enhances doxorubicin’s cytotoxicity received formal recognition as the first encapsulated tiny
and prevents drug accumulation in the heart compared phospholipid bilayer nanosystem. Liposomes are vesicles
to free doxorubicin [174]. Targeted delivery in the treat- that may be either spherical or ovoid and are composed
ment of cancer may be possible via the engineering of mostly of phospholipids. On average, a liposome may
exosomes. Macrophage-derived exosomes were modified range in size from 20 nm to over 1 µm [13]. The hydro-
using an aminoethylanisamide-polyethylene glycol (AA- phobic phospholipid bilayer surrounding the hydro-
PEG) moiety, and subsequently PTX was transferred philic center is what makes up a liposome. This kind of
to the modified exosomes [30]. The modified exosome structure may entrap both hydrophilic and hydrophobic
greatly improved therapy effectiveness in a mouse model medications, depending on the pharmacokinetic prop-
of lung metastases. Jeong et al. used exosomes to deliver erties of the treatment [13]. In a recent groundbreaking
miR-497 (microRNA-497) to A549 cells. These data sug- study conducted by Rosenblum et al., the limitations of
gest that an exosome-mediated miRNA therapy might be CRISPR-Cas9 technology in cancer therapeutics have
employed for the targeted treatment of cancer, since both been addressed through the development of a novel
tumor growth and the expression of associated genes delivery system. The study highlights the challenges of
were suppressed [169]. In contrast to synthetic nano- low editing efficiency in tumors and potential toxicity
particles, exosome nanoparticles benefit from inherent associated with existing delivery methods. The research
biocompatibility, higher chemical stability, and the abil- introduces a promising solution in the form of LNPs spe-
ity to regulate intercellular connections (NPs). However, cifically engineered for targeted delivery of Cas9 mRNA
there are obstacles to the widespread use of exosome NP, and sgRNAs. These LNPs utilize an innovative amino-
including the lack of standardized criteria for isolating ionizable lipid, which significantly enhances their safety
and purifying exosomal components; the lack of a well- and efficiency. In the context of cancer treatment, the
defined mechanism for exosomes’ role in cancer therapy; researchers demonstrated the remarkable potential of
the phenomenon of heterogeneity; and the difficulty of these LNPs. Intracerebral injection of CRISPR-LNPs
preserving exosomes [30]. Tumor cell exosomes are min- against PLK1 into glioblastoma resulted in up to ~ 70%
ute vesicles secreted by cancer cells that play a pivotal gene editing in vivo, leading to tumor cell apoptosis, a
role in intercellular communication and the progression 50% reduction in tumor growth, and a 30% improvement
of cancer [196]. These exosomes are found outside of in survival. Furthermore, LNPs engineered for antibody-
cells, typically circulating in bodily fluids such as blood targeted delivery exhibited exceptional efficacy against
and urine [197]. Nanocarriers, a cutting-edge technology disseminated ovarian tumors, achieving up to ~ 80% gene
Fig. 14 The cutting-edge development in the field of genetic drug delivery using self-assembled nanoparticles made from lipid and polymer
materials. Currently, the most advanced system for delivering genetic drugs in clinical settings is lipid nanoparticles incorporating an ionizable
lipid. These materials contain a tertiary amine that can acquire a charge at acidic pH, enabling the loading of nucleic acids during formulation
and facilitating their release from endosomes after cellular uptake. Examples of ionizable lipids include Dilinoleylmethyl-4-dimethylaminobuty
rate (DLin-MC3-DMA) found in the FDA-approved drug Onpattro, LP-01 in Intellia Therapeutics’ clinical candidates NTLA-2001 and NTLA-2002
for liver gene editing, and SM-102 and ALC-315, which are ionizable lipid components of the Moderna and Pfizer-BioNTech vaccines, respectively.
Alternatively, certain polymers containing ionizable amine groups can also be utilized for nanoparticle formulation, with the choice of monomers
affecting delivery efficiency and tissue selectivity. In both ionizable lipids and polymers, additional components can be added to enhance
nanoparticle stability, fusogenicity (ability to merge with cellular membranes), and selectivity. Furthermore, the surfaces of these nanoparticles can
be modified using synthetic or biological targeting ligands and stealth coatings to alter their circulation time, biodistribution, and cellular uptake.
By loading nucleic acid biomolecules into nanoparticles, it becomes possible to reprogram the fundamental principles of biology through gene
silencing, expression, and editing to correct disease processes. 18:1 PA (1,2-dioleoyl-sn-glycero-3-phosphatidic acid), CART (charge-altering
releasable transporter), DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), DOTAP (1,2-dioleoyl-3-trimethylammonium-propane), DSPC
(1,2-distearoyl-sn-glycero-3-phosphocholine), PBAE (poly(beta-amino ester)), PEI (polyethyleneimine), SORT (selective organ targeting). Reprint
from [200] with a permission from Springer Nature
editing in vivo, suppressing tumor growth, and increas- bilayer can protect hydrophobic drugs. The core chamber
ing survival by 80%. This innovative approach to CRISPR- of the liposome protects the medications from the exter-
Cas9 genome editing, utilizing nanocarriers, opens new nal environment as they travel through the circulatory
avenues for cancer treatment and research, showcasing system of a person [216]. Based on their size and the
its potential for precise gene editing not only in cancer- number of bilayers, liposomes may be divided into two
ous tissues but also in noncancerous ones [98]. Table 8 categories: unilamellar vesicles and multilamellar vesi-
presents the pharmacokinetic profiles of various nano- cles. Both the loading quantity and the half-life of medi-
carrier-loaded drugs. cines are affected by the size and number of bilayers
Liposomes are normally structured such that the water (MLV). Little SUVs and large SUVs are both types of uni-
core can encapsulate hydrophilic drugs while the lipid lamellar vesicles (LUV) [13, 216]. The structure of
Table 8 Pharmacokinetic profiles of nanocarrier-loaded drugs

Drug Type Administration Route Pharmacokinetic Clearance Pathway Drug Interaction Therapeutic References
Parameter Window
Doxorubicin Intravenous Area Under Curve (AUC) Hepatic Metabolism P-glycoprotein Narrow [201]
Paclitaxel Intravenous Half-life Renal Excretion Cytochrome P450 Wide [57]
Cisplatin Intraperitoneal Volume of Distribution Renal Excretion None Narrow [90, 102]
Irinotecan Oral Bioavailability Hepatic Metabolism UDP-glucuronosyltrans‑ Wide [202]
ferase
Methotrexate Intrathecal Cerebrospinal Fluid Con‑ Renal Excretion None Narrow [99]
centration
Gemcitabine Intravenous Clearance Rate Renal Excretion Deoxycytidine Kinase Wide [203]
Etoposide Intravenous Distribution Half-life Hepatic Metabolism Cytochrome P450 Wide [204]
Oxaliplatin Intravenous Total Clearance Renal Excretion None Narrow [205]
Topotecan Oral Bioavailability Hepatic Metabolism Cytochrome P450 Narrow [206]
Docetaxel Intravenous Protein Binding Hepatic Metabolism P-glycoprotein Wide [207]
Methotrexate Intravenous Clearance Renal Excretion None Narrow [208]
Trastuzumab Intravenous Volume of Distribution Proteolysis None Wide [189]
Docetaxel Intravenous Protein Binding Hepatic Metabolism P-glycoprotein Wide [117]
Bleomycin Intravenous Half-life Renal Excretion None Narrow [209]
Vinorelbine Oral Bioavailability Hepatic Metabolism P-glycoprotein Wide [210]
Daunorubicin Intravenous AUC Hepatic Metabolism P-glycoprotein Narrow [211]
Cisplatin Intravenous Half-life Renal Excretion None Narrow [212]
Pemetrexed Intravenous Protein Binding Renal Excretion None Narrow [213]
Everolimus Oral Bioavailability Hepatic Metabolism Cytochrome P450 Wide [214]
Tamoxifen Oral Clearance Hepatic Metabolism None Wide [215]
multilamellar liposomes resembles that of an onion. On when compared to other modified liposomes. Based on
the other hand, multilamellar concentric phospholipid these results, PEG-liposomes containing doxorubicin
spheres separated by water molecules may be created by (commonly known as DOX) were utilized to treat Kapo-
the formation of multiple unilamellar vesicles inside si’s sarcoma in HIV patients. Drug loading and controlled
other vesicles [92]. According to the results of extensive release of liposomes are only two of the many important
research on nanocarriers, modern liposomes exhibit a considerations that must be made during the design of
variety of distinguishable qualities and properties, and as liposome nanocarriers [90, 102]. Drug bioavailability has
a direct consequence, new applications based on lipo- a role in how well cancer treatment works. Because DOX
some materials have emerged [92]. Three major issues liposome bioavailability is lower than that of free DOX,
have been uncovered and addressed through the process designers of liposomes should work to improve bioavail-
of developing liposomes. The research community has ability [169]. The bioavailability of free DOX is greater.
been struggling to overcome biological hurdles and slow Liposomes have several applications, but controlled
the rapid clearance of their results. As was said previ- release and simultaneous administration are two of the
ously, one of the biggest technical hurdles confronting most significant [90, 102]. Chemical treatments, metals,
nanocarriers has always been getting past biological bar- gene agents, and others have been combined to create
riers [57]. Nanoliposomes are protected by cells of the chemotherapeutic cocktail drugs. Figure 15-A illustrates
human body’s mononuclear phagocyte system (MPS), the pathway of a nanoparticle within the human body
which are mostly located in the liver and spleen. Lipo- after being injected intravenously.Overactivation of spe-
some membrane modification is a crucial method for cific signaling pathways is thought to contribute to the
increasing their stability. Coating the membrane with development of cancer, and drugs that interfere with
molecules like proteins, peptides, polymers, and other these pathways are used to treat the disease [167]. The
sorts of molecules may increase the half-lives of liposo- study showed that synergistic effects contributed to an
mal substances. This makes escaping the MPS system increase in the cytotoxic impact by loading a novel
much easier [217]. For obvious reasons, these liposomes PEGylated liposomal with ncl-240 and cobimetinib, both
were given the moniker "stealth." A polyethylene glycol of which are small-molecule inhibitors of the phosphoi-
conjugated liposome was shown to have a longer half-life nositide 3-kinase/mammalian target of rapamycin (PI3K/
Fig. 15 A The path of a tiny particle within the human body after it is injected intravenously. When the particle enters the bloodstream, it often
attracts plasma proteins, forming a layer called the protein corona on its surface. The composition of this corona is affected by the properties
and makeup of the particle’s surface. In order to reach the intended organ, the particle needs to leave the blood vessels (a process known
as extravasation) by either passing through gaps in the endothelium (a size-dependent mechanism) or actively interacting with specific receptors
on the endothelium through transcytosis. After extravasation, the particle must interact with target cells and be internalized by them. It must
then escape from the endosome into the cytosol and release its genetic payload. Throughout this journey, the particle can be eliminated
from the bloodstream through various mechanisms such as the mononuclear phagocytic system (MPS), hepatobiliary elimination via feces,
or renal excretion through urine. These processes restrict the amount of the injected particle dose that actually reaches the intended target site.
Therefore, measures must be taken to minimize their impact. Reprint from [200] with a permission from Springer Nature. B Lipid nanoparticles
have reached an advanced stage of development for delivering genetic drugs to the liver. a) The liver consists of four distinct types of cells.
When nanoparticles are present in the bloodstream, they can be captured by Kupffer cells, absorbed by liver sinusoidal endothelial cells,
or pass through the wide openings in the liver endothelium into the Space of Disse. In the Space of Disse, the nanoparticles can target hepatic
stellate cells or hepatocytes. The hepatobiliary system can eliminate nanoparticles from the body through the bile duct. b) A clinically validated
approach for delivering small interfering RNA to hepatocytes involves the natural targeting of liver cells. For instance, in the case of Onpattro lipid
nanoparticles, the polyethylene glycol (PEG) lipid on the surface of the nanoparticles is exchanged with apolipoprotein E (ApoE) in the blood. The
binding of ApoE to the nanoparticle surface enables its interaction with the low-density lipoprotein receptor (LDL-R), which is highly expressed
by hepatocytes, leading to endocytosis. c) Another way to actively target hepatocytes is by modifying the nanoparticle surface with a ligand called
N-acetylgalactosamine (GalNAc) and reducing non-specific protein binding through extensive PEGylation. GalNAc binds to the asialoglycoprotein
receptor 1 (ASGR1), facilitating the uptake of nanoparticles by hepatocytes. Therefore, certain measures need to be taken to minimize their effects.
Reprint from [200] with a permission from Springer Nature
mTOR) pathway and the mitogen-activated protein and the liposome also carried the delivery of DOX. This
kinase/extracellular signal-regulated protein Innovative enhanced the efficacy of DOX and led to a decrease in
liposomal nanocarriers containing irinotecan and floxur- the size of the tumor mass in the breast cancer patients
idine have been shown to be very successful in the treat- being treated. Both triggered release and target
ment of advanced solid tumors [218]. Due to its complex approaches are the subjects of much study at present
multilayer structure, a single bilayer of a special liposome [219]. To avoid pharmaceutical waste, liposomes might
was able to effectively carry up to 3500 siRNA molecules, be designed to release their contents exclusively in
cancerous regions, where the extracellular pH is some- SLNs are more stable and have a longer release time.
what lower than in healthy tissue. This is because malig- Also, their lipid components are stable at body tempera-
nant tissues typically have an extracellular pH value of 6.8 ture [99, 222]. Despite this, SLNs have a few downsides,
to 7.0. Carboxymethyl chitosan (CMCS) was coated on such as a high gelation propensity that can’t be predicted
the surface of the cationic liposome (CL) that was and a low integration rate that comes from the molecules’
preloaded with sorafenib (Sf ) and siRNA (Si), giving it crystalline form. There has been a significant increase in
the pH-sensitive characteristic [115]. The results of the the number of liposomes and SLN that have been modi-
experiments showed that sorafenib release was aided and fied to serve as NLC carriers during the last two decades
cellular absorption was increased at a pH of 6.5. In addi- [29, 99, 222]. The building blocks of NLCs are a core
tion to the pH-sensitive property, liposomes may be matrix filled with a combination of solid and liquid lipids.
made with a range of responsive qualities depending on This is done so that the NLCs may maintain their natural
the tumor microenvironment (TME) and the characteris- protective function, biocompatibility, and non-immuno-
tics of the drug. Among them are the reactions to oxygen genicity while also increasing their stability and loading
radicals, enzymes, and light [220]. As a word, "tumor capacity. Many different routes of administration exist for
microenvironment" describes the surrounding condi- NLCs, such as oral, intravenous, inhalational, and topical
tions that foster tumor development. The tumor micro- (through the eye). Many of the chemical compounds
environment (TME) promotes tumor growth, invasion, used in cancer therapy are lipophilic, which has sparked a
migration, angiogenesis, and inflammatory processes and lot of interest in NLCs in recent years [223]. Figure 15-B
is associated with drug resistance. Tumor microenviron- illustrates the significance of lipid nanoparticles as an
ment characteristics include EPR presence, hypoxia, aci- established technology for delivering genetic drugs to the
dosis, substantial angiogenesis, and tumor-associated liver.
immune cells that aid the immune system in avoiding
cancer cells (TME) [221]. In general, liposomes’ useful Nanoemulsions
properties include their ability to protect their cargo Nanoemulsions are a kind of colloidal nanoparticle com-
from enzyme degradation, as well as their low toxicity, prised of an aqueous phase, emulsifying agents, and oil.
biocompatibility, flexibility, high biodegradability, and The typical range of nanoemulsion size is between 10 and
lack of immunogenicity. Short shelf life, low encapsula- 1000 nm. Nanoemulsions are often used as medication
tion efficiency, unsatisfactory stability, rapid removal by nanocarriers [117]. Nanoemulsions are spherical, solid
MPS, cell adsorption, and intermembrane transfer are particles that are often negatively charged and have an
only some of the issues that prohibit liposomes from amorphous, lipophilic surface [223]. Due to their nature
being widely used. SLNs, for instance, may be anywhere as heterogeneous mixtures, nanoemulsions can be for-
from 1 to 100 nm, placing them in the category of colloi- mulated in three common configurations: (a) water in oil
dal nanocarriers [222]. Due to the extreme size con- nanoemulsion systems, in which water is dispersed in an
straints, SLNs are considered "zero-dimensional" aqueous medium; (b) oil in water nanoemulsion systems,
nanomaterials. That’s because, on the nanoscale, they’re in which oil is dispersed in an aqueous medium; Optical
at least one dimension different from similarly sized clarity, thermodynamic stability, a large surface area, easy
nanomaterials [178, 179]. Solid lipid nanoparticles (SLNs) production, biodegradability, and an ideal drug release
are a kind of liposome that lack the liquid components of profile are only a few of these advantages. Recent years
liposomes and are instead composed of solid lipid, an have seen much study of membrane-modified nanoe-
emulsifier, and water. The constituent parts of SLNs are mulsions [117]. Co-delivery via nanoemulsions is one
listed below. Lipides of many different types are used in strategy for improving both bioavailability and therapeu-
SLNs, from partial glycerides and triglycerides through tic efficacy. After a battery of studies, it was shown that
fatty acids, waxes, steroids, and PEGylated lipids SLNs a NE drug carrier system including spirulina polysac-
[99]. When comparing the structure and function of charides and PTX has the ability to boost PTX’s anti-
SLNs with regular liposomes, there are certain parallels tumor impact by modulating immunity through Toll-like
and differences. It is interesting to note the parallels receptor 4/nuclear factor kappa B (TLR4/NF-B) sign-
between the lipidic membrane and the transport role of aling pathways. Using the medications temozolomide,
chemical treatments. Certain SLNs lack a continuous rapamycin, and bevacizumab, a nanoemulsion system
bilayer, instead generating a micelle-like structure in was designed to successfully treat metastatic melanoma.
which drugs are contained in a non-aqueous core [99]. Melanoma cells were more sensitive to parenteral ther-
When compared to traditional liposomes, which are apy, and tumor recurrence, migration, and angiogenesis
composed of lipid bilayers surrounding an aqueous suppression were all improved [49, 50]. In vitro human
pocket, they are monolayers. Compared to liposomes, and animal cell models were used to show these results.
Nanoemulsions may find use in immunotherapy thanks zeta potential of -25 mV, indicating good stability [226,
to their ability to be loaded with targeted immune-stim- 227]. The storage condition at 4 °C for 6 months is suit-
ulating moieties. In order to keep the cytokine interferon able for maintaining stability, and the release kinetics
gamma (IFN-) stable for three months, it was encapsu- indicate that 20% of the cytokine is released within 24 h.
lated in a customized nanoemulsion that could with- This nanoemulsion appears promising for anti-inflamma-
stand extreme temperatures. Testing showed that this NE tory therapy [228, 229]. Another noteworthy formulation
decreased the survival of MCF-7 human breast cancer is for Tumor Necrosis Factor-alpha (TNF-α). While it
cells and boosted the activity of phagocytes, suggesting it has a slightly lower encapsulation efficiency of 85%, the
may have a positive function in the treatment of cancer particle size is larger at 150 nm, and the zeta potential is
[106]. One use of NE that has seen a surge in attention -20 mV. It is stored at room temperature for 3 months,
is as a strategy for avoiding MDR. The ABC transport- indicating stability under ambient conditions [230]. The
ers, or ATP-binding cassette transporters, play a role in release kinetics show a controlled release of 15% over
multidrug resistance (MDR) in cancer cells. Medications 48 h, making it a candidate for targeted cancer therapies
fail to work in cancer patients due to the expression of [227]. Additionally, the nanoemulsion designed for Inter-
MDR transporters, which are encoded by ABCs [115]. feron-gamma (IFN-γ) demonstrates impressive encapsu-
The first ABC transporter was identified as P-glycopro- lation efficiency at 95% [228, 229]. With a small particle
tein (P-gp). The drug efflux pump expressed by the ABC1 size of 80 nm and a zeta potential of -30 mV, it is well-
gene may expel the anticancer drugs colchicine, vin- suited for potential autoimmune disease therapy. The
blastine, etoposide, and paclitaxel (PCX) [224]. To over- extended storage at -20 °C for one year ensures long-term
come this obstacle, Meng and his colleagues developed a stability, and a slow release rate of 5% after 72 h suggests
novel nanoemulsion that administers both baicalein and controlled cytokine delivery. These formulations cater to
paclitaxel at once. Co-encapsulation of these two drugs various applications, such as immune modulation, anti-
boosted oxidative stress, leading to an effective strat- inflammatory therapy, and cancer targeting, highlighting
egy for enhancing cell sensitivity to paclitaxel [117]. For the versatility of nanoemulsions for delivering encapsu-
example, one study found that baicalein-paclitaxel NE lated cytokines [226, 227]. The selection of emulsifiers,
was more effective against tumors than standard pacli- lipid phases, and aqueous phases, along with specific
taxel preparations in an in-vivo setting. The study found storage conditions, plays a crucial role in optimizing the
that the activity of caspase-3 was raised in MCF-7/Tax stability and release kinetics of these nanoemulsions,
cells, whereas the production of reactive oxygen species ensuring their efficacy in diverse biomedical applications.
(ROS) and glutathione (GSH) in the cells was reduced. Researchers and practitioners can reference this table
These studies highlight the potential advantages of using to choose the most suitable nanoemulsion formulation
NEs designed specifically for the treatment of MDR. for their specific needs in cytokine delivery and therapy
Despite the advantages that NEs may provide in theory, [225].
putting them into practice is challenging [99]. Produc-
tion of NEs often requires harsh conditions, including Dendrimers
high temperatures and pressures. As a result, not all raw Dendrimers are a class of macromolecules distinguished
materials may be used for NE projects. This is one of the by their hyperbranched and tailored structures. The
obstacles that must be conquered before NEs can be used most noticeable characteristics of dendrimers are their
in commercial production on a significant scale [121]. highly branching and easily modifiable surfaces [43].
Due to the need for expensive high-energy equipment These dendrimer polymers normally have a diameter of
like homogenizers and microfluidizers, the cost of creat- between 1 and 10 nm, while some very large dendrim-
ing NE is much greater than that of more conventional ers may reach 14–15 nm in size. Dendrimer molecules
formulations. In order to determine whether or not NE is have a core that encapsulates theragnostic medicines in
safe for use in humans, we need to do extensive research a noncovalent fashion, a dendritic internal structure, and
on the interactions between the drug’s numerous compo- a functional surface group-conjugated outside surface
nents and the metabolism of NE in the body, which we [15]. Many dendrimers have been developed for the pur-
cannot do without first learning more about the chemis- pose of cancer therapy. These include polyamidoamine
try involved in its production [117, 121]. (PAMAM), polypropylenimine (PPI), polyethylene gly-
Different emulsion compositions have been tailored col (PEG), bis-MPA (2,2-bis(hydroxymethyl) propionic
for specific cytokines and applications [225]. For exam- acid), 5-ALA (5-aminolevulinic acid), and tetraethylenea-
ple, the nanoemulsion designed for Interleukin-6 (IL-6) mine (TEA) (triethanolamine) [15]. Dendrimers’ unique
boasts a high encapsulation efficiency of 90%. It has a structure provides a number of benefits over more typical
relatively moderate particle size of 120 nm and a negative nanomaterials. The benefits include better solubility and
bioavailability of hydrophobic medications; molecular industries and medical fields because of their superior
weight control; flexible branching; a low polydispersity electrical, thermal, optical, and mechanical proper-
index; and a narrow molecular size distribution. Because ties [208]. When compared to nanoparticles made from
of their capacity to form compounds with nucleic acids, metal, CNMs are thought to be safer and more biocom-
dendrimers are promising candidates for use as effi- patible for use in cancer diagnostics. CNMs may load
cient nanocarriers of nucleic acids, especially cationic chemical treatments through stacking or hydrophobic
dendrimers with positively charged surfaces [99]. Two interactions because of their inherent hydrophobic prop-
dendrimers that have seen much study and have sev- erty [232]. This makes it possible for CNMs to serve as
eral potential applications are PAMAM and PPI. With reliable medication delivery systems. Numerous stud-
fluorescence imaging as the driving force, a PAMAM ies have focused on the potential of carbon nanomate-
dendrimer/carbon dot nanohybrid was designed to rials for use in cancer treatment, including graphene,
simultaneously accomplish MDR control and cancer cell fullerene, carbon nanotubes (CNTs), carbon nanohorns
monitoring. During production, two separate complexes (CNHs), carbon quantum dots (CQDs), and graphyne
emerged. The first part was CDs/DOX, a molecule made (GDY) [208, 232]. Despite their shared carbon-based
up of blue-emitting carbon dots (CDs) and the antican- constituents, these nanomaterials display a wide range
cer drug DOX via non-covalent interactions [15, 99]. A of morphological forms, physical features, and func-
second portion, designated G5-RGD-TPGS, included tional applications. Graphene, or sp2-hybridized carbon,
generation 5 (G5) PAMAM dendrimers specific for the is a two-dimensional substance that consists of a single
cyclic arginine-glycine-aspartic (RGD) peptide and the layer of carbon atoms [233]. Because of how it’s built, it’s
drug efflux inhibitor d-alpha-tocopheryl polyethylene capable of some truly impressive mechanical and electri-
glycol 1000 succinate (TPGS). We employed electro- cal feats. This is in addition to the fact that it has been
static attraction to join the two components that would the focus of a great deal of research in the realm of bio-
ultimately form a nanohybrid system loaded with two logical applications, such as the prevention and treat-
drugs [48]. In vitro fluorescence was generated by the ment of cancer. Graphene-based nanomaterials may be
luminescence of CDs, and targeting specificity was gen- classified into four main types according to their chemi-
erated by the presence of RGD ligands, which target v3 cal composition, structural arrangement, and physical
integrin receptors that are overexpressed in cancer cells. properties: single-layer graphene; multi-layer graphene;
The results showed that TPGS significantly impeded graphene oxide (GO); and reduced graphene oxide (rGO)
the expansion of cancer cells. Dendrimers, with their [234]. Graphene’s optical transparency, chemical inert-
potential for co-delivery, may also be used to distribute ness, high density, molecular barrier-forming properties,
chemicals that have no obvious chemical relationship and high hydrophobicity are only a few of its remark-
[202]. DOX is often used to treat cancers of the colon. able electrochemical and mechanical properties. As its
The apoptotic pathway requires TRAIL, or tumor necro- name suggests, graphene only has two dimensions. Gra-
sis factor-related apoptosis-inducing ligand. Both death phene’s high planar surface permits a greater drug-load-
receptors 4, and 5, or DR4 and DR5, are overexpressed in ing capacity, and its thermal conductivity (5000 W/mK)
many types of cancer cells, and TRAIL can bind to both is also rather remarkable [170]. Graphene’s anti-cancer
of them [219]. The Pishavar team encapsulated plasmids capabilities come from both of these factors. However,
for both DOX and TRAIL in a dendrimer nanocarrier, poor solubility and the aggregation of nanosheets gen-
producing a nanocarrier with more anticancer effects erated by graphene in solution are induced by van der
than modified carriers carrying DOX or TRAIL alone. A Waals pressures and a-b stacking interactions. This sig-
PAMAN nanocarrier based on dendrimer was developed nificantly increases the difficulty of producing graphene
to treat liver cancer cells more effectively. Even though and also increases the toxicity of graphene [204]. In light
unmodified PAMAN dendrimers have problems like of these drawbacks, scientists have been on the lookout
low transfection efficiency, poor cell internalization, and for nanomaterials based on graphene that are both more
unstable encapsulation, the nanomaterial’s competitive bioavailable and easier to manufacture. It is expected
contrast properties show that it has a lot of potential in that these nanomaterials will be both easy to create and
combination therapy [231]. retain graphene’s advantageous properties [173]. Gra-
phene oxide (GO) is a modified form of graphene that
Nano‑scale carbon materials has undergone a chemical transformation. Carbonyl
For example, there are many types of carbon nanoma- (C = O) and epoxy (C–O–C) groups locate on the basal
terials (CNMs) that may be further subdivided into plane of graphene, whereas functional oxygen groups like
subgroups based on the presence or absence of other carboxyl (-COOH) and hydroxyl (C–OH) locate towards
elements besides carbon. CNMs are used in many the edge of graphene, forming a typical GO molecule.
The notation for the GO derivative in its reduced form is therapeutic strategy for preventing cancer. It is specu-
rGO [166]. When compared to graphene, GO and rGO lated that GO may specifically target CSCs while sparing
provide greater properties for usage in biological applica- healthy cells [237]. Additionally, it has been shown that
tions. Defective oxygen-bound sp3 carbon atoms exhibit GO can induce CSC differentiation and prevent the for-
strong hydrophilicity, which aids in the development of mation of tumor spheres in a variety of cell lines, includ-
colloidal dispersions in aqueous solvents that are very ing breast, ovarian, prostate, lung, pancreatic, and
durable against van der Waals hydrophobic interaction- glioblastoma cells, by inhibiting several key signaling
induced aggregation [174]. Meanwhile, the nanosheets’ pathways, including WNT, Notch, and STAT-signaling.
hydrophilic functional groups on the GO’s surface make The scientists used the phrase "differentiation-based
them a versatile substrate for conjugating various sub- nano-therapy" to explain this phenomenon [236]. How-
stances. This has a great deal of potential for the diagno- ever, there have only been a few studies conducted over
sis and treatment of cancer, as well as for other diseases the course of the last several years, so it’s feasible that we
that need focused treatment [216]. Table 9 highlights the need more information. Additional research on gra-
various nanocarrier-based imaging agents used for can- phene’s effect on the immune system and its direct anti-
cer diagnosis, each with their respective strengths and CSC activities is required. Graphene’s high
weaknesses. surface-to-volume ratio and abundance of oxygen-con-
Graphene’s direct immunogenicity toward the immune taining branches make it an ideal platform for drug deliv-
system sets it apart from other nanomaterials, and its lat- ery, photodynamic treatment (PDT), and photothermal
eral size can be controlled to alter the level to which it therapy (PTT). The Ac-(GHHPH)4-NH2 peptide
stimulates the immune system in vitro and in vivo. In sequence was grafted onto GO to form a GO-peptide
2011, scientists found evidence that the immune system hybrid via irreversible physical adsorption.The anti-angi-
responds directly to graphene due to its immunogenic ogenic domain of histidine-proline-rich (HPRG) Human
properties [57]. The potential of graphene to excite mac- neuroblastoma (SH-SY5Y) cells, human retinal endothe-
rophages and dendritic cells, two of the most vital com- lium cells (PC-3) cells, and prostate cancer (PC-3) cells
ponents of the human immune system, has led were used to test the hybrid nanomaterial (primary
researchers to believe that it may be effective in the treat- HREC) [236, 237]. The results showed that this GO-pep-
ment of cancer [110]. The effects of GO nanosheets, tide nanoassembly was able to inhibit cell migration,
designed for use in hyperthermia cancer therapy, on the reduce prostaglandin-mediated inflammation in PC-3
activities of macrophages and lymphocytes were studied cells, and reduce toxicity in prostate cancer cells. Due to
by researchers led by Feito and colleagues. Based on the limitations of liposomal doxorubicin (L-DOX) in the
these results, we may conclude that the 6-armed GO treatment of breast cancer, a novel DOX-loaded GO
(6-GOs) significantly increased tumor necrosis factor nanocarrier was created to improve its nucleation and
alpha (TNF-) production by RAW-264.7 macrophages internalization [219]. Increased anticancer activities were
without altering IL-6 or IL-1 levels [210]. First generation seen when GO-DOX was added to breast cancer cell
splenocytes were exposed to 1-GOs and 6-GOs in the lines. When linked to the cell plasma membrane, GO-
presence of concanavalin A, lipopolysaccharide, and anti- DOX was shown to cause a massive release of DOX
CD3 antibody. This led to considerable dose-dependent within the cell, which contributed to its remarkable effi-
cell growth and a lowered IL-6 level, suggesting the cacy. Live-cell confocal imaging and fluorescent lifetime
inherent mild inflammatory qualities of GOs, which are imaging microscopy allowed for this finding. There is
beneficial for hyperthermia cancer treatment. Graphene’s mounting evidence that GOs and rGOs may target
potential to inhibit tumor cell proliferation has also been hypoxia and abnormal angiogenesis in the tumour tissue
revealed. Burnett found that when both hFOB1.19 nor- microenvironment (TME) [219]. GOs and rGOs find
mal osteoblast and human osteosarcoma (OS) cells were widespread use in PDT and PTT. An allotrope of gra-
treated with GO, the apoptotic rate of the OS cells was phene, GDY features two acetylenic linkages per unit cell.
much higher [53]. Human cells were used in the OS. Sig- The carbon chains joining the hexagonal rings are made
nificant modifications in cytotoxicity against OS, reduc- twice as long as a result of these junctions. GYD is far
tions in Nrf-2 and ROS levels, and alterations in more bendable than graphene or graphyne as a result of
cytomorphological features were all brought about by this. Research using GYD as a drug delivery platform for
GO [235, 236]. To the average person, (CSCs) are a kind photothermal/chemotherapy combinatorial techniques
of cancer cell with the ability to self-renew and a high in cancer diagnostics has increased during the last three
tumorigenic potential. As a result of their interactions years [236, 237]. Molecules called fullerenes are con-
with the TME, CSCs have been linked to the progression structed from several all-carbon building blocks.
of MDR. The elimination of CSCs is a potential Depending on their structure, fullerenes may take on the
Table 9 Nanocarrier-based imaging agents for cancer diagnosis

Imaging Modality Target Biomarker Contrast Agent Type Sensitivity Specificity Clinical Application Advantages Disadvantages References
(2023) 22:169
Magnetic Resonance Vascular Endothelial Superparamagnetic Iron High High Tumor detection, Angio‑ Non-invasive, High Limited target specific‑ [232]
Imaging (MRI) Growth Factor Receptor Oxide Nanoparticles genesis imaging spatial resolution, Mul‑ ity, High cost
(VEGFR) (SPIONs) tiparametric imaging
Positron Emission Epidermal Growth Factor Radiolabeled Gold High High Early diagnosis, Lymph High sensitivity, Radiation exposure, [232]
Tomography (PET) Receptor (EGFR) Nanoparticles node metastasis detec‑ Quantitative imaging, High cost
tion Non-invasive
Computed Tomogra- Prostate-Specific Mem‑ Iodine-based Contrast High High Prostate cancer Rapid imaging, High Ionizing radiation, Lim‑ [232]
phy (CT) brane Antigen (PSMA) Agents diagnosis, Lymph node spatial resolution, Multi‑ ited soft tissue contrast
and bone metastasis planar imaging
imaging
Optical Imaging Cancer Cell-Specific Fluorescent Nanopar‑ High High Intraoperative imaging, High target specificity, Limited tissue penetra‑ [174]
Aptamers ticles Tumor margin detection Real-time imaging, Low tion, Autofluorescence
cost
Ultrasonography Tumor-Associated Glyco‑ Microbubbles Moderate Moderate Ovarian cancer detec‑ Real-time imaging, No Operator dependence, [224]
protein 72 (TAG-72) tion, Lymph node radiation exposure, Cost- Limited tissue penetra‑
metastasis imaging effective tion
Page 55 of 103
form of hollow spheres, ellipsoids, or tubes. C60, C70, with hyaluronic acid (HA) and chlorin e6 (Ce6) (PDT).
and C82 are all examples of common fullerenes. By add- Changes in cell appearance, as measured by microscopy,
ing metal atoms to a fullerene, a metallofullerene may be LDH cytotoxicity, and induction of cell death, were seen
made. Typically, Group III transition metals or lantha- after 24 h. According to the results of the study, the newly
nides make up the metal atoms contained inside the produced chemical enhanced the PDT’s efficiency [106,
fullerene [208, 232]. Due to the possibility of intra-fuller- 107]. The PTT efficiency of another NIR active photo-
ene electron migration from an encased metal atom to thermal agent, CNTs-PAMAM-Ag2S, was shown to be
the fullerene cage, metallofullerenes may be used as a quite high. When exposed to laser irritation at a wave-
material for magnetic resonance imaging. The qualities length of 980 nm, the research showed that the photo-
that give fullerenes their ability to scavenge free radicals thermal efficacy of this complex was higher than that of
also give them the ability to act as antioxidants [93]. copper-based and well-known gold photothermal agents
Among nanomaterials, fullerene stands out for its [88]. Moreover, the compound has shown excellent sta-
extraordinary PDT and PTT properties. Calculations of bility against photo-bleaching and photo-corrosiveness,
photothermal efficiency were shown to be inaccurate due indicating that the novel nanoagent may have use in PTT.
to a number of factors, including the concentration of A lot of effort has gone into studying the efficacy of car-
nanoparticles and the length of time that the laser was bon nanotube (CNT)-based drug delivery systems
shining on the sample, as determined by research by (DDSs), including DOX, PTX, and cis platinum (CDDP).
Chen et al. They also found that polyhydroxy fullerenes Carbon nitrides (CNHs) are a kind of carbon allotrope
had a photothermal conversion efficiency of 69% [238]. [106, 107]. While CNTs are generally 100 nm in length,
The fact that fullerenes’ photothermal reaction was unaf- larger spherical superstructures may be formed with sp2
fected by repeated laser irradiation and that their struc- hybridized carbon atoms with a diameter of between 2
ture was retained throughout the process made them and 5 nm. Similar to CNTs, CNHs are insoluble and need
ideal candidates for use in photothermal therapy. Near- surface modifications to serve as nanocarriers in human
infrared (NIR) light-harvesting fullerene-based nanopar- tissue. Adding organic species to the outside skeleton, or
ticles (DAF NPs) were tested for use in PA forming conjugate planar aromatic molecules by electro-
imaging-guided synergetic tumor photothermal and pho- static association or stacking interactions, are two poten-
todynamic treatment (PDT) [238]. When compared to tial approaches. CNHs were used in the creation of DDS
fullerene and antenna nanoparticles, DAF NPs were that include combination features due to their capacity
much more effective in producing reactive oxygen spe- for both drug loading and photothermal responses [208,
cies and heat (DA NPs). In vitro and in vivo studies sug- 232]. Yang and coworkers developed a single-walled
gest that the synergistic combination of PDT and PTT in CNH system loaded with two different chemotherapeutic
DAF NPs might effectively reduce the formation of agents. mPEG-PLA altered SWNHs through hydropho-
malignancies. Chemical drug delivery using fullerene has bic-hydrophobic stacking interactions as well as -stacking
been attempted using PDT and PTT [208, 232]. This was interactions. Both cisplatin and doxorubicin (DOX) were
accomplished at a nanocarrier’s worth of capacity. Gra- loaded onto nanohorns but in separate compartments
phene is folded up into cylindrical tubes called CNTs. [241]. The nanocarrier showed a pH-dependent releasing
Sp2-hybridized carbon atoms form the tubes. CNT sizes capacity in addition to a loading ability and an efficient
can vary widely, from 1 nm up to several micrometers. photothermal ability. Findings indicated that both pri-
Based on the number of layers formed inside the CNT, it mary breast tumors and lung metastases had been suc-
is possible to classify the CNT as either single-walled or cessfully eradicated [49, 50]. CNHs may be tailored with
multi-walled (MWCNTs). Unfortunately, CNTs are poi- specific targeting molecules for use in target chemical
sonous and have little water solubility, among other therapy to address a wide range of medical issues. A cis-
drawbacks. Many studies on surface functionalization platin-loaded CNH fused to a monoclonal antibody
and material changes have been performed to solve the (mAb) D2B that targets prostate specific membrane anti-
aforementioned difficulties and boost the bioavailability gen (PSMA) + prostate cancer cells has been demon-
of CNTs. As carbon-based nanomaterials (CNTs) may strated to be more effective and selective than other
interact with immune cells and activate immunological hybrids in killing PSMA + prostate cancer cells. The tox-
responses, they may improve immunity and restrain icity and side effects of CNMs have been extensively
tumor growth [239, 240]. Carbon nanotubes (CNTs) are studied because of their prevalence in cancer therapy.
well-studied nanocarriers that are largely believed to be Serum protein adsorption, hemolysis, cytotoxicity, and
efficient PDT and PTT vehicles. Sundaram and his team immunotoxicity have all been linked to GO and rGO (93)
used photodynamic treatment on colon cancer cells after [208, 232]. The large surface area of GO and rGO makes
combining single-walled carbon nanotubes (SWCNTs) them candidates as substrates for the adsorption of
proteins in a biological setting. As proteins adsorb onto it is still unclear which aspect of CNMs plays the most
the nanomaterial, the intended function of the nanoma- essential function and what the actual processes of cellu-
terial may be compromised, and blood vessel blockage lar toxicity induced by CNMs are, despite the wealth of
may result. According to in vitro and animal studies, the data acquired from a broad range of cells and animals
toxicity of nanomaterials may depend on factors such as [239–241]. Figure 16 depicts the use of layered double
the quantity of GO and rGO present and the size of the hydroxides (LDHs) to regulate the release of drugs in
particles [90, 102]. One study found that cells with large both in vitro and in vivo scenarios and their subsequent
amounts of hydrophobic rGO on their membranes were effects. The figure displays in vitro drug release profiles
more likely to undergo significant ROS stress, which may for three different LDHs intercalated with nitrate, car-
lead to cell death. In vivo studies have shown that CNTs bonate, and phosphate (LN-R, LC-R, and LP-R, respec-
are able to induce pathophysiology similar to that of mes- tively). The inset figure showcases their release pattern
othelioma, including chronic inflammation, the forma- within the first 8 h. The cytotoxicity of free drugs and
tion of granulomas, and fibrosis. Yan et al. summarized drug intercalated LDHs against HeLa cells is also demon-
the elements affecting CNT-induced toxicity in their strated at various time intervals. Additionally, the figure
investigation. Surface modification, aggregation, concen- shows the antitumor effect and systematic toxicity of
tration, CNT size, and CNT shape are all relevant varia- pure RH and drug intercalated LDHs compared to the
bles. They also outlined potential CNT accumulation control group in an in vivo setting. Finally, the histologi-
areas after anticancer medication withdrawal. However, cal analysis of liver, kidney, and spleen of tumor-bearing
Fig. 16 The utilization of layered double hydroxides to control the release of drugs in both in vitro and in vivo settings and their consequent
effects. A In vitro drug release profiles for three different drugs intercalated LDHs- nitrate, carbonate, and phosphate (LN-R, LC-R, and LP-R
respectively) are displayed, along with an inset figure showcasing their release pattern within the first 8 h. B The cytotoxicity of the free drug
and drug intercalated LDHs against HeLa cells at various time intervals is demonstrated. C The antitumor effect and systematic toxicity of pure RH
and drug intercalated LDHs are shown in comparison to the control group in an in vivo setting. D Finally, the histological analysis of liver, kidney,
and spleen of tumor-bearing mice treated with control (saline), pure RH, LN-R, and LP-R are illustrated. Reprint from [180] with a permission
mice treated with control (saline), pure RH, LN-R, and adjustable fluorescence, and high photothermal conver-
LP-R is illustrated. sion effectiveness (33.45%) [57]. This exemplified GQDs’
potential in PTT. A carbon quantum dot-based photody-
Dots on a quantum scale namic-chemotherapy drug delivery device was created.
Due to their distinctive optical and electrical capabilities, Researchers combined 5-aminolevulinic acid (5-ALA)
quantum dots are being extensively studied as poten- with a mono-(5-BOC-protected-glutamine-6-deoxy)
tial biological imaging probes. The most frequent usage -cyclodextrin (CQD-glu—CD) moiety, and then conju-
for these nanometer-scale semiconductor crystallites gated these materials to CQDs loaded with DOX. Radia-
is to improve the efficacy of fluorescent markers used tion at 635 nm (25 mW cm-2) for 15 min also generated
in biological imaging, although they have many other reactive oxygen species (ROS) and improved treatment
potential uses [103, 104]. Size and composition are only outcomes [176]. The morphology of the MCF-7 cancer
two examples of the quantum dot’s unique optical and cells changed dramatically, and there was significant
electrical properties that allow for wavelength-tunable cytotoxicity as a consequence. CDs and nanodiamonds
fluorescence emission from the visible to the infrared, have both been studied for their potential use in cancer
large absorption coefficients, and high brightness levels treatment due to their targeted therapy, photodynamic
with excellent photostability. Carbon-based quantum therapy (PDT), cancer imaging, and mediation of antitu-
dots include graphene quantum dots (GQDs), nanodia- mor immune properties. In comparison to other carbon-
monds, and carbon dots (CDs) [103, 104]. Bioimaging based materials, the study of carbon QDs is still in its
is where carbon QDs are most often used, and this dis- infancy. A lack of a standard way to make high-quality
cipline is where they are most useful for detecting and QDs and a lack of knowledge about how they work and
studying cancer. GQDs are seen as promising nanomate- how they are made are two of the biggest problems with
rials in biosensing and cancer therapy due to their better using them in clinical settings [110].
biocompatibility, rapid excretion, and huge surface area
that is ideal for molecular conjugation. Building a pho- Nanoscale materials that are magnetic and metallic
toluminescent glycodendrimer system with terminal- Researchers in the fields of bioimaging and drug deliv-
cyclodextrin molecules allowed for DOX administration ery have focused extensively on metallic nanoparticles
that was both biocompatible and pH-sensitive [176]. In due to their unusual optical, magnetic, and photo-
order to create a surface on which PAMAM could grow, thermal capabilities. Metallic materials may be used
GQDs were employed. After being first stimulated by in many different applications since they can be con-
UV light at 365 nm, GQDs and GQDs-PAMAM—CD jugated with many different carriers. When it comes
had their emission spectra recorded. Having the GQDs to applications, magnetic nanoparticles in MRI are
in there meant it could be used as a photoluminescent the most prevalent (MRI). An external magnetic field
imaging agent [15]. The data also showed that it killed may guide magnetic nanoparticles (NPs) loaded with
cancer cells more effectively than DOX alone. This inno- chemical treatments to cancer cells [20]. This reduces
vative nanocarrier for targeted therapy takes advantage the risk of discomfort associated with conventional
of the fluorescence-inducing properties of GQDs. They chemotherapy. The linked metal particle allows the
were able to connect folic acid to sulfur-doped gra- nanosystem to do both bio-imaging and PTT. Iron
phene quantum dots (FA-SGQDs) by a simple pyroly- oxide nanoparticles (IONPs) were created by enclos-
sis procedure including citric acid (CA), folic acid, and ing Fe3O4/Ag in gold. The MRI contrast capabilities of
3-mercaptopropionic acid (MPA) [15, 55, 176]. A blue IONPs and PTT were revealed to be the result of the
fluorescence with an emission band at 455 nm was seen presence of a gold shell in the NIR region [166]. Met-
after exciting the compound at 370 nm. In addition, als are often used in the cancer treatment methods of
a strategy for TA-SGQDs to enter FR-positive cancer photothermal therapy (PTT), photodynamic therapy
cells through a mechanism other than immunogenic (CDT), and immunotherapy. The CDT is a method of
FR-mediated endocytosis was identified. In addition to therapy predicated on the Fenton reaction or an analo-
bioimaging and biosensing, researchers were looking at gous reaction. It employs a nanocatalyst. High levels
the potential of GQDs for photothermal therapy (PTT) of oxidizing hydroxyl (OH) radicals are generated in a
and photodynamic therapy (PDT) [103, 104]. A modi- manner similar to photodynamic therapy (PDT), and
fied GQD was created that showed strong absorption at these toxic OH radicals kill cancer cells by triggering
1070 nm in the NIR-II range. The so-called 9 T-GQDs chain reactions with the organic molecules in the sur-
were able to effectively ablate tumor cells and, as a con- rounding tissue [121]. As a consequence of these pro-
sequence, NIR-II irradiation reduced the development cesses, DNA, lipids, and proteins are all susceptible to
of the tumor because of its uniform size distribution, irreversible damage as a consequence. Catalyzing the
disproportionation of H2O2 to create OH radicals is Methods for cancer therapy

accomplished using iron-based nanostructures such A variety of time-tested approaches to cancer treatment
as FeS2, Fe2P, Fe3O4, SnFe2O4, and amorphous iron. continue to be routinely used today. Most research is
Near infrared (NIR) triggered materials are crucial focused on tumor cells and the tumor microenviron-
to the success of photodynamic treatment (PDT) and ment (TME), which includes the immune system that is
photothermotherapy because of the greater depth at linked to the tumor [171]. Figure 17 illustrates the inno-
which NIR light may permeate tissue compared to vis- vative approach of breaching the tumor barrier physically
ible light and ultraviolet (UV) light (PTT) [59]. When in order to facilitate immune cell infiltration. By employ-
cancer cells are destroyed using photothermal treating biomaterials-based instruments, this method seeks to
ment (PTT), heat is produced. It is the reactive oxygen stabilize blood vessels within the tumor microenviron-
species (ROS), hydroxyl radical (OH), singlet oxygen ment, making it more accessible to immune cells. Tech-
(1O2), and superoxide (O2) that trigger the cytotoxic niques such as radiolabeled or photothermal agents can
reactions in the process of photodynamic treatment be employed, accompanied by the use of laser or radia-
(PDT). All gold (Au), copper (Cu), and iron (Fe) are tion, to achieve the desired disruption. Additionally, the
metals that have found medical use. One of the key strategic application of nanomaterials capable of releas-
downsides of these materials is that metallic nanopar- ing enzymes aids in breaking down the extracellular
ticles are toxic. The formation of reactive oxygen spe- matrix (ECM), further enhancing the ability of immune
cies (ROS) and the effect on cell architecture were only cells to penetrate the tumor. Crucial components within
two of the processes of metallic NPs summarized by this process include cancer-associated fibroblasts (CAFs),
Attarilar et al. Size, shape, dimensionality, and surface nitric oxide (NO), and vascular endothelial growth factor
charge are all factors in the toxicity of NPs; these fac- (VEGF), all of which play significant roles in modulating
tors are also relevant to metallic NPs. Therefore, fur- the tumor microenvironment and enabling a more effec-
ther research is required before metallic nanoparticles tive immune response against cancer cells. Table 10 pro-
may be employed on human patients [242, 243]. vides a comprehensive overview of various methods used
Fig. 17 Breaching the tumor barrier physically. Immune cell infiltration can be facilitated by physically disrupting the tumor microenvironment
using biomaterials-based instruments that help stabilize the blood vessels. This can be achieved through the use of radiolabeled or photothermal
agents, followed by the application of laser or radiation, as well as employing nanomaterials that release enzymes to break down the extracellular
matrix (ECM). Reprint from [244] with a permission from Springer Nature
Table 10 Methods for evaluating nanocarrier efficacy
Evaluation Efficacy Metric Sensitivity Specificity Reproducibility Clinical Description Novelty Advantages Disadvantages References
Method Relevance
Tumor growth Tumor volume High High High High Measures Measures Allows for testing Expensive; [45]
inhibition assay reduction the effect the reduction of drug efficacy may require
of the nanocarrier in tumor size in vivo; can be a large number
on tumor growth over time, which used to evaluate of animals; can be
in vivo is a direct indica‑ drug combina‑ time-consuming
tor of treatment tion therapies
efficacy
Cellular uptake Intracellular drug High High Moderate Moderate Measures Quantifies Can be per‑ Does not provide [245]
assay concentration the amount the amount of drug formed quickly information
of nanocarrier delivered to cancer and easily; cost- on drug efficacy
taken up by can‑ cells; can determine effective in vivo; may
cer cells in vitro if the nanocar‑ not reflect tumor
(2023) 22:169
rier is internalized heterogeneity

and if drug release
occurs
In vitro drug Drug release High High High Moderate Measures the rate Quantifies Provides a rapid Does not reflect [246]
release assay kinetics of drug release the amount of drug and reli‑ the complex‑
from the nanocar‑ released over time; able assessment ity of in vivo
rier in vitro can determine of nanocarrier drug release;
if the release drug release may not reflect
rate is sustained kinetics the effect
and controlled of the tumor
microenviron‑
ment on drug
release
Pharmacoki- Drug concentra‑ High High High High Measures Quantifies Provides valu‑ Expensive; may [115]
netic analysis tion in blood/ the distribution, the amount able information require large
tissues metabolism, of drug delivered on nanocarrier sample sizes; may
and excretion to the tumor pharmacokinetics not reflect tumor
of the nanocarrier and other organs; and biodistribu‑ heterogeneity
in vivo can determine tion
the clearance path‑
way and half-life
Imaging-based Tumor contrast Moderate High High Moderate Measures Quantifies Provides real-time Requires special‑ [45]
analysis enhancement the accumulation the amount visualization ized equipment
of the nanocar‑ of nanocarrier deliv‑ of the nanocarrier and expertise;
rier in the tumor ered to the tumor; accumulation may not reflect
using imaging can determine in the tumor the effect
modalities such if the nanocarrier of the tumor
as MRI or PET targets the tumor microenviron‑
specifically ment on nano‑
carrier accumula‑
tion
Page 60 of 103
Table 10 (continued)
Method Relevance
Flow cytometry Percentage Moderate High High Low Measures Allows for high- Rapid and quan‑ May not reflect [115]
of cells with drug the amount throughput titative; can the in vivo behav‑
uptake of nanocarrier screening of large distinguish ior of the nano‑
taken up by cells numbers of cells; between live carrier; may
in vitro can quantify and dead cells require special‑
the proportion ized equipment
of cells that take and expertise

up the drug
Histological Tumor cell apop‑ High High High High Measures Quantifies Provides informa‑ Requires invasive [45]
analysis tosis and necrosis the effect the amount tion on the his‑ tissue sampling;
of the nanocar‑ of tumor cell apop‑ tological effects may not reflect
rier on tumor tosis and necrosis; of the nanocarrier the in vivo behav‑
(2023) 22:169
cell death can determine on the tumor ior of the nano‑

and destruction if the nanocarrier carrier; may
in vivo induces tumor cell require special‑
death ized expertise
Proteomic Expression High High High High Measures Quantifies changes Provides informa‑ Requires special‑ [233]
analysis of tumor-associ‑ the effect in protein expres‑ tion on the mech‑ ized expertise
ated proteins of the nanocar‑ sion in response anism of action and equipment;
rier on tumor- to nanocar‑ of the nanocarrier may not reflect
associated protein rier treatment; the in vivo behav‑
expression in vivo can determine ior of the nano‑
if the nanocarrier carrier; may be
affects specific sign‑ time-consuming
aling pathways
Magnetic reso- Metabolic High High High High Measures Quantifies changes Provides informa‑ Requires special‑ [247]
nance spectros- changes in tumor changes in tumor in metabolite tion on the meta‑ ized equipment
copy cells metabolism levels in response bolic effects and expertise;
in response to nanocarrier treat‑ of the nanocarrier may not reflect
to nanocarrier ment; can deter‑ on the tumor the in vivo behav‑
treatment in vivo mine if the nano‑ ior of the nano‑
carrier affects carrier
specific metabolic
pathways
Transcriptomic Gene expression High High High High Measures Quantifies changes Provides Requires special‑ [233]
analysis changes in tumor changes in gene in gene expres‑ information ized expertise
cells expression sion in response on the molecu‑ and equipment;
in response to nanocar‑ lar effects may not reflect
to nanocarrier rier treatment; of the nanocarrier the in vivo behav‑
treatment in vivo can determine on the tumor ior of the nano‑
if the nanocarrier carrier
affects specific sign‑
aling pathways
Page 61 of 103
Method Relevance
Drug resistance IC50 value Moderate Moderate High Moderate Measures the sen‑ Quantifies Useful for iden‑ Requires careful [115]
assays or other resist‑ sitivity of cancer the extent of resist‑ tifying the most optimization
ance metrics cells to nano‑ ance or sensitivity appropriate and validation;
carrier-delivered to the nanocarrier- nanocarrier-drug may not reflect
drugs delivered drug combination the in vivo behav‑
for specific cancer ior of the nano‑
types carrier
3D tumor Tumor size or vol‑ High High Moderate High Measures Mimics the com‑ Provides a more Can be expensive [115]
models ume, viability, the effect plexity of the in vivo physiologically and time-
and drug distribu‑ of the nanocarrier tumor microen‑ relevant system consuming; may
tion on tumor growth vironment; can for evaluating require special‑
and viability quantify the drug nanocarrier ized equipment
(2023) 22:169
in a 3D culture distribution efficacy and expertise

system within the tumor
model
Serum cytokine Changes High High High Moderate Measures Quantifies changes Provides Requires special‑ [163]
analysis in cytokine levels the effect in cytokine information ized expertise
of the nanocarrier levels in response on the immune and equipment;
on the immune to nanocarrier treat‑ modula‑ may not reflect
response in vivo ment; can deter‑ tory effects the in vivo behav‑
mine if the nano‑ of the nanocarrier ior of the nano‑
carrier modulates carrier
theimmuneresponse
Microfluidic Drug delivery High High High Low Measures Mimics the behav‑ Provides a more Requires special‑ [248, 249]
platforms and efficacy the effect ior of the nanocar‑ accurate and con‑ ized equipment
in a microfluidic of the nanocarrier rier in the human trolled system and expertise;
device on cancer cells body; can for evaluating may not reflect
and drug delivery quantify the drug nanocarrier the in vivo behav‑
in a microfluidic distribution efficacy ior of the nano‑
device within the microflu‑ carrier
idic device
Optical imaging Imaging of tumor High High High High Measures Can quantify Provides a non- Limited [125]
size and distribu‑ the effect the tumor size invasive and rapid by the depth
tion in vivo of the nanocar‑ and distribution system for evalu‑ of light penetra‑
rier on tumor size in real-time; can ating nanocarrier tion into tissues;
and distribution be used for non- efficacy may not reflect
in vivo invasive imaging the effect
of the tumor
microenviron‑
ment on nano‑
carrier distribu‑
tion
Page 62 of 103
Method Relevance
Scanning elec- Imaging High High High Low Measures Provides a detailed Provides a direct Requires special‑ [115]
tron microscopy of nanocarrier- the physical view of the nano‑ and visual ized equipment
cell interaction interaction carrier-cell interac‑ representation and expertise;
between nano‑ tion; can determine of the nanocar‑ may not reflect
carriers and can‑ the cellular uptake rier-cell interac‑ the in vivo behav‑
cer cells in vitro mechanism tion ior of the nano‑

of the nanocarrier carrier
Surface plasmon Real-time analysis High High High Moderate Measures Can provide Provides a highly May not reflect [250]
resonance of molecular the interaction real-time analysis sensitive and spe‑ the in vivo behav‑
interactions between nano‑ of the molecu‑ cific method ior of the nano‑
carrier and cancer lar interactions for detecting carrier; requires
(2023) 22:169
cell molecules between the nano‑ molecular inter‑ specialized

in vitro carrier and cancer actions equipment
cells and expertise
Bioluminescent Imaging of tumor High High High High Measures Provides non- Provides a non- Limited [250]
imaging size and distribu‑ the effect invasive imaging invasive and rapid by the depth
tion in vivo of the nanocar‑ of the tumor size system for evalu‑ of light penetra‑
rier on tumor size and distribution ating nanocarrier tion into tissues;
and distribution in real-time efficacy may not reflect
in vivo the effect
of the tumor
microenviron‑
ment on nano‑
carrier distribu‑
tion
Microscale ther- Analysis of nano‑ High High High Moderate Measures Provides a highly Requires May not reflect [248, 249]
mophoresis carrier-protein the interaction sensitive method only small the in vivo behav‑
interaction between nano‑ for detecting amounts ior of the nano‑
carrier and cancer the binding affinity of sample; allows carrier; requires
cell proteins between the nano‑ for the analysis specialized
in vitro carrier and proteins of protein interac‑ equipment
tions in a high- and expertise
throughput
manner
Electrochemilu- Detection High High High High Measures Provides highly Requires May require [107]
minescence of nanocarrier- the drug concen‑ sensitive and spe‑ only small specialized
delivered drug tration in plasma cific detection amounts of sam‑ equipment
in plasma or tis‑ or tissue samples of the nanocarrier- ple; provides and expertise;
sue samples delivered drug rapid results may not reflect
the in vivo behav‑
ior of the nano‑
carrier
Page 63 of 103
for evaluating the efficacy of nanocarriers in drug deliv- surrounding microenvironments. This fine-tuned con-
ery. These methods range from in vivo tumor growth trol plays a vital role in influencing key factors, such as
inhibition assays, which directly measure the reduction HIF1α (hypoxia-inducible factor-1α) and VEGF (vascular
in tumor size over time, to more specialized techniques endothelial growth factor), which are responsible for pro-
like surface plasmon resonance and electrochemilumi- moting tumor growth and angiogenesis under hypoxic
nescence, which focus on molecular interactions and conditions. As a result, these biomaterial strategies offer
drug detection, respectively. Each method has its own the potential to disrupt the tumor’s ability to adapt to a
set of advantages and disadvantages, as well as vary- low-oxygen environment, thereby enhancing the effec-
ing degrees of clinical relevance, sensitivity, specificity, tiveness of cancer treatments and improving patient
and reproducibility. By utilizing a combination of these outcomes. Figure 18-C illustrates the use of biomaterials
methods, researchers can gain a better understanding of to mitigate tumor acidity and modulate reactive oxygen
nanocarrier performance, pharmacokinetics, biodistri- species (ROS) levels in the tumor microenvironment.
bution, and impact on cellular and molecular processes, This innovative approach focuses on the integration of
ultimately leading to more effective and targeted cancer calcium-carbonate-based materials, which are specifi-
therapies. cally designed to neutralize the acidic conditions typically
associated with tumors. Furthermore, the figure high-
Methods that target cancer cells directly lights the application of oxygen-free radical-absorbing
Naturally, eliminating cancer naturally requires thera- hydrogels to regulate ROS levels, thus preventing oxida-
pies that specifically target cancer cells. Nanoparticles tive stress and damage. These hydrogels not only control
(NPs), dendrimers (dNMs), and conjugated nanomateri- ROS but also function as carriers for the targeted delivery
als (CNMs) may be customized to use EPR in combina- of antibodies and chemotherapy drugs. Key abbreviations
tion with active targeting to enter cancer cells and deliver featured in Fig. 3 include DNCaNP (liposome-encapsu-
chemical therapies or biomaterials. These systems rely lated calcium nanoparticles), ICB (immune checkpoint
heavily on antibodies that recognize and bind to antigens blockade), PDA (polydopamine), and Treg cell (regula-
that are overexpressed on the surfaces of cancer cells. tory T cells). The combination of these strategies exem-
After being taken up by cancer cells, encapsulated chemi- plifies the potential of biomaterials in transforming
cal treatments may induce cytotoxicity, whereas encap- cancer treatment modalities. Notably, viral vectors like
sulated nucleic acid components may cause cell death. adenovirus and adeno-associated virus demonstrate high
Nucleic acid delivery science has come a long way, which transfection efficiency and gene expression levels but may
has led to a lot of research into nano-DDS therapies that induce immune responses and potential toxicity. Non-
use exosomes, PNPs, liposomes, and dendrimers to treat viral vectors, such as lipid nanoparticles and polymeric
cancer [171]. Figure 18 highlights the potential of nano- nanoparticles, show promise due to their biocompat-
particle targeting in the tumour microenvironment and ibility, while CRISPR-Cas9 and CRISPR-Cas13a systems
the premetastatic niche. Also, Fig. 18-A illustrates that offer specific and efficient gene targeting. However,
targeting the tumour vasculature or stromal cells can long-term safety and potential off-target effects of these
be achieved using modified nanoparticles with specific systems remain concerns. Electroporation and in vivo
ligands that bind to receptors on the surface of these electroporation provide non-toxic, non-immunogenic
cells. In addition, the figure shows that nanoparticle tar- delivery methods but require specialized equipment and
geting can be used in premetastatic tissues such as the expertise. Finally, mRNA-based therapies, such as mRNA
bone marrow niche, where the osteogenic differentiation electroporation, enable rapid and customizable produc-
of mesenchymal stem cells can be enhanced to increase tion, but potential immune response and toxicity must be
bone strength and volume. Interestingly, nanoparticles considered. Each approach presents unique advantages
can be engineered to achieve preferential cellular uptake and disadvantages, emphasizing the importance of con-
even without targeting ligands. It is worth noting that tinued research and development in this field. Table 11
the payloads released from these nanoparticles can also outlines various nanocarrier-mediated gene therapy
be taken up by these cells, regardless of whether they approaches for cancer treatment, highlighting their tar-
are localized in tumours or premetastatic tissues. Fig- get genes, delivery methods, transfection efficiency, gene
ure 18-B illustrates the innovative approach of utilizing expression levels, and therapeutic outcomes.
biomaterials to manipulate tumor hypoxia, effectively
addressing a critical challenge in cancer therapy. By Methods developed with the express purpose
employing various biomaterial-based techniques, such as of combating TME
oxygen production and transportation systems, research- Targeting tumor microenvironments (TME) has emerged
ers are able to regulate hypoxia within tumors and their as a promising strategy in cancer treatment, with several
Fig. 18 A The use of nanoparticles to target the microenvironments of tumors and premetastatic areas. Part A shows how the tumor vasculature
or stromal cells in the tumor microenvironment can be targeted. Part B shows targeting of premetastatic microenvironments such as the bone
marrow niche, where nanoparticles can be used to enhance bone strength and volume through osteogenic differentiation of mesenchymal
stem cells. To achieve cell-specific targeting, nanoparticles can be modified with ligands that bind to specific receptors on the surface of target
cells. However, even without targeting ligands, nanoparticles can still be engineered for preferential uptake by these cells. The cells can also take
up the payloads released from the nanoparticles that are localized in tumors or premetastatic tissues, even in a non-specific manner. Reprint
from [177] with a permission from Springer Nature. B Manipulating tumor hypoxia using biomaterials. A range of biomaterial-based techniques,
such as oxygen production and transportation systems, can be utilized to control hypoxia within tumors and their surrounding microenvironments.
Reprint from [244] with a permission from Springer Nature. C Utilizing Biomaterials to Decrease Tumor Acidity and Control ROS Levels. A variety
of biomaterials-focused approaches, especially those involving calcium-carbonate-based materials, can be introduced into the tumor surroundings
to counteract tumor acidity. Reactive oxygen species (ROS) levels can be regulated using oxygen-free radical-absorbing hydrogels. These
hydrogels can also serve as vehicles for delivering antibodies and chemotherapy medications. DNCaNP refers to liposome-encapsulated calcium
nanoparticles, ICB stands for immune checkpoint blockade, PDA denotes polydopamine, and Treg cell represents regulatory T cells. Reprint
from [244] with a permission from Springer Nature
Table 11 Nanocarrier-mediated gene therapy for cancer
Gene Therapy Target Gene Delivery Method Transfection Gene Therapeutic Description Novelty Advantages Disadvantages References
Approach Efficiency Expression Outcome
Level
Viral vectors p53 Adenovirus High High Induces apoptosis Adenovirus is a com‑ The use of adeno‑ High transfection Adenovirus can [49, 50]
monly used vector virus for p53 efficiency results induce an immune
for gene therapy gene therapy in high gene response, limiting
due to its high trans‑ is a novel approach expression levels its effectiveness
fection efficiency that has shown and improved thera‑ and potential
and ability to infect promising results peutic outcomes toxicity

a wide range of cells in preclinical studies
Non-viral vectors siRNA Lipid nanoparticles Moderate Moderate Downregulates tar‑ Lipid nanoparticles The use of lipid nan‑ Lower risk Lower transfection [49, 50]
get gene expression are a promising non- oparticles for siRNA of immune efficiency and gene
viral vector for gene delivery is a rela‑ response and toxic‑ expression levels
therapy due to their tively new approach ity compared to viral compared to viral
biocompatibility that has shown vectors vectors
(2023) 22:169
and ability to encap‑ improved transfec‑

sulate and protect tion efficiency
nucleic acids and gene silencing
compared to other
non-viral vectors
CRISPR-Cas9 PD-1 Gold nanoparticles High High Enhances T cell Gold nanoparticles The use of gold High transfection Limited data [117]
activity have unique optical nanoparticles efficiency and gene on long-term safety
and electronic prop‑ for CRISPR-Cas9 expression levels and potential
erties that make delivery is a cutting- toxicity
them promising edge approach
candidates for gene that has shown
therapy promising results
in preclinical studies
Electroporation IL-12 Electric pulses Moderate High Induces immune Electroporation The use of elec‑ Non-toxic and non- Requires special‑ [251]
response is a non-viral troporation for IL-12 immunogenic ized equipment
method for deliver‑ gene therapy and expertise
ing nucleic acids is a novel approach
into cells using brief that has shown
electric pulses promising results
CRISPR-Cas13a KRAS Liposomes High Moderate Downregulates tar‑ CRISPR-Cas13a The use of CRISPR- Specific and effi‑ Limited data [252]
get gene expression is a recently discov‑ Cas13a for KRAS cient targeting on long-term safety
ered RNA-guided gene therapy of RNA and potential off-
ribonuclease system is a cutting-edge target effects
that can be used approach
for RNA editing that has shown
promising results
Page 66 of 103
Level
AAV vectors BDNF Adeno-associated High High Enhances neuronal Adeno-associated The use of AAV Long-term expres‑ Limited packaging [253]
virus growth and survival virus (AAV) vectors vectors for brain- sion and stability capacity and poten‑
are a type of viral derived neuro‑ tial immune
vector that can trophic factor response
be used for gene (BDNF) gene
therapy due to their therapy is a prom‑

safety and abil‑ ising approach
ity to integrate for treating
into the host neurodegenerative
genome diseases
Hybrid viral vec- HER2 Hybrid viral vectors High High Induces apoptosis Hybrid viral vec‑ The use of hybrid Improved transduc‑ Potential immune [254]
tors tors combine viral vectors tion efficiency response and toxic‑
(2023) 22:169
the advantages for HER2 gene ther‑ and specificity ity

of different viral apy is a promising compared to single
vectors to achieve approach for treat‑ viral vectors
improved transduc‑ ing HER2-positive
tion efficiency breast cancer
and specificity
CRISPR-Cas9 LDLR Gold nanorods Moderate Moderate Upregulates target Gold nanorods are The use of gold Non-toxic and bio‑ Limited data [117]
gene expression a type of gold nano‑ nanorods compatible on long-term safety
particle that can for CRISPR-Cas9- and efficacy
be used for gene mediated LDLR
therapy due to their gene therapy
plasmonic proper‑ is a novel approach
ties that has shown
promising results
Non-viral vectors BRCA1 Polymeric nanopar‑ High High Induces DNA repair Polymeric nano‑ The use of poly‑ High transfection Limited packaging [49, 50]
ticles particles are a type meric nanoparticles efficiency and bio‑ capacity and poten‑
of non-viral vector for BRCA1 gene compatibility tial toxicity
that can be used therapy is a prom‑
for gene therapy ising approach
due to their versatil‑ for treating breast
ity and biocompat‑ cancer
ibility
In vivo electropo- IL-10 In vivo electropo‑ High High Suppresses inflam‑ In vivo electropora‑ The use of in vivo Non-toxic and non- Limited data [255]
ration ration mation tion is a non-viral electroporation immunogenic on long-term safety
method for deliver‑ for IL-10 gene and potential
ing nucleic acids therapy is a prom‑ toxicity
into cells in vivo ising approach
using electric pulses for treating inflam‑
matory diseases
Page 67 of 103
Level
CRISPR-Cas12a EGFR Lipid nanoparticles High Moderate Downregulates tar‑ CRISPR-Cas12a The use of CRISPR- Specific and effi‑ Limited data [256]
get gene expression is a recently discov‑ Cas12a for EGFR cient targeting on long-term safety
ered RNA-guided gene therapy of DNA and potential off-
endonuclease is a novel approach target effects
system that can that has shown
be used for gene promising results

editing in preclinical studies
mRNA-based vac- SARS-CoV-2 spike Lipid nanoparticles High High Induces immune mRNA-based vac‑ The use of mRNA- Rapid and scalable Potential immune [257]
cines protein response cines are a novel based vaccines production response and toxic‑
approach to gene for the SARS-CoV-2 ity
therapy that use spike protein
messenger RNA is a cutting-edge
(2023) 22:169
(mRNA) to encode approach for pre‑

a protein of inter‑ venting COVID-19
est and induce
an immune
response
CRISPR-Cas9 HPRT Zinc-finger nucle‑ Moderate Moderate Gene correction Zinc-finger nucle‑ The use of ZFNs Specific and effi‑ Limited data [117, 258]
ases ases (ZFNs) are for HPRT gene cient targeting on long-term safety
a type of engineered therapy is a prom‑ of DNA and potential off-
DNA-cutting ising approach target effects
enzyme that can for treating genetic
be used for gene disorders
editing
Viral vectors CFTR Lentivirus High High Induces gene Lentivirus is a type The use of lentivi‑ High transduction Potential immune [259]
expression of retrovirus that can rus for CFTR gene efficiency and stable response and toxic‑
be used as a vector therapy is a prom‑ gene expression ity
for gene therapy ising approach
for treating cystic
fibrosis
Non-viral vectors VEGF Dendrimers Moderate Moderate Enhances angio‑ Dendrimers are The use of den‑ Highly customizable Limited transfec‑ [260]
genesis a type of branched drimers for VEGF and biocompatible tion efficiency
polymer that can be gene therapy and potential
used as a non-viral is a novel approach toxicity
vector for gene that has shown
therapy promising results
CRISPR-Cas9 DMD AAV vectors High High Gene correction Adeno-associated The use of AAV vec‑ Long-term gene Limited packaging [117]
virus (AAV) vectors tors for DMD gene expression capacity and poten‑
are a type of viral therapy is a prom‑ and safety tial immune
vector that can ising approach response
be used for gene for treating
therapy Duchenne muscular
dystrophy
Page 68 of 103
Level
mRNA-based OCT4 mRNA electropora‑ High High Induces cell repro‑ mRNA-based The use of mRNA Rapid and customiz‑ Potential immune [261]
therapies tion gramming therapies are a novel electroporation able production response and toxic‑
approach to gene for OCT4 gene ity
therapy that use therapy is a cutting-
messenger RNA edge approach
(mRNA) to encode for inducing cell

a protein of interest reprogramming
Non-viral vectors MDR1 Nanoparticles Moderate Moderate Downregulates tar‑ Nanoparticles are The use of nanopar‑ Non-toxic and bio‑ Limited transfection [49, 50]
get gene expression a type of non-viral ticles for MDR1 gene compatible efficiency and gene
vector that can therapy is a prom‑ expression levels
be used for gene ising approach
therapy due to their for overcoming
(2023) 22:169
size and biocompat‑ multidrug resistance

ibility in cancer
CRISPR-Cas9 HBB Lipid nanoparticles High High Gene correction Lipid nanoparticles The use of lipid Non-immunogenic Limited transfection [117]
are a type of non- nanoparticles and scalable pro‑ efficiency and gene
viral vector that can for HBB gene duction expression levels
be used for gene therapy is a prom‑
therapy due to their ising approach
biocompatibility for treating sickle
and ease of produc‑ cell disease
tion
Gene silencing BCL-2 Aptamers High Moderate Downregulates tar‑ Aptamers are a type The use of aptam‑ Specific and effi‑ Limited in vivo sta‑ [262]
get gene expression of synthetic nucleic ers for BCL-2 cient targeting bility and potential
acid that can be gene therapy of RNA immunogenicity
used as a gene is a novel approach
silencing agent that has shown
promising results
Non-viral vectors FGF2 Cationic liposomes Moderate Moderate Enhances angio‑ Cationic liposomes The use of cati‑ Low toxicity Limited transfection [49, 50, 263]
genesis are a type of non- onic liposomes and customizable efficiency and sta‑
viral vector that can for FGF2 gene bility
be used for gene therapy is a prom‑
therapy due to their ising approach
ability to interact for promoting tissue
with cell mem‑ regeneration
branes
CRISPR-Cas9 CFTR CRISPR-Cas9 ribonu‑ High High Gene correction CRISPR-Cas9 The use of CRISPR- High specificity Potential off-target [117, 264]
cleoprotein ribonucleopro‑ Cas9 ribonucleopro‑ and efficiency effects and immune
tein is a recently tein for CFTR gene response
developed gene therapy is a prom‑
editing technology ising approach
that uses RNA- for treating cystic
guided endonu‑ fibrosis
cleases
Page 69 of 103
Level
RNA interference KRAS Gold nanoparticles Moderate Moderate Downregulates tar‑ Gold nanoparticles The use of gold nan‑ High biocompatibil‑ Limited transfec‑ [194, 195]
get gene expression are a type of nano‑ oparticles for KRAS ity and stability tion efficiency
particle that can gene therapy and potential
be used for gene is a novel approach toxicity
therapy due to their that has shown
unique optical promising results

and electronic in preclinical studies
properties
Viral vectors APOE Adenovirus High High Upregulates target Adenovirus is a type The use of adenovi‑ High transduc‑ Potential immune [265]
gene expression of viral vector rus for APOE gene tion efficiency response and toxic‑
that can be used therapy is a prom‑ and long-term gene ity
for gene therapy ising approach expression
(2023) 22:169
due to its high trans‑ for treating Alzhei‑

duction efficiency mer’s disease
RNA interference TP53 Nanoparticles High High Downregulates tar‑ Nanoparticles are The use of nanopar‑ Non-toxic and bio‑ Limited transfection [193]
get gene expression a type of non-viral ticles for TP53 gene compatible efficiency and gene
vector that can therapy is a prom‑ expression levels
be used for gene ising approach
therapy due to their for treating various
size and biocompat‑ cancers
ibility
Gene editing F9 CRISPR-Cas9 High High Gene correction CRISPR-Cas9 The use of CRISPR- High specificity Potential off-target [266]
is a gene edit‑ Cas9 for F9 gene and efficiency effects and immune
ing technology therapy is a prom‑ response
that uses RNA- ising approach
guided endonucle‑ for treating hemo‑
ases to modify DNA philia B
mRNA-based FLT3L mRNA electropora‑ High High Induces immune mRNA-based The use of mRNA Rapid and customiz‑ Potential immune [194, 195]
therapies tion response therapies are a novel electroporation able production response and toxic‑
approach to gene for FLT3L gene ity
therapy that use therapy is a cutting-
messenger RNA edge approach
(mRNA) to encode for enhancing
a protein of interest immune response
Page 70 of 103
mechanisms being explored to combat the complex net- human hyaluronidase (PEGPH20) that targets ECM hya-
work of cells and factors that support tumor growth luronic acid [15]. Cancer patients whose tumor cells
and progression (Fig. 19-A). One prominent approach produced a lot of hyaluronidases were hit the worst by
is immunotherapy, which aims to activate the patient’s these changes. There have been attempts made, such as
immune system to recognize and attack cancer cells coating nanocarriers with hyaluronidase, to increase the
within the TME [190]. Checkpoint inhibitors, such as ability of chemical treatments conveyed by nanocarriers
PD-1 and CTLA-4 inhibitors, have shown remarkable to enter solid tumors (HAase). This easy-to-implement
success in this regard [241]. Additionally, researchers are strategy still achieves success and is very powerful against
investigating strategies to normalize the abnormal blood tumors [190]. Figure 19-B illustrates the complex inter-
vessels found in the TME, enhancing drug delivery to the actions within the TME, where various physicochemical
tumor. Angiogenesis inhibitors, like anti-VEGF drugs, factors play critical roles in shaping cancer progression
are employed to hinder the formation of new blood ves- and immune responses. Oxygen levels, pH, and reactive
sels within the tumor. Furthermore, the development of oxygen species (ROS) in the TME directly influence the
targeted therapies that disrupt specific signaling path- behavior and function of cancer cells and immune cells,
ways crucial for TME maintenance, such as the PI3K/ including M2-type macrophages. In response to these
AKT/mTOR pathway, holds promise in altering the TME conditions, cancer cells can release vascular endothelial
to make it less hospitable to cancer cells [190]. Collec- growth factor (VEGF), which promotes angiogenesis,
tively, these mechanisms offer a multifaceted approach further contributing to the heterogeneity of the TME.
to target the TME and improve the efficacy of cancer The presence of M2-type macrophages, known for their
treatment, potentially leading to more effective and per- tumor-promoting characteristics, also impacts the over-
sonalized therapeutic strategies [267]. Most cancers all TME dynamics. Collectively, these components and
have very active angiogenesis because their unchecked their interactions within the TME determine the fate of
cell division requires a great deal of energy. This is so tumor growth and metastasis, as well as the efficacy of
because, as was just said, almost all tumors are cancer- immune responses and potential therapies.
ous. Positive results from studies focusing on this quality
were found. Sengupta developed a nanoparticle delivery The use of nanomaterials in combination
approach to specifically target aberrant tumor angio- with immunotherapy treats cancer patients
genesis by encapsulating the drug combretastatin into In the realm of cancer research, several theories are rel-
the PLGA core with the chemotherapy drug DOX [90, evant to understanding the interplay between tumors
102]. Due to combretastatin causing rapid closure of and the immune system. These theories provide crucial
malignant arteries, the DOX was readily absorbed by the insights into the mechanisms by which cancer cells
tumor. With this improvement, the therapeutic index was evade immune surveillance and how immunotherapy
raised while the harmful effects were minimized. Extra- can be applied to counteract these evasive strategies
cellular matrix, generally known as ECM, has been the [215]. One prominent theory is the Tumor Immune
focus of investigation in the area of cancer treatment, in Evasion Theory, which posits that tumors can develop
addition to aberrant vasculature [267]. In cancer prolif- mechanisms to evade the immune system, enabling
eration, migration, invasion, and angiogenesis, the extra- their unchecked growth. Immune checkpoint inhibi-
cellular matrix (ECM) works as a guiding scaffold [241]. tors, such as PD-1/PD-L1 or CTLA-4 inhibitors, have
These carcinogenic properties are contributed mostly emerged as key tools in immunotherapy. These inhibi-
by collagen, HA, and a variety of enzymes. Hydroxyapa- tors block signals that would otherwise prevent immune
tite (HA) contributes to high interstitial fluid pressure cells from attacking cancer cells, thereby enhancing the
(IFP), which impedes medicine diffusion and penetra- immune response against the tumor [214]. Another piv-
tion, while collagen (the principal structural protein of otal theory is the Cancer Immunoediting Theory, which
the ECM) is responsible for establishing migratory path- describes the dynamic interaction between the immune
ways for tumor cells. Matrix metalloproteinases (MMPs) system and developing tumors. This theory identifies
and other enzymes control TME through modulating the three phases: elimination, equilibrium, and escape
activity of molecules that are not part of the extracellular [269]. Immunotherapy strategies aim to enhance the
matrix [105]. Growth factors, receptors, and cytokines elimination phase and prevent the escape of cancer cells
are examples of non-ECM molecules. Electron-current- from immune surveillance [241]. Personalized treat-
matter (ECM) interaction is one factor to consider while ments based on a patient’s unique tumor antigens are
developing nanocarriers. Patients with metastatic pan- also a focus of research within this theory [269]. The
creatic cancer benefited from a combination of standard Tumor Microenvironment Theory underscores the sig-
chemical medicines and a PEGylated type of recombinant nificance of the tumor’s surroundings [15]. Tumor
Fig. 19 A The key elements within the cancerous tumor environment, focusing on how immune cells are influenced. It highlights the role
of MDSCs (myeloid-derived suppressor cells) and Tregs (regulatory CD4 + T cells) in shaping the immune cell composition within this environment.
Reprint from [268] with a permission from Springer Nature. B The Cancer Microenvironment. The physical and chemical characteristics of the cancer
microenvironment, such as oxygen levels, pH, and reactive oxygen species (ROS), have an impact on both cancer and immune cells. M2 refers
to M2-type macrophages, while VEGF denotes vascular endothelial growth factor. Reprint from [244] with a permission from Springer Nature
microenvironments consist of various components, nanoparticles boosting innate immune signaling in

including immune cells, stromal cells, and blood vessels. APCs, anionic nanoparticles inducing tumor-specific
Some elements within this microenvironment can be immunity, and zwitterionic nanoparticles capturing
immunosuppressive and hinder immune responses antigens and releasing DAMPs from dying tumor cells
against tumors, facilitating tumor growth [215]. Immu- to activate antigen-specific T cell immune responses.
notherapy can modulate the tumor microenvironment Cancer vaccine therapy, immune checkpoint blockade
to make it more conducive to immune attacks [269]. therapy, chimeric antigen receptor (CAR)-T cell ther-
Combination therapies, like pairing checkpoint inhibi- apy, and immune system modulator therapy are only a
tors with drugs targeting angiogenesis or stromal cells, few of the immunotherapeutic approaches now in use
aim to disrupt the tumor’s protective shield [15]. Lastly, [215]. These cancer immunotherapies employ either
the Cancer Stem Cell Theory proposes that tumors con- naturally occurring chemicals or synthesized substances
tain a subpopulation of cancer stem cells with self- to stimulate or restore immune system function in order
renewal and tumor-initiating properties. These cells are to provide an anti-tumor effect. Programmed cell death
often resistant to conventional treatments and immune protein 1 (PD-1) and programmed cell death ligand 1
responses [214]. Immunotherapy approaches targeting (PD-L1) are two crucial immunological checkpoints
cancer stem cells involve identifying unique markers or (PD-L1). There has been investigation into the feasibil-
antigens associated with these cells. Such targeted strat- ity of loading immune checkpoint inhibitors (ICIs) that
egies can disrupt tumor growth and prevent recurrence target PD-1/PD-L1 onto nanocarriers for the purpose of
by eliminating the source of tumor initiation [269]. The cancer therapy. The typical immune checkpoint inhibi-
immune system plays a crucial role in cancer’s initiation tors (ICIs) of PD-1/PD-L1 showed variable advantages,
and progression. Figure 20 highlights the significant role and research conducted by BU and other institutions
of nanomaterials’ physical properties in regulating suggested that over-expression of PD-1 allowed cancer
immune responses during cancer immunotherapy. cells to perform antitumor immunity evasion [215]. To
Nanomaterial shape (Fig. 20-A) can directly or indi- provide a strong connection between PD-L1 and ICIs,
rectly influence immune responses in innate immune multivalent poly (amidoamine) dendrimers were used.
cells. For example, spherical DNA nanoparticles stimu- This enhanced medication accumulation at the tumor
late the TLR9 pathway more effectively than linear DNA location and further enhanced the PD-L1 inhibiting
fragments, while pointed gold nanoparticles exhibit action. The cytotoxic T-lymphocyte-associated protein
higher photothermal efficiency, leading to stronger anti- 4, or CTLA-4, may suppress immune responses and act
tumor immunity. The size of nanomaterials (Fig. 20-B) as an immunological checkpoint. Some common exam-
impacts lymph node targeting, retention kinetics, and ples of such molecules are antibodies, proteins, and
overall immunogenicity. By adjusting nanoparticle size, small-molecule inhibitors. One important role that nan-
one can selectively target lymph nodes or antigen-pre- oparticles play in the delivery of drugs is as carriers for
senting cells (APCs). Larger nanoparticles, such as those the drugs themselves. Using these technologies, new
with CD3/CD28 antibodies, bind more effectively to T nanoplatforms could be made, and it is hoped that they
cell receptors, thus enhancing T cell immunity. Moreo- will be more effective and bioavailable than current
ver, surface charge (Fig. 20-C) can directly or indirectly therapies [269]. This approach includes the use of
stimulate immune responses, with cationic immune checkpoint inhibitors, oncolytic viruses,
(See figure on next page.)

Fig. 20 The regulation of immune responses in cancer immunotherapy by nanomaterials’ physical properties. A, The shape of nanomaterials can
directly or indirectly influence immune responses in innate immune cells. Spherical DNA nanoparticles more effectively stimulate the TLR9 pathway
to enhance innate immunity compared to linear DNA fragments. Pointed gold nanoparticles have a higher photothermal efficiency than spherical
ones, resulting in greater DAMP release and stronger antitumor immunity. pH-responsive shape transitions from spheres to nanosheets promote
inflammasome activation by destabilizing lysosomes, yielding better antitumor immunity than nanorods. The size of organic or inorganic
nanomaterials impacts lymph node targeting and nanoparticle retention kinetics, affecting both innate and adaptive immunity for antigen-specific
immunogenicity. B, Nanoparticle size influences immunological responses in both innate and adaptive immunity. Adjusting nanoparticle size
affects targeting locations; smaller nanoparticles target lymph nodes, while larger ones target antigen-presenting cells (APCs). Large nanoparticles
with CD3/CD28 antibodies bind more effectively to T cell receptors than small ones, enhancing T cell immunity. Mesoporous silica nanoparticles
with larger pores enable rapid release of immunostimulatory molecules, sensitizing APCs to trigger antitumor responses. C, The surface charge
of nanomaterials can directly or indirectly stimulate immune responses. Cationic nanoparticles boost innate immune signaling in APCs, leading
to antitumor responses. Anionic nanoparticles, such as mRNA vaccines, when administered systemically, preferentially target the spleen, inducing
tumor-specific immunity. Zwitterionic nanoparticles can capture antigens and release DAMPs from dying tumor cells, reprogramming APCs
to activate antigen-specific T cell immune responses. Reprint from [130] with a permission from Springer Nature
Fig. 20 (See legend on previous page.)

adoptive cell therapy, immune stimulators, and cytokine nanoparticles to develop cancer vaccines, with the aim
therapy in combination with various nanoparticle drug of boosting their efficacy [15].
delivery systems. These combinations have been shown
to have synergistic effects, improving the overall efficacy Metabolic effects of nanomaterials on drugs
of the treatments [241]. The administration sequence Figure 21 illustrates the significant impact of nanomate-
and dose ratio of these drug combinations vary, with rial physical properties on immune cell function. In par-
some being administered simultaneously and others ticular, T cell immunity is influenced by substrate stiffness
sequentially. Despite the promising therapeutic out- and external forces, with rigid substrates enhancing cyto-
comes, these combinations may lead to adverse effects toxic capabilities through the facilitation of immunologi-
such as immune-related adverse events, flu-like symp- cal synapse formation. Additionally, mechanical stress
toms, injection site reactions, and neurotoxicity. serves as a stimulant for T cells by activating PIEZO1
Table 12 highlights the potential of combining nanoma- mechanosensory ion channels. Substrate rigidity plays a
terials with immunotherapy for the treatment of cancer crucial role in regulating natural killer (NK) cell immunity
patients [215]. Nanoparticles have gained significant as well. Furthermore, B cells demonstrate selectivity in
attention in the field of cancer immunotherapy due to antigen extraction from antigen-presenting cells (APCs)
their versatile applications. These nanomaterials pri- based on the rigidity of the APC membranes. The physi-
marily target cancer cells, allowing for enhanced drug cal factors in nanomaterial design, such as dimensions
delivery while minimizing side effects. By encapsulating and surface charges, also have implications for T cell acti-
immunotherapeutic agents within liposomal nanoparti- vation by modifying direct binding to T cell receptors.
cles, researchers have been able to achieve controlled The size and multivalency of nanoparticles that mimic
and precise drug delivery to tumor sites [269]. However, APCs are important determinants of T cell activation and
challenges remain, such as the potential for these nano- growth. Notably, multivalent spiky protein nanoparticles
particles to evade the immune system and concerns exhibit enhanced interaction with B cell receptors, lead-
regarding their toxicity. Some examples of these nano- ing to a more efficient promotion of antibody production
particles in action include liposomal nanoparticles compared to uncoated spike proteins. Drug metabolism
loaded with immunotherapeutic agents for cancer treat- is a convoluted process. The MPS, which is also known
ment [15]. Quantum dots, another class of nanomateri- as the reticuloendothelial system or the macrophage
als, are being explored for their role in targeted system, is a network of immune cells that includes both
immunotherapy. These tiny semiconductor particles blood-borne monocytes and tissue-based macrophages.
have shown promise in the precise imaging and target- Components of the MPS, such as immune cells in the
ing of tumor-associated antigens, allowing for real-time liver, spleen, or lungs, may react to exogenous molecules,
monitoring of immunotherapy progress. However, in this case, chemical drugs [92]. The drugs’ half-life will
quantum dots also face challenges, including potential be significantly shortened due to the rapid elimination by
toxicity and concerns about immunogenicity. Research- activated macrophages or leukocytes. Surface modifica-
ers have developed quantum dot-based systems for tar- tions, such as PEG or a specific peptide, on nanocarriers
geted drug delivery with the goal of improving cancer have been demonstrated to inhibit MPS clearance, result-
treatment [270]. Nanotubes, such as carbon nanotubes, ing in an increased half-life of the medication. Impor-
have emerged as potential vehicles for delivering tant to the function of the kidneys is their ability to filter
immune checkpoint inhibitors in cancer immunother- blood and other chemicals. Numerous characteristics,
apy. They offer advantages like controlled drug release including particle size, shape, and surface charge, corre-
and sustained immunomodulation. However, issues late with renal clearance rate. Renal clearance is a crucial
related to their clearance from the body and concerns component in the dispersion of traditional pharmaco-
about biocompatibility have to be addressed. Some logic medicines [9]. Optimal renal clearance is crucial for
studies have explored the use of carbon nanotubes for decreasing nanocarrier toxicity. Table 13 highlights the
the delivery of immune checkpoint inhibitors, aiming to toxicity profiles of various nanocarrier types, revealing
enhance their therapeutic effectiveness [109]. Nanopar- important information about their potential hazards and
ticles have also found applications in the development how to mitigate them. For example, liposomes can induce
of vaccines for immunotherapy. By improving antigen dose-dependent hepatotoxicity through the generation
presentation and enhancing the immune response, nan- of reactive oxygen species (ROS), resulting in apopto-
oparticle-based vaccines show promise. However, chal- sis in an acute time frame. To counteract this, the use of
lenges include limited vaccine stability and potential antioxidants or reduction of drug dose can be employed.
toxicity. Researchers have investigated the use of gold Polymeric nanoparticles, on the other hand, exhibit non-
linear nephrotoxicity in a sub-acute duration, primarily
Table 12 The use of nanomaterials in combination with immunotherapy treats cancer patients
Therapeutic Approach Drug Combination Administration Synergy Adverse Effects References
Sequence
Immune Checkpoint Inhibi- Anti-PD-1 antibody + Paclitaxel- Simultaneous Synergistic Immune-related adverse events [215]
tor + Nanoparticle Drug Deliv- loaded polymeric nanoparticles (irAEs) such as rash, fatigue,
ery System diarrhea
Oncolytic Virus + Nanoparticle T-VEC + Docetaxel-loaded liposo‑ Sequential Synergistic Influenza-like symptoms, mild [215]
Drug Delivery System mal nanoparticles rash
Adoptive Cell Therapy + Nano- CAR-T cells + siRNA-loaded nano‑ Simultaneous Synergistic Cytokine release syndrome, [214]
particle Drug Delivery System particles neurotoxicity
Immune Stimulator + Nanopar- CpG-ODN + Doxorubicin-loaded Sequential Synergistic Flu-like symptoms, injection site [269]
ticle Drug Delivery System liposomal nanoparticles reactions
Nanoparticle Drug Delivery IL-2-loaded nanoparticles + Doxo‑ Simultaneous Synergistic Fever, chills, hypotension [271]
System + Cytokine Therapy rubicin-loaded liposomes
Immune Checkpoint Inhibi- Anti-CTLA-4 antibody + Sirolimus- Sequential Synergistic Diarrhea, rash, colitis [241]
tor + Nanoparticle Drug Deliv- loaded polymeric nanoparticles
ery System
Oncolytic Virus + Nanoparticle Adenovirus + Docetaxel-loaded Simultaneous Synergistic Fatigue, fever, nausea [215]
Drug Delivery System lipid nanoparticles
Adoptive Cell Therapy + Nano- TILs + Paclitaxel-loaded dendrim‑ Simultaneous Synergistic Cytokine release syndrome, [215]
particle Drug Delivery System ers neurotoxicity
Immune Stimulator + Nanopar- CpG-ODN + Curcumin-loaded Sequential Synergistic Injection site reactions, mild [269]
ticle Drug Delivery System polymeric nanoparticles gastrointestinal symptoms
Nanoparticle Drug Delivery Imiquimod-loaded nanoparti‑ Simultaneous Synergistic Injection site reactions, flu-like [43]
System + TLR Agonist cles + Gemcitabine symptoms
Immune Checkpoint Inhibi- Anti-PD-1 antibody + Docetaxel- Sequential Synergistic Fatigue, neutropenia, anemia [15]
tor + Nanoparticle Drug Deliv- loaded nanocrystals
ery System
Oncolytic Virus + Nanoparticle Measles virus + Paclitaxel-loaded Simultaneous Synergistic Injection site reactions, fever, [215]
Drug Delivery System liposomes fatigue
Adoptive Cell Therapy + Nano- CAR-T cells + Nanogels loaded Simultaneous Synergistic Cytokine release syndrome, [214]
particle Drug Delivery System with anti-PD-1 antibody hypotension
Immune Stimulator + Nanopar- Poly(I:C) + Doxorubicin-loaded Sequential Synergistic Flu-like symptoms, injection site [269]
ticle Drug Delivery System liposomes reactions
Nanoparticle Drug Delivery Polymeric nanoparticles loaded Simultaneous Synergistic Injection site reactions, fever [101]
System + Cancer Vaccine with tumor antigens + Adjuvant
Immune Checkpoint Inhibi- Anti-PD-L1 antibody + Paclitaxel- Sequential Synergistic Nausea, fatigue, neuropathy [215]
tor + Nanoparticle Drug Deliv- loaded nanofibers
ery System
Nanoparticle Drug Delivery Oxaliplatin-loaded nanoparti‑ Simultaneous Synergistic Peripheral neuropathy, diarrhea [49, 50]
System + Chemotherapy cles + 5-FU
Immune Checkpoint Inhibi- Anti-CTLA-4 antibody + Paclitaxel- Sequential Synergistic Diarrhea, fatigue, neutropenia [272]
tor + Nanoparticle Drug Deliv- loaded micelles
ery System
Oncolytic Virus + Nanoparticle Newcastle disease virus + Irinote‑ Simultaneous Synergistic Influenza-like symptoms, mild [25, 26]
Drug Delivery System can-loaded liposomes rash
Adoptive Cell Therapy + Nano- CAR-T cells + DOX-loaded gold Simultaneous Synergistic Cytokine release syndrome, [214]
particle Drug Delivery System nanoparticles neurotoxicity
Immune Stimulator + Nanopar- MPLA + Gemcitabine-loaded Sequential Synergistic Injection site reactions, flu-like [269]
ticle Drug Delivery System liposomes symptoms
Nanoparticle Drug Delivery R848-loaded nanoparticles + Doc‑ Simultaneous Synergistic Injection site reactions, myelosup‑ [43]
System + TLR Agonist etaxel pression
Immune Checkpoint Inhibi- Anti-PD-1 antibody + Doxoru‑ Sequential Synergistic Fatigue, neutropenia, anemia [109]
tor + Nanoparticle Drug Deliv- bicin-loaded carbon nanotubes
ery System
Oncolytic Virus + Nanoparticle Reovirus + Cisplatin-loaded Simultaneous Synergistic Injection site reactions, flu-like [215]
Drug Delivery System liposomes symptoms
Adoptive Cell Therapy + Nano- TCR-T cells + Paclitaxel-loaded Simultaneous Synergistic Cytokine release syndrome, [215]
particle Drug Delivery System solid lipid nanoparticles neurotoxicity
Therapeutic Approach Drug Combination Administration Synergy Adverse Effects References
Sequence
Immune Stimulator + Nanopar- R848 + Gemcitabine-loaded Sequential Synergistic Injection site reactions, flu-like [43]
ticle Drug Delivery System dendrimers symptoms
Nanoparticle Drug Delivery PLGA nanoparticles loaded Simultaneous Synergistic Injection site reactions, fever [273]
System + Cancer Vaccine with tumor antigen + CpG-ODN
Immune Checkpoint Inhibi- Anti-PD-L1 antibody + Paclitaxel- Sequential Synergistic Nausea, fatigue, neuropathy [215]
tor + Nanoparticle Drug Deliv- loaded nanocapsules
ery System
due to accumulation in renal tubules and glomeruli. signaling through multivalent interactions that induce
PEGylation and adjustment of molecular weight are STING condensation. The physical properties of nano-
viable mitigation strategies for this issue. Carbon nanomaterials, such as shape, structure, chirality, size, and
tubes cause dose-dependent pulmonary toxicity, which multivalency, can also impact innate immune signaling
manifests as inflammation, oxidative stress, fibrosis, and in DCs and macrophages. For instance, different shapes
granuloma formation over a chronic time course. Surface and structures of gold nanoparticles can modulate pro-
modification and reducing the length and aspect ratio of inflammatory signaling pathways, with nanorods activat-
the nanotubes can minimize these adverse effects. Gold ing NLRP3 inflammasomes and nanospheres/nanocubes
nanoparticles display dose-dependent cytotoxicity in a inducing ROS-mediated inflammation. The chirality of
sub-chronic period, primarily through the uptake and inorganic nanoparticles can influence immunogenicity
accumulation in mitochondria, inducing oxidative stress by interacting with specific chiral receptors like adhe-
and apoptosis. Surface coating and the use of size-lim- sion G protein-coupled receptors (AGPCRs). Moreover,
ited particles can help mitigate these risks. Iron oxide small gold nanoparticles (< 10 nm) stimulate the inflam-
nanoparticles lead to dose-dependent hemotoxicity in an masome axis, while large gold nanoparticles (> 100 nm)
acute time frame, stemming from ROS-induced apop- activate NF-κB pathways. The efficiency of DC matura-
tosis and complement activation. Surface coating and tion and antigen cross-presentation can be enhanced by
chelation of iron ions can address these concerns. Lastly, combining multivalent TLR agonists with antigens.
dendrimers have the potential to induce dose-dependent
neurotoxicity in a sub-acute duration by disrupting the Benefits and drawbacks of using nanomaterials
blood–brain barrier, activating microglia, and causing in cancer therapy
oxidative stress. Modifying the size and surface charge Nanocarriers have shown significant potential in modu-
of dendrimers, as well as using biodegradable dendrim- lating immune responses, as evidenced in Table 14. They
ers, can alleviate these problems. Many traditional drug can impact both innate and adaptive immune responses
delivery methods have trouble with these problems, through various mechanisms, such as activation of the
which makes the medicine less effective at malignant complement system, toll-like receptor signaling, and
sites and, by extension, increases the dose and makes it enhanced antigen presentation. The immune response
more toxic for normal tissue [99]. Figure 22 illustrates generated by these nanocarriers is dose-dependent and
the factors that influence immune functions in dendritic can lead to increased infiltration of immune cells and
cells (DCs) and macrophages, specifically highlighting cytokine secretion within the tumor microenvironment.
the impact of physical properties of their environment However, the use of nanocarriers can also cause adverse
and nanomaterials. The immune responses of DCs and effects, including cytokine release syndrome, infusion
macrophages are affected by various factors, including reactions, cytotoxicity, and genotoxicity. A wide range
shape, mechanical forces, surface charge, and multiva- of nanocarrier types, such as lipid-based nanoparticles,
lency. These cells can identify the shape of foreign sub- polymeric nanoparticles, dendrimers, and iron oxide
stances, such as viruses, and adjust immune signaling nanoparticles, among others, have been studied for their
accordingly. Mechanical stress activates the PIEZO1 ion immunomodulatory effects. These findings indicate
channels in antigen-presenting cells, triggering calcium the potential of nanocarriers to be utilized for various
influx and cell activation. Cationic natural polysaccha- therapeutic applications, including cancer immunother-
rides, like chitosan, can impair mitochondria, leading to apy, vaccine development, and targeted drug delivery.
the release of mitochondrial DNA (mtDNA) and upregu- While conventional chemical cancer treatments have
lating type I interferon responses via the cGAS-STING their drawbacks, nanomaterials utilized in therapy have
pathway. Poly-STING agonists further activate STING advantages. Carcinogenesis and tumorigenesis have
Fig. 21 Impact of nanomaterial physical properties on immune cell function. A, T cell immunity is affected by substrate stiffness and external
forces. Rigid substrates facilitate the formation of immunological synapses with T cells, enhancing their cytotoxic capabilities. Mechanical stress
activates T cells by stimulating PIEZO1 mechanosensory ion channels. Substrate rigidity is also crucial for regulating natural killer (NK) cell immunity.
B cells selectively extract antigens from APCs based on the rigidity of the APC membranes. B, Several physical factors in nanomaterial design
influence T cell activation. The dimensions and surface charges of nanomaterials modify direct binding to T cell receptors. The size and multivalency
of nanoparticles mimicking APCs affect T cell activation and growth. Multivalent spiky protein nanoparticles interact more effectively with B cell
receptors, promoting antibody production compared to uncoated spike proteins. Reprint from [130] with a permission from Springer Nature
been characterized by a number of telltale features. by their inability to target cancer cells while sparing
Replication-independent immortality, angiogenic stimu- healthy ones. Because of this, finding the optimal dos-
lation, invasion and metastasis activation, inflamma- age while also using an advanced targeting DDS is crucial
tory response, genomic instability, and mutation are in cancer therapy. Cancer patients who are treated with
all potential outcomes [238]. The efficiency and safety chemical treatments must endure several "fortifications"
of traditional chemotherapy and radiation are limited before the drugs may reach their tumors. Among these
Table 13 Nanocarrier toxicity profiles

Nanocarrier Type Toxicity Endpoint Dose–Response Time Course Mechanism of Toxicity Mitigation Strategies References
Liposomes Hepatotoxicity Dose-dependent Acute Reactive oxygen species- Use of antioxidants; [13]
induced apoptosis reduction of drug dose
Polymeric nanoparticles Nephrotoxicity Nonlinear Sub-acute Accumulation in renal Use of PEGylation; [90, 102]
tubules and glomeruli adjustment of molecular
weight
Carbon nanotubes Pulmonary toxicity Dose-dependent Chronic Inflammation, oxidative Surface modification; [90, 102]
stress, fibrosis, and granu‑ reduction of length
loma formation and aspect ratio
Gold nanoparticles Cytotoxicity Dose-dependent Sub-chronic Uptake and accumula‑ Surface coating; use [121]
tion in mitochondria, of size-limited particles
inducing oxidative stress
and apoptosis
Iron oxide nanopar- Hemotoxicity Dose-dependent Acute ROS-induced apoptosis; Surface coating; chelation [121]
ticles complement activation of iron ions
Dendrimers Neurotoxicity Dose-dependent Sub-acute BBB disruption, microglial Modification of den‑ [99]
activation, oxidative stress drimer size and surface
charge; use of biodegrad‑
able dendrimers
"fortifications" are the innate immune system, the vascu- while surface charge and size direct the targeting of
lar system, the immune system, the blood–brain barrier, tumor-associated macrophages (TAMs) within the tumor
and the kidneys [48, 54]. The normal tissue microenvi- microenvironment.
ronment, vasculature, RES, and BBB, in addition to renal
filtration, all play important roles in the body’s resistance Biotechnology and nanomaterials in blood–brain
to infections under physiological conditions. The use of barrier penetration and drug delivery
chemical drugs to combat cancer is impacted by these The Blood–Brain Barrier (BBB) is a complex and essential
defenses. The proliferation pattern of normal cells is dif- protective barrier that regulates the passage of substances
ferent from that of malignant cells. Cancerous tissues between the bloodstream and the brain [286]. Its primary
have a high concentration of interstitial fluid, hyperactive role is to prevent harmful chemicals and pathogens from
angiogenesis due to an excess of angiogenic agents, and a entering the brain, while allowing essential nutrients to
dense extracellular matrix [95]. Figure 23 illustrates the pass through. This natural barrier, while crucial for brain
significant influence of nanomaterial physical properties health, presents a significant challenge when it comes to
on physiological outcomes, emphasizing the importance delivering drugs to treat brain diseases, including can-
of tailoring these properties to achieve specific objectives. cer [287]. The use of nanocarriers has shown promise in
Figure 23-A, it is demonstrated that altering nanoparticle targeting the blood–brain barrier (BBB), as depicted in
surface charges affects protein adsorption and immune Fig. 24. One promising approach to overcome this chal-
system interactions, as well as the preservation of serum lenge involves the use of nanocarriers, which are specially
proteins that are recognized by circulating macrophages. designed nanoparticles that can transport drugs across
Furthermore, the rigidity of liposomes influences the type the BBB. These nanocarriers are often modified with
of protein adsorbed to their surface, which subsequently specific ligands on their surface to enhance their ability
impacts liposome clearance by macrophages. Figure 23-B to target the BBB and facilitate drug delivery to the brain
highlights the role of nanomaterial properties in target- [288]. In the rapidly evolving landscape of biotechnology
ing specific locations. By manipulating the surface charge and nanomaterials, professionals on LinkedIn are at the
of systemically delivered liposomes, target organs can forefront of pioneering breakthroughs in drug delivery
be determined. Additionally, the size of subcutaneously to the brain. With the challenges posed by the Blood–
injected nanoparticles can directly or indirectly control Brain Barrier, experts in this field leverage their exper-
lymph node targeting and retention kinetics within these tise in nanocarrier modification, innovative techniques
nodes. Finally, (Fig. 23-C), adjusting physical properties like the Enhanced Permeability and Retention (EPR)
in nanomaterial design steers interactions with particular effect, and the potential of gold nanoparticles (AuNPs) to
immune cell subtypes. Nanomaterial shapes engage with develop targeted therapies for brain diseases [289]. They
distinct innate immune cell subsets from various organs, share insights, collaborate on cutting-edge research, and
Fig. 22 Factors affecting immune functions in dendritic cells and macrophages. A, The immune responses of dendritic cells (DCs)
and macrophages are influenced by the physical properties of their surrounding environment, including shape, mechanical forces, surface charge,
and multivalency. DCs and macrophages can detect the shape of foreign substances (e.g., viruses) and modify immune signaling accordingly.
Mechanical stress activates PIEZO1 ion channels in antigen-presenting cells, leading to calcium influx and cell activation. Natural polysaccharides
with cationic charges (e.g., chitosan) can damage mitochondria, causing the release of mitochondrial DNA (mtDNA) and the upregulation of type I
interferon responses via the cGAS-STING pathway. Poly-STING agonists activate STING signaling through multivalent interactions that cause STING
condensation. B, The physical properties of nanomaterials, such as shape, structure, chirality, size, and multivalency, can affect innate immune
signaling in DCs and macrophages. Different shapes and structures of gold nanoparticles can alter pro-inflammatory signaling pathways (nanorods
activate NLRP3 inflammasomes; nanospheres and nanocubes induce ROS-mediated inflammation). The chirality of inorganic nanoparticles
can also impact immunogenicity by interacting with specific chiral receptors like adhesion G protein-coupled receptors (AGPCRs). Small gold
nanoparticles (< 10 nm) stimulate the inflammasome axis, while large gold nanoparticles (> 100 nm) activate NF-κB pathways. Multivalent TLR
agonists combined with antigens enhance DC maturation and antigen cross-presentation more efficiently. cGAMP, cyclic GMP–AMP; LLPS, liquid–
liquid phase separation; TNF, tumor necrosis factor. Reprint from [130] with a permission from Springer Nature
Table 14 Influence of nanocarriers on immune response
Nanocarrier Type Immune Response Type Immunomodulatory Dose–Response Tumor Immune Adverse Effects References
Mechanism Microenvironment
Lipid-based nanoparticles Innate immune response Activation of complement Dose-dependent Increased infiltration of myeloid Cytokine release syndrome, [57]
system, TLR signaling cells, pro-inflammatory infusion reactions
cytokine secretion
Polymeric nanoparticles Adaptive immune response Enhanced antigen presenta‑ Dose-dependent Increased infiltration of CD8 + T T cell exhaustion, autoimmune [90, 102]
tion, T cell activation cells, cytokine secretion reactions
Dendrimers Innate and adaptive immune Toll-like receptor (TLR) agonist, Dose-dependent Increased infiltration of den‑ Hemolysis, thrombocytopenia, [99]
response enhanced antigen presentation dritic cells, T cells, and natural anaphylaxis
killer cells
Iron oxide nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Iron overload, liver toxicity [121]
natural killer cells cells, cytokine secretion
Gold nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Thrombosis, renal toxicity [121]
(2023) 22:169
inflammasome activation cells, cytokine secretion

Quantum dots Adaptive immune response Enhanced antigen presenta‑ Dose-dependent Increased infiltration of CD8 + T Cytotoxicity, genotoxicity [176]
tion, T cell activation cells, cytokine secretion
Mesoporous silica nanopar- Innate immune response TLR signaling, inflammasome Dose-dependent Increased infiltration of myeloid Silica-induced lung fibrosis, [23]
ticles activation cells, pro-inflammatory inflammation
cytokine secretion
Protein-based nanoparticles Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, allergic [57]
activation cells, cytokine secretion reactions
Carbon-based nanoparticles Innate immune response Phagocytosis, cytokine secre‑ Dose-dependent Increased infiltration of myeloid Pulmonary toxicity, fibrosis [57]
tion cells, pro-inflammatory
cytokine secretion
Liposomes Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Hypersensitivity reactions, [13]
response delivery of adjuvants of immune cells, cytokine phagocytosis by macrophages
secretion
Virus-like particles Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, autoim‑ [274]
activation cells, cytokine secretion munity
Nanogels Innate immune response Encapsulation of drugs, TLR Dose-dependent Increased infiltration of myeloid Cytotoxicity, renal toxicity [275]
signaling cells, pro-inflammatory
cytokine secretion
Nanodiamonds Innate and adaptive immune Cytokine secretion, dendritic Dose-dependent Increased infiltration Pulmonary toxicity, genotoxic‑ [238]
response cell activation of immune cells, cytokine ity
secretion
Magnetic nanoparticles Innate immune response Induction of heat shock Dose-dependent Increased infiltration of myeloid Magnetic field-induced tissue [276]
proteins, activation of mac‑ cells, cytokine secretion damage, cellular stress
rophages
Nanotubes Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Cytotoxicity, genotoxicity [18, 19]
activation cells, cytokine secretion
Metal–organic frameworks Innate immune response TLR signaling, inflammasome Dose-dependent Increased infiltration of myeloid Biodegradation products, metal [101]
activation cells, pro-inflammatory toxicity
cytokine secretion
Page 81 of 103
Polymer-lipid hybrid nano- Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [57]
particles response delivery of adjuvants of immune cells, cytokine
secretion
Exosomes Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Immunogenicity, clearance rate [30]
response delivery of adjuvants of immune cells, cytokine
secretion
RNA nanoparticles Innate and adaptive immune Antigen presentation, TLR Dose-dependent Increased infiltration Immunogenicity, stability [277]
response signaling of immune cells, cytokine
secretion
Metal nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Biodegradation products, metal [277]
inflammasome activation cells, cytokine secretion toxicity
(2023) 22:169
Supramolecular nanopar- Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [278]
ticles response delivery of adjuvants of immune cells, cytokine
secretion
Hydrogels Innate immune response Encapsulation of drugs, TLR Dose-dependent Increased infiltration of myeloid Biocompatibility, mechanical [279]
signaling cells, cytokine secretion stability
Lipid-coated calcium phos- Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, stability [57]
phate nanoparticles activation cells, cytokine secretion
Metallic oxide nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Biodegradation products, metal [243]
inflammasome activation cells, cytokine secretion toxicity
Core–shell nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [243]
secretion
Janus nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [57]
secretion
Lipid-protein nanoparticles Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, stability [57]
Layer-by-layer nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [99]
secretion
Polymeric micelles Innate immune response Encapsulation of drugs, TLR Dose-dependent Increased infiltration of myeloid Biocompatibility, stability [90, 102]
signaling cells, cytokine secretion
Polymer vesicles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [90, 102]
secretion
Plasmonic nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Thrombosis, renal toxicity [280]
Page 82 of 103
Protein-coated nanoparticles Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, stability [100]
Silica nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Silica-induced lung fibrosis, [88]
response delivery of adjuvants of immune cells, cytokine inflammation
secretion
Smart nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [281]
secretion
Supramolecular assemblies Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [282]
secretion
(2023) 22:169
Theranostic nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [130]
response delivery of imaging agents of immune cells, cytokine
secretion
Cell-derived nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Immunogenicity, clearance rate [196]
secretion
Multifunctional nanopar- Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [18]
secretion
Carbon dots Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [18]
secretion
Exosome-mimetic nanopar- Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [283]
secretion
Lipid-polymer hybrid nano- Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [57]
particles response delivery of adjuvants of immune cells, cytokine
secretion
Iron oxide nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Iron overload, oxidative stress [121]
Gold nanoparticles Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Thrombosis, renal toxicity [121]
Carbon nanotubes Adaptive immune response Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Cytotoxicity, genotoxicity [18]
Albumin nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [27]
secretion
Page 83 of 103
Liposomes Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [13]
secretion
(2023) 22:169
Solid lipid nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [57]
secretion
Graphene oxide nanopar- Innate immune response Activation of macrophages, Dose-dependent Increased infiltration of myeloid Pulmonary toxicity, genotoxic‑ [174]
ticles inflammasome activation cells, cytokine secretion ity
Self-assembled nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [272]
secretion
Polymer-drug conjugates Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [90, 102]
secretion
Peptide-based nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [56]
secretion
Viral nanoparticles Innate and adaptive immune Antigen presentation, T cell Dose-dependent Increased infiltration of CD8 + T Immunogenicity, potential [109]
response activation cells, cytokine secretion for viral replication
Hybrid nanoparticles Innate and adaptive immune Encapsulation of drugs, co- Dose-dependent Increased infiltration Biocompatibility, stability [284]
secretion
Polyplexes Innate and adaptive immune Encapsulation of nucleic acids, Dose-dependent Increased infiltration Biocompatibility, stability [285]
response TLR signaling of immune cells, cytokine
secretion
Page 84 of 103
explore the latest advancements in focused ultrasound Nanoparticles (AuNPs), have been extensively researched
(FUS) technology. By connecting with these visionar- for their potential in drug delivery to the brain [289]. For
ies on LinkedIn, you can stay informed about the latest example, methotrexate (MTX) loaded onto glutathione
developments in biotechnology and nanomaterials, fos- PEGylated liposomes has shown promise in increasing
tering professional growth and contributing to the future drug uptake in the brain. Gold nanoparticles (AuNPs)
of brain disease treatment [289]. One such modifica- have garnered significant attention due to their unique
tion involves attaching a glucose ligand (Gluc(6)/m) to properties [288]. Researchers have found that certain-
the nanocarrier’s surface. This modification enables the sized AuNPs can be targeted to brain tumors through
nanocarriers to bind to receptors in the BBB, allowing the EPR effect. Surface modifications using peptides
them to traverse this protective barrier effectively. Real- and antibodies have further enhanced the selectivity of
time observations using techniques like intravital mul- AuNPs for cancer cells [287]. Additionally, AuNPs have
tiphoton microscopy have demonstrated the successful been explored for their photothermal therapy (PTT) and
passage of Gluc(6)/m nanocarriers across the BBB [288]. immunological applications. One notable development is
These nanocarriers have been shown to accumulate in the creation of peptide-modified AuNPs, such as AuNPs-
various brain cell types, including neurons, microglia, A&C-R, which can penetrate the BBB and bind to glioma
and astrocytes, while sparing the surrounding healthy cells [290]. When loaded with chemotherapeutic agents
tissue. This promising evidence suggests that Gluc(6)/m like DOX, these AuNPs have demonstrated higher effi-
nanocarriers hold great potential for targeted drug deliv- cacy compared to free drugs. Finally, ultrasound treat-
ery to the brain [289]. Traditional methods of administer- ment has emerged as a potential method to improve the
ing chemotherapy for brain cancer often involve invasive delivery of AuNPs and other nanomaterials through the
procedures like intraventricular or intracerebral injec- BBB. Studies have shown that ultrasound can temporarily
tions, which can lead to side effects due to the high toxic- open tight junctions, facilitating the entry of nanoparti-
ity and poor distribution of drugs within the brain [287]. cles and enhancing their therapeutic effects [288].
To address these issues, researchers are exploring the use
of various nanomaterials as drug carriers to improve drug Strategies for using nanoparticles to target
delivery across the BBB. Several techniques and nano- individual cancer cells in cancer therapy
materials have been studied for their ability to facilitate Targeted therapies have become an important tool in the
BBB penetration and enhance drug delivery [289]. These fight against cancer, as they aim to specifically interfere
include: 1) Enhanced Permeability and Retention (EPR) with biological pathways or proteins involved in cancer
Effect: This phenomenon takes advantage of the leaky growth and progression. Apoptosis and angiogenesis are
vasculature in tumors, allowing nanomaterials to accu- two key areas of focus in targeted therapy, and small-
mulate selectively in cancerous tissues [290]. 2) Pep- molecule inhibitors and monoclonal antibodies are two
tide-Modified Endocytosis and Transcytosis: Peptides of the most important tools in this field [52]. Nanopar-
attached to nanomaterials can promote their uptake by ticles offer a promising platform for targeted therapies,
brain cells through receptor-mediated endocytosis and as they can be loaded with targeted therapeutic drugs or
transcytosis processes. 3) Focused Ultrasound (FUS): modified with specifically targeted monoclonal antibod-
Ultrasound treatment has been investigated as a means ies on the surface. Compared to non-targeted therapies,
to temporarily disrupt the tight junctions of the BBB, nanoparticles with targeted modifications have shown
creating a temporary pathway for nanomaterials to cross higher efficacy and lower toxicity [15]. The EPR effect,
[287]. Various types of nanomaterials, such as Nano- which allows nanoparticles to passively target tumors
structured Lipid Carriers (NLCs), liposomes, and Gold by exploiting leaky vasculature and poor lymphatic
(See figure on next page.)

Fig. 23 Influence of nanomaterial physical properties on physiological outcomes. A, Various nanomaterial features impact protein adsorption
and immune system interactions. Altering nanoparticle surface charges influences the preservation of serum proteins, which can be identified
by circulating macrophages. The rigidity of liposomes determines the specific protein type that adsorbs to the surface, which in turn affects
liposome clearance by macrophages. (B), Several nanomaterial properties also affect targeting locations. Surface charge manipulation
of systemically delivered liposomes helps determine the target organs. The size of subcutaneously injected nanoparticles can directly or indirectly
control lymph node targeting and nanoparticle retention kinetics within lymph nodes. C, Adjusting physical properties in nanomaterial design
dictates interactions with particular immune cell subtypes. Nanomaterial shapes play a role in their engagement with specific innate immune cell
subsets from various organs. Both surface charge and size help direct the targeting of tumor-associated macrophages (TAMs) within the tumor
microenvironment. APC denotes antigen-presenting cell; ApoA1 represents apolipoprotein A1; and DC refers to dendritic cell. Reprint from [130]
Fig. 23 (See legend on previous page.)

Fig. 24 The use of nanocarriers to target the blood–brain barrier (BBB). The nanocarriers are modified with a glucose ligand on their surface
(referred to as Gluc(6)/m), which allows them to bind to receptors in the BBB. Real-time observations show that the 25%Gluc(6)/m nanocarriers can
successfully cross the BBB. Intravital multiphoton microscopy images of mouse cerebrum 48 h after administration show the presence of Gluc(6)/m
nanocarriers (in red) in the brain. Immunohistochemical staining of mouse brains after administration of Null/m, 10%Gluc(6)/m, 25%Gluc(6)/m,
and 50%Gluc(6)/m (in red) for 48 h, while the brain capillary endothelial cells, neurons, microglia, and astrocytes are stained in green color. These
results demonstrate the potential of the Gluc(6)/m nanocarriers for targeted drug delivery to the brain. Reprint from [34] with a permission
from Wiley
drainage, is a crucial part of the developing nanocarrier to enhance their accumulation in tumors and improve
targeting strategy. Figure 25 illustrates how nanocarri- their anti-tumor efficacy. Figure 25-B demonstrates how
ers equipped with ligands can target tumor vasculature. GLUT1-mediated vascular translocation of CDDP/m
Figure 25-A shows how polymeric micelles loaded with into tumors can take place. Figure 25-A and B dem-
cisplatin and installed with glucose (Gluc-CDDP/m) can onstrate the targeting of tumor vasculature by ligand-
target tumors by utilizing the GLUT1-glucose pathway installed nanocarriers. This approach has the potential to
Fig. 25 The targeting of tumor vasculature by nanocarriers equipped with ligands. The first image (A) shows the targeting of tumors
by cisplatin-loaded polymeric micelles with glucose installed (Gluc-CDDP/m). These micelles use the GLUT1-glucose pathway to enhance their
accumulation in tumors and improve their anti-tumor efficacy. The second image (B) demonstrates the GLUT1-mediated vascular translocation
of CDDP/m into tumors. Both images (A and B) depict the targeting of tumor vasculature by ligand-installed nanocarriers. Reprint from [34]
with a permission from Wiley
increase the effectiveness of chemotherapy by specifically [48, 54]. This can be achieved by incorporating thera-
targeting tumor vasculature, which plays a critical role peutic agents into the nanocarriers or modifying their
in tumor growth and metastasis. In addition to passive surfaces to improve their ability to target cancer cells.
targeting, nanoparticles can also be actively targeted by Overall, targeted therapies and nanotechnology have the
conjugating them with antibodies, peptides, aptamers, potential to revolutionize cancer treatment by offering
and small compounds [97]. The success of active target- more effective and targeted treatments with lower toxic-
ing depends on interactions between the nanocarriers ity to normal cells. Continued research and development
and the tumor microenvironment, multi-partite sym- in this field will help us to overcome the challenges asso-
biosis, and the immune system. Both passive and active ciated with nanomaterials and develop more effective
targeting approaches can be used to design drug delivery cancer treatments [48, 54].
systems (DDS) that can increase the efficacy of targeted
therapies and improve the success of cancer treatment
Fig. 26 A visual representation of nanocarriers equipped with ligands that facilitate targeted cellular internalization. Reprint from [34]
with a permission from Wiley
Considerations for the future of nano‑DDS circuit the targeting moiety, binding to transferrin receptors
design on cancer cells, particularly those over-expressing this
Figure 26 serves as a visual representation of nanocarri- receptor, such as HepG2 cells [44]. Experimental evi-
ers designed for the targeted delivery of drugs or thera- dence has demonstrated that modifying the surface of
peutic agents to specific cells or tissues within the body. SLNs/pEGFP enhances their efficiency as gene deliv-
These nanocarriers are equipped with ligands, mol- ery vehicles, whether in vitro or in vivo. This increased
ecules capable of binding to specific receptors present selectivity results in drug accumulation predominantly
on cell surfaces [172]. This design enables precise cel- at cancer sites, reducing toxicity and minimizing the risk
lular internalization, ensuring that the nanocarriers are of drug resistance [178, 179]. Despite the rapid growth
primarily taken up by cells expressing the correspond- of nanomaterial utilization in cancer treatment, numer-
ing receptors. This targeted approach holds immense ous unresolved challenges persist [31]. A significant
potential for enhancing drug efficacy while minimiz- concern revolves around the potential toxicity of nano-
ing side effects by limiting exposure to non-target cells materials. Due to their minuscule size, nanomaterials
[60]. may overcome physiological barriers, potentially leading
In the context of anti-cancer nano-drug delivery to unforeseen health hazards. Nanoparticles (NPs) have
systems (nano-DDS), there are three primary objec- been shown to induce free radical damage to biological
tives: improving therapeutic effectiveness, reducing structures such as membranes, organelles, and DNA [31].
side effects, and preventing the development of drug Moreover, nanomaterials delivered into cells might trig-
resistance. Nano-DDS, operating on an intuitive level, ger immune responses by engaging cell surface receptors.
can address multiple challenges simultaneously, mak- Addressing nanomaterial toxicity requires adjustments
ing them versatile tools in combating cancer [171]. One in their production to reduce potential harm [57]. The
noteworthy example involves the use of a dexametha- enhanced permeability and retention (EPR) effect is the
sone-conjugated lipid to create solid lipid nanoparticles primary passive delivery mechanism for nanoparticles
(SLN), followed by the attachment of transferrin-PEG- and has been extensively studied. However, the trans-
PE ligands to these SLNs [172]. Transferrin serves as lation of engineered nanomaterials to therapeutic use
remains a significant challenge. Researchers have endeav- large quantities of nanomaterials with the right mix of
ored to reevaluate the EPR hypothesis and explore its role attributes is a crucial step in the clinical translation of
in cancer therapy [60]. Interestingly, the EPR effect in anticancer nanoparticles [295]. A "hard" corona may
rats operates through a mechanism distinct from that in develop with proteins that have a high binding affin-
humans [9]. Recent research by Sindhwani et al. sought ity, whereas a "soft" corona arises with proteins that
to map the nanoparticle route to solid tumors using attach to nanoparticles relatively weakly [296]. This
various animal models, human tumor cells, mathemati- finding was enabled by the fact that various proteins
cal modeling, and simulation [291]. Surprisingly, they have varying binding affinities. This means that, over
found no correlation between tumor gap frequency and time, the proteins with the highest affinity for their tar-
nanoparticle accumulation in tumors. Trans-endothelial get will displace the more numerous proteins that first
routes were identified as the critical aspect of nanoparti- formed the PC [9]. The name for this phenomenon is
cle tumor extravasation [292]. These findings underscore the Vroman effect. Proteomic techniques, including
the need for further investigation into EPR efficiency quantitative analysis by means of MS, LC–MS, surface
across different cell and tissue types, suggesting that the plasmon resonance (SPR), and isothermal microcalo-
EPR effect is both species- and tumor-specific. To opti- rimetry, have been widely used in PC research (ITC)
mize the use of the EPR effect in cancer therapy, research [243]. To what extent an NP carrier might be employed
into its diverse patterns and mechanisms of nano-carrier in therapeutic applications depends in part on its phys-
transport is essential [271]. Another formidable obsta- icochemical properties (PC), which influence the way
cle to the widespread adoption of nanomaterial-based in which NP interacts with the biological environment
cancer therapies is their translation into clinical practice [208, 232]. Thus, proteomic methods add to our under-
[280]. Most studies on nanocarriers have been conducted standing of PC production and the study of NP-protein
in cell and animal models, which may not accurately rep- interactions. Proteomics of cancer looks at how many
resent human responses. While animal models can pro- proteins are present in tumor cells and in the blood
vide more accurate EPR detection than human patients, [208, 232]. Figure 27 depicts the formation of biologi-
replicating genuine human responses remains chal- cal nanovectors, which are nanoscale biological entities
lenging [293]. Metastasis is a common occurrence in that can be used for targeted drug delivery. These nan-
malignant tumors, necessitating the inclusion of metas- ovectors can be derived from various sources, includ-
tasis models in research [294]. Although finding precise ing prokaryotic, eukaryotic, and viral sources. Bacterial
solutions to these challenges is challenging, innovative minicells are created through genetic engineering of
modeling techniques such as biomimetic ’organ/tumor- Gram-positive or Gram-negative bacteria, by delet-
on-a-chip’ systems and organoid model systems could ing the Min operon, resulting in achromosomal vesi-
accelerate the research process. Utilizing suitable animal cles. Extracellular vesicles are produced by eukaryotic
models is also encouraged in these investigations [280]. cells and can be either microvesicles, formed by out-
To advance the field, collaboration between medical ward budding of the plasma membrane, or exosomes,
and materials science researchers is crucial. Modifying formed by inward budding and exocytosis. Live-atten-
the attributes of nanomaterials that significantly impact uated oncolytic viruses and virus-like particles are
nanocarrier efficacy—including size, shape, chemical viral sources of nanovectors. Oncolytic viruses con-
composition, and surface charge—requires joint efforts tain a complete genome that enables them to replicate
[60]. While nanoparticles and liposomes constitute the in transformed cells, while virus-like particles consist
majority of approved nanocarriers for cancer therapy, only of structural proteins and are incapable of replica-
translating nanocarriers with more complex architec- tion. These biological nanovectors offer great potential
tures and production processes into clinical use poses a in targeted drug delivery due to their ability to specifi-
challenge. Developing methods for efficiently producing cally interact with the target cells. Cancer proteins and
large quantities of nanomaterials with the ideal combina- surface biomarkers that aid in diagnosis and prognosis
tion of attributes is a pivotal step in realizing the clinical can be more easily identified thanks to this study. Pro-
potential of anti-cancer nanoparticles [13]. teomics has also been used to look for biomarkers that
might assist in the early detection of cancer, as well as
Nanoplatform development for proteomics to learn more about the processes underlying treatment
and cancer therapy resistance. Post-translational modifications (PTMs)
Protein coronae are the structures formed by serum are important mechanisms in the development, dis-
and cellular proteins around nanoparticles after they semination, and recurrence of cancer; kinases play
have been introduced into a biological system (PC). central roles in the corresponding alterations and path-
Finding methods that will aid in the manufacturing of ways [58]. Cancer proteomics methods identify kinase
Fig. 27 The formation of biological nanovectors, which can be derived from either prokaryotic (bacterial minicells), eukaryotic (extracellular
vesicles), or viral sources (oncolytic viruses and virus-like particles). Bacterial minicells are achromosomal vesicles that can be generated by deleting
the Min operon through genetic engineering in Gram-positive or Gram-negative bacteria. On the other hand, extracellular vesicles are produced
by eukaryotic cells through the outward budding of the plasma membrane (microvesicles) or the inward budding and exocytosis (exosomes). With
regard to viruses, live-attenuated oncolytic viruses contain a complete genome that enables them to replicate specifically in transformed cells,
while virus-like particles consist only of structural proteins and are not capable of replication. Reprint from [131] with a permission from Springer
Nature
inhibitors and other new therapeutic agents, such as Challenges and strategies in advancing
siRNA, mRNA, and gene editing materials, that may be nanocarrier clinical applications
put into a nanocarrier to increase treatment effective- Translating nanotechnology from laboratory experiments
ness [2]. It is true that research is now concentrated on to clinical applications presents a multitude of challenges
chemical medications, but it does not exclude inves- that have hindered the progress of this promising field
tigation into other innovative therapeutic agents. To [309]. One of the most prominent challenges is the com-
discover novel molecular targets, proteomic methods plex and rigorous regulatory pathway that nanocarriers
may be used to improve upon established targeting must navigate before reaching clinical approval [310].
moieties. Improvements in high throughput proteom- Nanoparticles, often used as carriers for drug delivery or
ics and other methods are making it easier for prot- imaging agents, are subject to stringent safety and effi-
eomic studies to find molecules that could be made into cacy requirements, which can be difficult to meet due to
nanocarriers for anticancer drugs [13]. By targeting their unique properties [311]. For instance, the precise
specific molecular biomarkers, such as EGFR, BRCA1, characterization of nanoparticles, including their size,
KRAS, and HER2, tailored nanocarrier formulations shape, surface charge, and stability, is essential for regula-
have shown promising clinical outcomes in patients tory approval but can be challenging due to the dynamic
with various cancer types, including non-small cell nature of nanomaterials [312]. This lack of standardized
lung cancer, breast cancer, and pancreatic cancer. These characterization methods can slow down the translation
targeted therapies have been associated with partial or process and lead to inconsistencies in data, making it dif-
complete responses, improved quality of life, and pain ficult to compare results across different studies [313].
control. The duration of these treatments varies, with Another challenge in clinical translation is the potential
some patients experiencing complete responses within for unexpected biological interactions with nanocarriers.
6–18 months. Although the cost-effectiveness of these Nanoparticles can interact with various components of
therapies ranges from low to high, the overall benefits the biological system, such as proteins, cells, and tissues,
of personalized nanocarrier-based cancer treatments which may influence their behavior and safety profile
provide a compelling case for their continued devel- [314]. Understanding these interactions and predicting
opment and implementation in oncology practice. their consequences in a clinical setting is a complex task,
Table 15 highlights the potential of nanocarrier-based as it requires interdisciplinary expertise in both nano-
personalized cancer therapy to improve treatment out- technology and biology [312]. Additionally, the long-term
comes across a diverse range of cancers.
Table 15 Nanocarrier-based personalized cancer therapy

Molecular Biomarker Treatment Strategy Clinical Outcome Cost-effectiveness References
EGFR mutation Erlotinib-loaded nanocarriers Partial response with improved High [297]
targeted to EGFR quality of life
BRCA1 mutation Poly(ADP-ribose) polymerase Complete response Moderate [190]
(PARP) inhibitor-loaded nanocarri‑ with no adverse events
ers targeted to BRCA1
KRAS mutation Gemcitabine-loaded nanocarriers Stable disease with improved pain Low [234]
targeted to tumor stroma control [298]
BRAF mutation Vemurafenib-loaded nanocarriers Complete response with skin rash High [299]
targeted to BRAF
KRAS wild-type Irinotecan-loaded nanocarriers Stable disease with improved Moderate [218]
targeted to CD44v6 quality of life
BRCA2 mutation Doxorubicin-loaded nanocarriers Partial response with improved High [300]
targeted to BRCA2 pain control
HER2 overexpression Trastuzumab-loaded nanocarriers Complete response High [301]
targeted to HER2 with no adverse events
KRAS mutation Paclitaxel-loaded nanocarriers Stable disease with improved Low [302]
targeted to tumor stroma appetite
AR overexpression Enzalutamide-loaded nanocarriers Complete response High [303]
targeted to AR with no adverse events
KRAS mutation Gemcitabine-loaded nanocarriers Partial response with improved Low [234]
targeted to tumor stroma appetite [220]
HER2 overexpression Trastuzumab-loaded nanocarriers Complete response High [221]
targeted to HER2 with no adverse events [301]
BRAF mutation Cetuximab-loaded nanocarriers Partial response with improved Moderate [304]
targeted to EGFR quality of life
BRCA1 mutation Olaparib-loaded nanocarriers Partial response with improved High [193]
targeted to BRCA1 pain control
ALK rearrangement Crizotinib-loaded nanocarriers Complete response with improvedHigh [305]
targeted to ALK appetite
KRAS mutation 5-Fluorouracil-loaded nanocarriers Stable disease with improved Low [95]
targeted to tumor stroma quality of life
HER2 overexpression Lapatinib-loaded nanocarriers Partial response with improved Moderate [306]
targeted to HER2 appetite
BRAF mutation Dabrafenib-loaded nanocarriers Complete response with skin rash High [267]
targeted to BRAF
AR overexpression Abiraterone-loaded nanocarriers Partial response with improved High [307]
targeted to AR quality of life [219]
PARP1 overexpression Olaparib-loaded nanocarriers Partial response with no adverse High [308]
targeted to PARP1 events
biocompatibility and toxicity of nanoparticles need to be efforts. This lack of harmonization can result in duplica-
thoroughly evaluated, which often involves lengthy pre- tion of efforts and hinder the accumulation of data nec-
clinical studies and can delay the progress of nanomedi- essary to convince regulatory agencies of the safety and
cine development [315]. The limited number of approved efficacy of nanocarriers [311]. To overcome these hur-
nanocarriers in clinical applications can also be attrib- dles, several strategies can be implemented. Firstly, there
uted to the substantial financial investments required is a need for increased collaboration and communication
for research, development, and regulatory compliance between researchers, regulatory agencies, and industry
[309]. Many startups and researchers lack the resources stakeholders to establish clear guidelines and standards
needed to bring their nanotechnology-based therapies for characterizing and testing nanocarriers [315]. Stand-
or diagnostics through the entire translational pipeline ardization of protocols for nanoparticle characteriza-
[310]. Furthermore, the lack of standardized protocols tion, toxicity assessment, and preclinical studies can
and guidelines for nanocarrier development and testing streamline the regulatory process and improve the con-
can lead to inefficiencies in research and development sistency of data generated in different laboratories [310].
Secondly, investments in interdisciplinary research and invasive cancer treatments, concerns about accessibility
training programs that bridge the gap between nanotech- and affordability must be addressed. There is a risk that
nology and biology are crucial [313]. Researchers with these cutting-edge treatments may only be accessible to
expertise in both fields can better understand and pre- a privileged few, exacerbating existing healthcare dispari-
dict the biological interactions of nanocarriers, leading to ties [323]. Ethical frameworks should be in place to pro-
more informed design choices and improved safety promote equitable access to these therapies, ensuring that
files. This could potentially reduce the time and resources they benefit a broad spectrum of society [320]. Moreo-
required for preclinical studies. Lastly, increased fund- ver, the ethical considerations extend to the research and
ing and support for nanotechnology research in health- development phase of nanotechnology-based cancer
care should be encouraged. Public–private partnerships, therapies [324]. Researchers and institutions involved
grants, and incentives can provide much-needed in this field have a moral responsibility to conduct their
resources to accelerate the translation of nanocarrier work with the utmost integrity. This includes disclos-
technologies [311]. This would enable more innova- ing any potential conflicts of interest, being transpar-
tors to progress their promising nanomedicine concepts ent about their research methodologies, and adhering
through the rigorous regulatory pathways and ultimately to ethical guidelines and regulations [323]. Additionally,
benefit patients with safer and more effective therapies the responsible dissemination of information is cru-
and diagnostics [310]. Overall, addressing the challenges cial. While advancements in nanotechnology for cancer
in clinical translation of nanotechnology requires a con- therapy should be shared with the scientific community
certed effort from various stakeholders, fostering col- and the public, researchers must be cautious not to ove-
laboration, standardization, and increased investment in rhype their findings or create unrealistic expectations
this transformative field [309]. [324]. Ethical communication should focus on providing
Ethical considerations accurate and balanced information, avoiding sensational-
The ethical considerations surrounding the use of ism or exaggeration of potential benefits [325]. Further-
nanotechnology in cancer therapy are multifaceted and more, the environmental impact of nanomaterials used
demand careful scrutiny [316]. Patient safety is para- in cancer therapy should be considered [321]. The ethi-
mount in any medical intervention, and this holds true cal implications of introducing new nanoparticles and
for nanotechnology-based therapies [317]. The unique nanomaterials into the environment must be thoroughly
properties of nanomaterials raise concerns about poten- assessed. Researchers and industries must strive to mini-
tial unforeseen side effects or long-term consequences mize any potential harm to ecosystems and public health
that must be thoroughly investigated before these thera- through responsible waste disposal and recycling prac-
pies can be applied to patients [318]. Preclinical testing tices [324].
should be rigorous and transparent, encompassing thor-
ough toxicity studies and a comprehensive understand- Future directions
ing of how these nanomaterials interact with the body’s Nanotechnology has emerged as a promising frontier in
biological systems. This not only ensures the safety of the the field of cancer therapy, offering innovative solutions
patients but also upholds the ethical obligation to "do no to the complex challenges associated with treating this
harm [318]". Informed consent is another crucial ethical devastating disease [326]. As we look ahead, the future
aspect in the deployment of nanotechnology in cancer of nanotechnology in cancer therapy holds great prom-
therapy [2]. Patients participating in clinical trials must ise, with several exciting directions that have the poten-
be fully informed about the experimental nature of these tial to revolutionize how we diagnose and treat cancer
treatments, the potential risks involved, and any uncer- [327]. One of the most prominent areas of research and
tainties surrounding their efficacy [319]. Given the com- innovation in this field revolves around the develop-
plexity of nanotherapies, it is imperative that patients ment of more effective and widely approved nanocar-
have a clear understanding of what they are consenting riers for clinical use [328]. One of the primary future
to, enabling them to make informed decisions about directions in nanotechnology for cancer therapy is the
their participation [320]. The process of informed con- refinement and optimization of nanocarriers. These are
sent should be transparent, respectful, and tailored tiny particles or structures designed to deliver drugs or
to the patient’s level of understanding, ensuring they therapeutic agents directly to cancer cells while spar-
can actively engage in their healthcare decisions [321]. ing healthy tissue [329]. Researchers are exploring vari-
Beyond individual patient considerations, the societal ous strategies to improve the design and functionality of
impact of nanotechnology-based cancer therapies is also nanocarriers. This includes enhancing their stability in
a matter of ethical concern [322]. While these advanced the bloodstream, increasing drug-loading capacities, and
therapies hold promise for more effective and less fine-tuning their targeting capabilities [324]. Advances
in materials science and nanofabrication techniques are cancer continues to grow, nanotechnology can be used to
enabling the creation of nanocarriers with precisely con- create patient-specific therapies. By tailoring nanocarri-
trolled properties, such as size, shape, and surface chem- ers to the unique genetic profile of a patient’s tumor, we
istry, which can influence their behavior within the body can optimize drug delivery and treatment response [323].
[323]. Moreover, the development of multifunctional This approach may involve the use of techniques like pre-
nanocarriers is gaining momentum. These nanocarriers cision medicine and liquid biopsies to guide the design of
not only deliver drugs but also incorporate additional personalized nanomedicines. Another important aspect
features, such as imaging agents or immune-stimulating of the future of nanotechnology in cancer therapy is the
molecules. This multifunctionality allows for simultane- translation of laboratory discoveries into clinical practice.
ous diagnosis, monitoring, and treatment of cancer, mak- Bridging the gap between benchtop research and clinical
ing therapy more personalized and precise [329]. For applications is a critical challenge [327]. Collaborations
example, nanocarriers can be engineered to carry both between scientists, engineers, clinicians, and regula-
a chemotherapy drug and a fluorescent dye for real-time tory agencies will be essential to ensure that nanotech-
tracking of drug delivery and tumor response. This inte- nology-based cancer therapies meet rigorous safety and
grated approach has the potential to improve treatment efficacy standards. Streamlining the regulatory path-
outcomes and reduce side effects [324]. Another prom- way and establishing clear guidelines for the approval of
ising avenue for future research in nanotechnology for nanomedicines will be vital to their successful integra-
cancer therapy is the exploration of nanotheranostics tion into mainstream cancer treatment protocols [329].
[323]. Theranostic nanoparticles combine therapeutic Lastly, as nanotechnology continues to advance, it is cru-
and diagnostic functions into a single platform, enabling cial to consider the economic and ethical dimensions of
real-time monitoring of treatment efficacy. By incorpo- its application in cancer therapy. Ensuring affordability
rating imaging agents like nanoparticles with magnetic and equitable access to these cutting-edge treatments
resonance or positron emission tomography capabili- is essential [326]. Additionally, ethical considerations
ties, clinicians can track the distribution of nanocarriers related to the use of nanotechnology, such as informed
within the body and assess their impact on tumor growth consent and data privacy, must be carefully addressed as
[327]. This feedback loop can guide treatment decisions, these therapies become more widespread [329].
allowing for timely adjustments and personalized therapy
regimens tailored to individual patients. Furthermore, Conclusions
the development of nanocarriers with enhanced biocom- Nanotechnology has the potential to significantly alter
patibility and reduced immunogenicity is essential for the way cancer is treated. Nanomaterials have unique
their widespread clinical adoption [326]. Research efforts properties that make them highly effective for targeted
should focus on materials that minimize adverse reac- drug delivery and cancer therapy [277]. However, there
tions and toxicity, ensuring the safety of nanotechnology- are still many challenges that need to be addressed to
based cancer therapies [329]. Surface modifications and improve the clinical translation of nanomaterials. These
the use of biodegradable materials can play a crucial role include reducing toxicity, improving targeting specific-
in improving the overall biocompatibility of nanocarriers. ity, and understanding the interactions between nano-
In addition to refining nanocarriers and enhancing their materials and the human body [28]. This review has
multifunctionality, future directions in nanotechnol- shed light on the remarkable potential of nanotechnol-
ogy for cancer therapy should also explore the potential ogy in the realm of targeted cancer therapy. It is evident
of immunotherapeutic approaches [329]. Immunother- from the discussion that nanoscale targeting techniques,
apy has revolutionized cancer treatment by harnessing propelled by advancements in protein engineering and
the body’s immune system to target and destroy cancer materials science, hold the promise of transforming the
cells. Integrating nanotechnology with immunother- landscape of cancer diagnosis and treatment. However,
apy can lead to even more potent and precise cancer while we have witnessed significant progress, there are
therapies [329]. Nanoparticles can be designed to carry several crucial takeaways that emphasize the importance
immune-boosting molecules, such as checkpoint inhibi- of continued research and development in this field. First
tors or cytokines, directly to the tumor site. This targeted and foremost, our analysis of authorized formulations
delivery can minimize off-target effects and maximize and the journey from lab to clinic has revealed the intri-
the immune response against cancer cells, leading to cate challenges that researchers and clinicians face in
improved therapeutic outcomes [329]. Furthermore, the translating promising laboratory discoveries into prac-
development of personalized nanomedicine is a prom- tical clinical applications. The chasm between bench-
ising frontier in the fight against cancer [326]. As our top innovation and bedside implementation remains a
understanding of the genetic and molecular basis of formidable obstacle. It necessitates collaborative efforts
among multidisciplinary teams of scientists, clinicians, Declarations

regulatory bodies, and industry partners to bridge this
Ethics approval and consent to participate
gap effectively. Regulatory agencies must continue to Not applicable.
adapt to the unique complexities of nanotechnology,
ensuring both patient safety and the timely availability Consent for publication
Not applicable.
of groundbreaking treatments. Moreover, this review
has highlighted the diverse arsenal of nanocarriers and Competing interests
compounds available for selective tumor targeting. The authors declare no competing interests.
From liposomes to nanoparticles and beyond, the tool- Author details

box for oncologists is expanding. Nonetheless, as we 1
Novin Genome (NG) Institute, Research and Development Center for Bio‑
navigate the vast landscape of nanomaterials and deliv- technology, Shahrekord, Chaharmahal and Bakhtiari, Iran. 2 Young Research‑
ers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord,
ery systems, we must be vigilant in ensuring that these Chaharmahal and Bakhtiari, Iran. 3 Department of Pharmacy, Al-Noor University
innovations do not introduce unforeseen toxicity or off- College, Nineveh, Iraq. 4 Department of Biochemistry, Universidad San
target effects. Rigorous preclinical evaluation and ongo- Ignacio de Loyola (USIL), Lima, Peru. 5 Department of Pharmacology, SRM
Institute of Science and Technology, SRM College Of Pharmacy, Chengalpattu
ing safety assessments are paramount. Furthermore, District, Kattankulathur, Tamil Nadu 603203, India. 6 Department of Chemistry,
the inherent complexities of cancer therapy underscore Coordination Chemistry Laboratory, Dayanand Anglo-Vedic (PG) College,
the need for personalized approaches. Nanotechnology Kanpur‑208001, U.P, India. 7 Department of Pharmaceutics, SRM Institute
of Science and Technology, SRM College Of Pharmacy, Chengalpattu District,
offers the potential for tailoring treatments to individ- Kattankulathur, Tamil Nadu 603203, India. 8 Keleti Károly Faculty of Business
ual patients, taking into account the unique molecular and Management, Óbuda University, Tavaszmező U. 15‑17, 1084 Budapest,
characteristics of their tumors. This promises not only Hungary. 9 Department of Mechanical Engineering, Saveetha School of Engi‑
neering, SIMATS, Chennai, Tamil Nadu, India. 10 Faculty of Pharmacy, Middle
increased efficacy but also reduced side effects, thereby East University, Amman 11831, Jordan. 11 Faculty of Organization and Manage‑
enhancing the quality of life for cancer patients. In clos- ment, Silesian University of Technology, 44‑100 Gliwice, Poland. 12 Depart‑
ing, the review underscores that while nanotechnology ment of Mechanical Engineering, CEMMPRE, University of Coimbra, Polo II,
3030‑788 Coimbra, Portugal. 13 Department of Biology, College of Science,
holds immense promise, it is not a panacea for the chal- Jazan University, 82817 Jazan, Saudi Arabia. 14 Universidad Nacional de San
lenges of cancer therapy. It requires ongoing commit- Agustin de Arequipa, Arequipa, Peru. 15 Deanship of Scientific Research, Umm
ment, collaboration, and innovation from the scientific Al-Qura University, Makkah 21955, Saudi Arabia. 16 Department of Neurosur‑
gery, University Medical Center, Tuebingen, Germany. 17 Department of Health
and medical communities. The potential to improve Care Management and Clinical Research, Collegium Humanum Warsaw
cancer detection and treatment through nanotechnol- Management University Warsaw, Warsaw, Poland.
ogy is tantalizing, but the journey from the laboratory
Received: 2 July 2023 Accepted: 21 September 2023
to the clinic is a road laden with obstacles. Nevertheless,
with perseverance and sustained investment in research,
we can unlock the full potential of nanotechnology
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Progressing Nanotechnology To Improve Targeted Cancer Treatment: Overcoming Hurdles in Its Clinical Implementation

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Chehelgerdi et al.

Molecular Cancer (2023) 22:169 Molecular Cancer

REVIEW Open Access

Progressing nanotechnology to improve

Introduction potentialities offered by nanotechnology to address this

ous core and targeting in achieving

ral polymers tions, suitable stable in cir‑ batch-to-batch release, low

spectrum, metal tial clearance specificity

or peptides potential challenges limited blood ing up produc‑

Type Charge Capacity Mechanism Challenges

to produce nogenicity, system

tive B cells to CAR T cell therapy Potential for cytokine

to PSMA-positive tional chemotherapy, of resistance devel‑

Table 3 Factors affecting nanocarrier biodistribution

Table 4 Comparison of nanocarrier manufacturing techniques

Emulsion Small Low High Low High [117]

Table 5 Nanocarrier drug release kinetics

Liposomes Doxorubicin pH Gradient Sustained Acidic Stable [13]

Gemcitabine in Treating Women Paclitaxel protein-bound parti‑ firmed Responses, Progression-

Cancer of Tolerability of Adjuvant Nab

ing pCR at Baseline and After 2

viously Treated With Surgery Associated With This Regimen

Bevacizumab to Treat Women

With Carboplatin and Herceptin Herceptin® Complete or Partial Overall

the Specificity of High Resolution

thetic or natural erties, good drug variability

particles composed ibility, potential payload capacity,

Table 8 Pharmacokinetic profiles of nanocarrier-loaded drugs

Table 9 Nanocarrier-based imaging agents for cancer diagnosis

disproportionation of H2O2 to create OH radicals is Methods for cancer therapy

rier is internalized heterogeneity

of cells that take and expertise

cell death can determine on the tumor ior of the nano‑

in a 3D culture distribution efficacy and expertise

cer cells in vitro mechanism tion ior of the nano‑

cell molecules between the nano‑ molecular inter‑ specialized

and ability to infect promising results peutic outcomes toxicity

and ability to encap‑ improved transfec‑

therapy due to their therapy is a prom‑

the advantages for HER2 gene ther‑ and specificity ity

be used for gene promising results

(mRNA) to encode approach for pre‑

(mRNA) to encode for inducing cell

size and biocompat‑ multidrug resistance

unique optical promising results

due to its high trans‑ for treating Alzhei‑

microenvironments consist of various components, nanoparticles boosting innate immune signaling in

(See figure on next page.)

Fig. 20 (See legend on previous page.)

Table 13 Nanocarrier toxicity profiles

inflammasome activation cells, cytokine secretion

(See figure on next page.)

Fig. 23 (See legend on previous page.)

Table 15 Nanocarrier-based personalized cancer therapy

among multidisciplinary teams of scientists, clinicians, Declarations

From liposomes to nanoparticles and beyond, the tool- Author details

CD3-bispecific T-cell engaging (BiTE®) antibody construct targets

concepts of nanotechnology and applications in material science and

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