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Materials Today d Volume 62 d January/February 2023 RESEARCH
RESEARCH: Review
Self-therapeutic nanomaterials:
Applications in biology and medicine
Joshua Seaberg 1,2, John R. Clegg 3, Resham Bhattacharya 4, Priyabrata Mukherjee 1,5,⇑
1
Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
2
M.D./Ph.D. Program, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
3
Stephenson School of Biomedical Engineering, University of Oklahoma, Norman, OK 73019, USA
4
Department of Obstetrics and Gynecology, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
5
Peggy and Charles Stephenson Cancer Center, University of Oklahoma Health Science Center, Oklahoma City, OK 73104, USA
Over past decades, nanotechnology has contributed to the biomedical field in areas including
detection, diagnosis, and drug delivery via opto-electronic properties or enhancement of biological
effects. Though generally considered inert delivery vehicles, a plethora of past and present evidence
demonstrates that nanomaterials also exude unique intrinsic biological activity based on composition,
shape, and surface functionalization. These intrinsic biological activities, termed self-therapeutic
properties, take several forms, including mediation of cell–cell interactions, modulation of interactions
between biomolecules, catalytic amplification of biochemical reactions, and alteration of biological
signal transduction events. Moreover, study of biomolecule-nanomaterial interactions offers a
promising avenue for uncovering the molecular mechanisms of biology and the evolution of disease.
In this review, we observe the historical development, synthesis, and characterization of self-
therapeutic nanomaterials. Next, we discuss nanomaterial interactions with biological systems,
starting with administration and concluding with elimination. Finally, we apply this materials
perspective to advances in intrinsic nanotherapies across the biomedical field, from cancer therapy to
treatment of microbial infections and tissue regeneration. We conclude with a description of self-
therapeutic nanomaterials in clinical trials and share our perspective on the direction of the field in
upcoming years.
Keywords: Self-therapeutic nanomaterials; Intrinsic nanotherapy; Biomolecule-nanoparticle interaction; Bioactive

nanomaterial; Cancer therapy; Disease biomarker
detection
Abbreviations: AD, Alzheimer’s disease; AgNC, silver nanocluster; AgNP, silver nanoparticle; AlOH NP, aluminum hydroxide nanoparticle; AlPO4 NP, aluminum
phosphate nanoparticle; APC, antigen-presenting cell; ATTR, amyloidogenic transthyretin; AuNC, gold nanocluster; AuNP, gold nanoparticle; AuNR, gold nanorod;
BMP2, bone morphogenic protein 2; C60, fullerene; CAF, cancer-associated fibroblast; CAR, chimeric antigen receptor; CNT, carbon nanotube; CuO NP, cuprous oxide
nanoparticle; CPNP, calcium phosphate nanoparticle; DLS, dynamic light scattering; ELS, electrophoretic light scattering; EPR, enhanced permeability and retention;
FTIR, Fourier-transform infrared spectroscopy; GeNP, germanium nanoparticle; GQD, graphene quantum dot; IAPP, islet amyloid polypeptide; ICAM, intercellular
adhesion molecule; IONP, iron oxide nanoparticle; La2O3 NP, lanthanum oxide nanoparticle; MMP9, matrix metalloproteinase 9; MnO2 NP, manganese oxide
nanoparticle; MoO3-x NP, molybdenum oxide nanoparticle; MSN, mesoporous silica nanoparticle; NP, nanoparticle; PAMAM, poly(amidoamine); PARP, poly-(ADP-
ribose) polymerase; PEG, poly(ethylene glycol); PEI, polyethyleneimine; PLGA, poly(lactic-co-glycolic acid); PtNP, platinum nanoparticle; ROS, reactive oxygen species;
SeNP, selenium nanoparticle; SiNP, silica nanoparticle; SLNP, solid lipid nanoparticle; SnO2 NP, tin oxide nanoparticle; STNM, self-therapeutic nanomaterial; TRAIL,
tumor necrosis factor-related apoptosis-inducing ligand; VDW, van der Waals; VEGF, vascular endothelial growth factor; V2O5 NP, vanadium pentoxide nanoparticle;
ZnO NP, zinc oxide nanoparticle.
⇑ Corresponding author.
E-mail address: Mukherjee, P. ([email protected])
190 1369-7021/Ó 2022 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.mattod.2022.11.007

Introduction crobial but has also been deployed in treatment of cancers [11],
Nanomatter is comprised of materials on the scale of 1 to 100 nm viral infections [12], and diseases of biomolecule aggregation
that exhibit properties not observed in similar bulk samples [1,2]. [13]. Intriguingly, though silver nanoparticles (AgNPs) are potent
Nanomaterial development has exploded within the biomedical antimicrobials, select microorganisms can synthesize AgNPs as a
community in recent decades in an attempt to harness these way to mitigate Ag ion toxicity [14]. Silver nanostructures can
properties; as a result, biomedical nanomaterials have been also be formed via bottom-up chemical or biological methods
shown to exhibit opto-electronic properties and selectively inter- or through top-down physical processes [5]. For additional read-
RESEARCH: Review
act with biomacromolecules in ways not characteristic of either ing, we recommend the review on AgNP synthesis and biomedi-
bulk materials or small-molecule therapeutics. While frequently cal application by Lee & Jun [15].
utilized to accentuate the efficacy of other therapeutic modali- Though evidence suggests that the Egyptians had platinum in
ties, many nanomaterials also display “self-therapeutic” proper- the 8th Century BC, it only became known to Europeans after its
ties based on chemical composition and nanoscale geometry. reemergence in the New World [9]. Unlike other noble metals,
These self-therapeutic nanomaterials (STNMs) utilize mecha- platinum was rarely used medicinally until the discovery of cis-
nisms ranging from selective surface adsorption to ion leaching platin; since then platinum-based therapies have been a main-
in order to mediate cell–cell signaling, modulate biomolecular stay [16]. Platinum nanoparticles (PtNPs) are most commonly
interactions, expose molecular manifestations of pathology, or synthesized by the reduction of platinum salts with ethylene gly-
catalyze substrate transformation. Herein, we review advances col or sodium borohydride as reducing agents, but PtNPs can also
made in STNM technologies within the biomedical field. We be synthesized through radiolytic reduction of platinum com-
highlight STNMs sequentially, offering notes on synthesis and plexes or through biological methods [9,17]. Further information
characterization before overviewing the principles of interac- on PtNP synthesis, characterization, and biomedical applications
tions between STNMs and biological systems. Next, we observe can be found in Jeyaraj et al. [17].
the diverse contributions of intrinsic nanotherapeutics ranging Several types of metal oxide NPs exhibit intrinsic therapeutic
from cancer therapy to tissue regeneration and inhibition of bio- properties. Magnetite (Fe3O4) iron oxide nanoparticles (IONPs)
molecule aggregation. Finally, we discuss clinical trials utilizing were recognized in the late 1980s for use as MRI contrast agents
STNMs and offer our perspective on the direction of field in [18], and now IONPs composed of maghemite (c-Fe2O3) and
the immediate future. magnetite are commonly utilized in biomedical applications
due to their low toxicity and superparamagnetic properties
[19]. IONPs have been acknowledged as intrinsically therapeutic
Nanoparticle development, synthesis, and characterization through induction of ferroptosis and conversion of hydrogen
The history of nanoparticle (NP) therapy dates to the ancient peroxide to hydroxyl radicals (termed the “Fenton reaction” after
world. Though macroscale gold was utilized medicinally for cen- it was described by H.G.H. Fenton in 1894) [20]. Fenton-like
turies prior, the elusive gold solution (“elixir of life”) was not syn- chemistry has also been observed in other metal oxide NPs
thesized until the 8th Century AD when Jabir ibn Hayyan including tin (SnO2 NPs), manganese (MnO2 NPs), and molybde-
produced gold tetrachloride in a solution of nitric and num (MoO3-x NPs) [21–23]. Zinc oxide NPs (ZnO NPs) do not dis-
hydrochloric acid [3]. For the next few centuries, potable gold play Fenton-like chemistry, but are antibacterial, treat diseases of
was applied to myriad conditions and by 1890 was being utilized bioaggregation, and mediate cellular pathways [24–26]. Finally,
to treat diseases ranging from lupus to alcoholism [3]. Since then, cuprous oxide nanoparticles (CuO NPs) display intrinsic catalytic
nanoscale gold has been noted to display properties of immune activity in addition to inducing apoptosis in cancer cells [27,28].
modulation and mediation of cellular interactions [4]. Current Synthesis methods for metal oxide NPs include chemical, physi-
synthesis processes for nanoscale gold include chemical, biolog- cal, and biological means, though chemical methods of coprecip-
ical, or physical methods, the most prevalent of which is the for- itation, thermal decomposition, microemulsion, and Sol-gel
mation of gold nanoparticles (AuNPs) from HAuCl4, a reducing techniques predominate [25,29]. We recommend reviews on
agent, and a stabilizing agent [5]. Further methods exist for pro- IONPs as therapeutic nanomaterials by Dadfar et al. [29], on
ducing nanoscale gold of varying geometries, such as nanorods ZnO NP synthesis and biological activity by Król et al. [25], and
(AuNRs), nanoclusters (AuNCs), and nanoshells (AuNSs) [5]. on CuO NP synthesis and biomedical applications by Verma &
For additional information, we recommend reviews by Elahi Kumar [28].
et al. [6], on biomedical applications of AuNPs, Grzelczak et al. Inorganic compounds such as calcium phosphates (CaPO4-
on shape control in nanoscale gold [7], and Perez-Juste et al. on family) also exhibit self-therapeutic properties. First mentioned
AuNR synthesis and characterization [8]. around the turn of the 21st Century, NPs composed of calcium
Like gold, silver has been touted for its therapeutic properties phosphate (CPNPs) were noted as non-viral gene delivery vectors
for centuries [9]. Hippocrates was among the early proponents of before their self-therapeutic properties were elucidated [30].
its use, and it was most frequently applied to treating impair- Since then, CPNPs have been notable for antimicrobial proper-
ments of the central nervous system [9]. The antimicrobial prop- ties along with immunogenicity and promotion of bone remod-
erties of silver were harnessed to prevent food spoilage, wound eling [31–33]. CPNPs of hydroxyapatite (Ca10(PO4)6(OH)2) and
infection, and even vertical transmission of venereal diseases a/b-tricalcium phosphate (a/b-Ca3(PO4)2) have shown the great-
[9,10]. Currently, nanoscale silver is mainly utilized as an antimi-
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RESEARCH Materials Today d Volume 62 d January/February 2023
est promise in bone remodeling by promoting osteoinduction NP synthesis and characterization, and we recommend the
and resorption [34]. CPNPs can be formed through chemical review by Wang & Urban for additional information on self-
methods including precipitation, with process modifications healing polymers [68].
allowing continuous synthesis or hybrid particle formation Nanogels are a subset of polymeric NPs formed when nanos-
through co-precipitation [34,35]. The review by Levingstone cale networks of hydrophilic polymers are swollen in aqueous
et al. is an excellent reference for CPNP design and applications medium. Nanogels are typically formed by polymerizing mono-
[34]. mers and crosslinking agents in an inverse emulsion (e.g. syn-
Among the more recently developed STNMs are nanoclays: thetic acrylic or acrylamide nanogels) [69–71]. Other synthesis
layered nanomaterials composed of hydrous silicates found in methods include crosslinking of hydrophilic polymers in emul-
soil clay fractions [36]. Biomedical nanoclays vary in charge sion droplets (e.g. hyaluronic acid, alginate, and chitosan nano-
RESEARCH: Review
and include several compositions such as montmorillonite, gels) [72,73] or the forming nanoscale particles by antisolvent
kaolinite, laponite, halloysite, bentonite, hectorite, laponite, precipitation (e.g. protein nanogels) [74,75]. As nanogels exist
sepiolite, saponite, and vermiculite [37–39]. For example, lapo- in a state of thermodynamic equilibrium with the surrounding
nite was among the first to be recognized for its biomedical environment, they offer unique responsiveness to the local pH,
potential and displays a negative charge along its face and a pos- temperature, ionic strength, and relative concentration of solutes
itive charge along its edges [40]. Nanoclays have been utilized as such as proteins, nucleic acids, reducing agents, or reactive oxy-
bioadhesives and drug delivery systems, though most widespread gen species (ROS) [76]. Further, therapeutic peptides and proteins
use is found in tissue engineering [41,42]. Methods of producing can be incorporated into nanogels [77], and these nanogel-
bioactive nanoclays vary and include 3D printing, self-assembly, peptide conjugates typically retain the native activity of the pep-
and phase separation [43–45]. For further information, we rec- tide [78–80]. For further information, we recommend reviews by
ommend the review on nanoclay-based drug delivery systems Soni et al. [81] and Mitchell et al. [82].
by Khatoon, Chu, & Zhou [46] along with Gaharwar et al.’s Since introduction by Donald Tomalia in 1985, dendrimers
review on biomedical nanoclays [40] and Erezuma et al. on (branching, radially-symmetric molecules composed of repetitive
nanoclay-reinforced biomaterials [47]. units dispersing from a common origin) have spread throughout
Though carbon-based materials have existed for millenia, the the biomedical field [83]. The dendrimer archetype polyami-
widespread use of carbon nanostructures in the biomedical field doamine (PAMAM) exhibits monodispersity and stability along
has been initiated within the last two decades. Carbon-based with brain penetrant properties, making it markedly useful treat-
nanomaterials take several forms based on the atomic binding ing diseases of the central nervous system [84]. Dendrimer syn-
structure [48]. Nanodiamonds exhibit tetrahedral covalent bond- thesis follows a stepwise process along either convergent,
ing, while graphene nanosheets and quantum dots (GQDs) con- divergent, or hybrid paths in which additional layers (genera-
sist of single layers of covalently bonded carbon atoms [48]. tions) are added via sequential reactions [5]. For additional infor-
Layers of carbon can also be formed into cylinders or shells to mation, we recommend Svenson & Tomalia’s review of the field
create bioactive nanotubes or nanospheres [49]. Due to the vari- [85] along with Abbasi et al. [86] and Santos, Veiga, & Figueiras
ation in geometry and functionalization, intrinsic therapeutic [87].
properties of carbon-based nanomaterials have been applied Rigorous characterization is required for each of these nano-
throughout the biomedical field with emphasis on tissue engi- materials. Some characterization methods provide useful infor-
neering, prevention of biomolecular aggregation, and comple- mation about the majority of nanomaterials, whereas other
mentation of enzymatic activity [50–52]. Additionally, we methods are most applicable to a few distinct nanostructures
recommend reviews on carbon nanospheres by Nieto-Márquez (Table 1). For example, dynamic light scattering (DLS) is applied
et al. [49], carbon-based nanosystems for cancer therapy by almost universally to rapidly determine the size and polydisper-
Augustine et al. [53], graphene oxide nanostructures by Smith sity of a sample, whereas electrospray ionization mass spec-
et al. [54], and carbon nanotube synthesis by Eatemadi et al. [55]. troscopy (ESI-MS) is particularly valuable for nanoclay and
Polymers in biotechnology are plentiful and varied. Natural polymer characterization. As each characterization method pro-
polymers have been applied medicinally for centuries, but the vides a narrow window through which to observe nanoscale real-
first mention of a polymer NP in the Pubmed database dates to ity, several techniques must be united to provide a sufficient
1978 [56,57]. Though regularly utilized as delivery systems, understanding of STNM properties.
self-therapeutic polymers can modulate immune responses and Nanomaterial synthesis processes have been further con-
neutralize viral particles [58–60], and some “self-healing” poly- strained by novel design parameters in recent years. Increased
mers can even recover from physical damage to promote wound understanding of the detrimental impact that NP synthesis has
healing and tissue regeneration [61]. Monomers such as lactic on human health and the environment has driven the develop-
acid and glycolic acid can be polymerized via addition or conden- ment of “green” synthesis processes that produce nanomaterials
sation reactions, whereas chitosan can be naturally derived [5]. in a cost-efficient and eco-friendly manner [88]. Likewise,
Polymers can be tuned to exhibit stimulus responsivity or be enhanced understanding of NP elimination and sequestration
combined into block or grafted copolymers that exhibit a combi- has introduced additional design parameters for nanomedicine
nation of properties from their constituent elements [5,62,63]. As synthesis [89,90]. Finally, synthesis processes must be scalable
the subject has been thoroughly documented, we defer to Gupta if they are to be translated to the clinic.
et al. [64], Deirram et al. [65], Saldívar-Guerra & Vivaldo-Lima After initial synthesis, nanomaterials can be modified with
[66], and Braun et al. [67] for rigorous descriptions of polymer hydrophilic polymers to extend circulation time by preventing
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TABLE 1
Common nanomaterial characterization techniques.
Material
Characterization Abbreviation Properties AuNP, IONP, CuO NP, SnO2 Nanoclay Graphene Polymer, Dendrimer
method elucidated AgNP, NP, MnO2 NP, MoO3-x nanosheet, nanogel
PtNP NP, ZnO NP, CPNP, GQD, CNT
AlOH NP
adsorption/ ADI surface adsorption/ x x x x x
desorption desorption
isotherms
RESEARCH: Review
dynamic light DLS/ELS hydrodynamic x x x x x x
scattering, diameter,
electrophoretic polydispersity index,
light scattering surface zeta potential
differential scanning DSC heat capacity, phase x x x x x
calorimetry transitions
electrospray ESI-MS macromolecular x x
ionization mass composition
spectroscopy
fourier transform FTIR infrared absorbance, x x x x x x
infrared emission, and
spectroscopy conductivity
gel permeation GPC hydrodynamic x x x x x
chromatography volume
high-performance HPLC adsorptive surface x x x x x
liquid properties
chromatography
inductively coupled ICP-MS elemental x x x x x
plasma mass composition
spectrometry
nuclear magnetic NMR molecular structure, x x x x x x
resonance content, purity
spectroscopy
potentiometric PT concentration x x x x
titration
small-angle neutron SANS size, morphology, x x x x x
scattering solvation
transmission TEM/SEM morphology, size x x x x x x
electron distribution
microscopy,
scanning electron
microscopy
thermogravimetric TGA purity, stability, x x x x
analysis biomolecule
adsorption/
desorption
ultraviolet–visible UV–Vis absorbance x x x x x x
spectroscopy
X-ray photoelectron XPS elemental x x x x x x
spectroscopy composition,
bonding
conformation
X-ray diffraction XRD crystallinity x x x x x
non-specific protein adsorption and promoting selective protein eters for NP PEGylation [95] and Spicer et al. discuss the potential
corona formation [62,91]. Further, receptor-specific nanomate- for peptide- and protein-NP conjugation [96].
rial accumulation can be achieved by conjugating targeting As STNMs are diverse, we have separated them into four broad
ligands to the material surface, and some peptides have been categories (Fig. 1). Metal-based nanomaterials modulate cellular
shown to facilitate endocytosis for conjugated nanoparticles interactions and pathways, inactivate microbes, or alter protein
[92]. As the focus of this article is on inherent nanomaterial prop- conformation. Nanomaterials based on inorganic compounds
erties, we defer discussion on post-synthesis surface modifica- are utilized in tissue regeneration applications, while carbon-
tions to authoritative reviews: Zongmin et al. explain strategies based nanomaterials are useful in tissue engineering and
for NP targeting [93] and Rosenblum et al. describe challenges biomolecular aggregation. Finally, organic nanomaterials pro-
specific to cancer targeting [94], while Suk et al. describe param- vide in vivo scavenging, immune modulation, or treatment of
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RESEARCH: Review
FIGURE 1
Self-therapeutic nanomaterials (STNMs) for biomedical applications. STNMs can be broadly grouped into categories of metal-based nanomaterials, carbon-
based nanomaterials, organic nanomaterials, and inorganic-compound-based nanomaterials, each with their own distinct characteristics and applications.
AgNC: silver nanocluster; AgNP: silver nanoparticle; AlOH NP: aluminum hydroxide nanoparticle; AlPO4 NP: aluminum phosphate nanoparticle; AuNC: gold
nanocluster; AuNP: gold nanoparticle; AuNR: gold nanorod; CuO NP: cuprous oxide nanoparticle; CPNP: calcium phosphate nanoparticle; GeNP: germanium
nanoparticle; IONP: iron oxide nanoparticle; La2O3 NP: lanthanum oxide nanoparticle; MnO2 NP: manganese oxide nanoparticle; MoO3-x NP; molybdenum
oxide nanoparticle; MSN: mesoporous silica nanoparticle; NP: nanoparticle; PAMAM: poly(amidoamine); PEI: polyethyleneimine; PLGA: poly(lactic-co-glycolic
acid); PtNP: platinum nanoparticle; SeNP: selenium nanoparticle; SLNP: solid lipid nanoparticle; SnO2 NP: tin oxide nanoparticle; V2O5 NP: vanadium pentoxide
nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with BioRender.com.
neuroinflammatory conditions. Structure determines function, STNMs in biological systems

and thus understanding the structure of these nanomaterials The complex interplay between STNMs and a biological system
provides insight into discussion of their specific applications. begins immediately upon STNM administration. NPs develop a
194
corona of adsorbed serum proteins in vivo, the composition of temically, NP size is critical to biodistribution: small NPs
which is dependent on NP material, shape, charge, and surface (<10 nm) are cleared through the glomerular capillary whereas
functionalization as well as serum composition and flow condi- large NPs (>200 nm) are taken up by systemic macrophages
tions [97,98]. Interactions between STNMs and their protein (Fig. 2a) [104]. NPs below 100 nm can accumulate in the bone
coronas are central to self-therapeutic function. The protein cor- marrow, spleen, and liver while NPs smaller than 35 nm can dif-
ona consists of the “soft” corona composed of rapidly- fuse from the blood across the pulmonary capillary barrier [105].
exchanging biomolecules formed early upon plasma exposure Other reports emphasize that NPs 10–50 nm in diameter tend to
and the tightly-packed “hard” corona proteins that gradually dis- accumulate within the reticuloendothelial system whereas long-
place them [99]. The process of adsorption can alter protein con- circulating carriers of 50–200 nm can deposit within the brain or
formation, potentially modifying protein function or even tumor environment [105]. Along with size, nanomaterial unifor-
RESEARCH: Review
introducing “cryptic” epitopes and triggering an immune mity is critical for medicinal translation; a low polydispersity
response [100]. The protein corona is instrumental in STNM cel- index (PDI) indicates population monodispersity and conse-
lular uptake and determines its biological fate [100]. Fascinat- quent therapeutic predictability [105].
ingly, analysis of the protein corona formed from the serum of Biodistribution of STNMs can be measured several ways. His-
an individual experiencing a pathology can identify biomarkers torically, 14C-, indium-111-, or iodine-125-radiolabeled NPs
specific to that disease state [99,101,102]. Once identified, NPs were tracked with autoradiography [106–109], while current
can be tuned to enrich adsorption of these biomarkers, vastly methods of determining biodistribution include fluorescence
improving early disease detection [99,101]. imaging [110], positron emission tomography [111], and mass
STNMs must reach their area of action before bioactive prop- cytometry [112]. One early investigation traced the distribution
erties can be therapeutically harnessed. Methods of nanomaterial of radio-labeled polyhexyl cyanoacrylate NPs in an osteosarcoma
delivery vary from direct topical application to oral delivery [89], mouse model and found that radioactivity was forty times higher
and each of these methods can be complicated by disease states in tumor tissues than in muscle [107]. Higher levels of radioactiv-
and variations in transport properties [103]. When delivered sys- ity correlated to areas of lower tumor necrosis, suggesting that NP
FIGURE 2
Nanomaterial biodistribution and toxicity. (a) In general, nanoparticles less than 10 nm are rapidly cleared by the kidney while those greater than 200 nm are
taken up by systemic macrophages. Nanoparticles between these extremes travel through the body until they are cleared or sequestered by the liver. (b)
AuNPs can induce apoptosis in myotubes. (c) PAMAM dendrimers exhibit embryotoxicity. (d) SLNPs can induce macrophage apoptosis. (e) Fullerene induces
inflammation and alveolar collapse by inhibiting ATP production. (f) Insulin fibrillation is enhanced by ZnO NPs and GQDs. (g) Amorphous silica nanoparticles
increase ROS-associated cellular damage resulting in vascular endothelial injury. AuNP: gold nanoparticle; C60: fullerene; GQD: graphene quantum dot;
PAMAM: poly(amidoamine); SiNP: silica nanoparticle; SLNP: solid lipid nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with BioRender.com.
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accumulation was dependent on tumor tissue viability [107]. excrete NPs into the intestine in bile [125]. Hepatobiliary elimi-
More recently, Yang et al. mapped the biodistribution of AuNPs nation offers opportunity for an undesirable extension of NP res-
in a murine melanoma model with single-cell mass cytometry idence time within the body through sequestration. While in the
and determined that cell-specific targeting is possible via rational liver, 30% 99% of administered NPs are sequestered in stellate
selection of surface-ligands [112]. Consequently, we can measure macrophages (Kupffer cells), the removal of which has been
the biodistribution of a nanomaterial with high sensitivity and shown to increase NP clearance by a factor of 10 [90,125]. To sur-
specificity. mount this obstacle, some nanosystems disassemble into sub-
STNMs must overcome endothelial barriers to escape the cir- 10 nm elements allowing passage through glomerular fenestra-
culatory system. Solid tumors with disorganized vasculature tions for kidney elimination [89,104]. Thus, STNMs are most
and convoluted lymphatic drainage exhibit the enhanced per- commonly cleared through bile, but can be occasionally cleared
RESEARCH: Review
meability and retention (EPR) effect, which STNMs can passively in urine.
exploit to bypass the endothelial barrier [94]. Alternatively, NPs
can alter endothelial permeability [113]; mesoporous silica Intrinsic nanoparticle toxicity
nanoparticles (MSNs) have been linked to NP-induced endothe- While STNMs in human medicine are emphasized in the remain-
lial leakiness (NEL), a density-dependent phenomenon in which der of this review, it is important to acknowledge potential dele-
NPs exert a cumulative gravitational-mediated force along vascu- terious effects of exposing mammalian cells to toxic NP doses
lar adherens junctions to dramatically increase the permeability (Fig. 2b–g). CTAB-stabilized gold nanoprisms have been reported
of an endothelial barrier [113]. Huang et al. identified that NEL for cytotoxicity [126], and PEGylated (5 kDa) 4.5 nm AuNPs
involves NP interactions with vascular endothelial cadherin increase the likelihood of myotube death through heightened
(VE-cad) and posited that it can facilitate cancer cells crossing expression of IFN-c, TGF-b1, and caspases-3/7 [127]. Caldeira
the endothelial barrier. To address this, they designed NPs cap- et al. document that lungs exposed to fullerene show increased
able of avoiding VE-cad interactions to mitigate vascular leaki- elastance, enhanced inflammation, and amplified alveolar col-
ness and cancer migration [114]. However, some evidence lapse when compared to unexposed controls [128]. ZnO NPs
suggests that the blood brain barrier is not disrupted by MSNs detrimentally alter cytoskeletal composition [129] and the pres-
[115], so additional research is needed to determine if NEL can ence of ZnO NPs can also increase insulin fibrillation [130].
be harnessed to therapeutically target the central nervous GQDs have been reported to induce insulin fibrillation in a
system. charge- and size-dependent manner, seemingly contradicting
Many nanotherapeutics must be taken up into the cell to their subsequently discussed properties for treating amyloidosis
exert therapeutic effects. Primary uptake pathways and rate of (Section ‘Biomolecule aggregation’) [131]. Amorphous silica
uptake are affected by NP composition [116], size [104], shape NPs trigger vascular endothelial injury through multiple ROS-
[117], surface charge [118,119], and functionalization [120]. For associated pathways [132] and chronic exposure has been linked
example, 20 nm AuNPs are taken up primarily by clathrin- to liver and kidney lesions in mice [133]. PAMAM dendrimers are
mediated endocytosis [121]. Interestingly, AuNP uptake path- severely embryotoxic due to alteration of proliferation, growth,
ways can be independent of those utilized by identically-sized apoptosis, and angiogenic signaling pathways [134]. SLNPs can
IONPs, yet colocalization within cells suggest that they share reduce the quantity of liver macrophages by interfering with
portions of intracellular pathways [116]. Polysaccharide NP the Bax/BCL-2 balance, leading to the cleavage of caspase-3
uptake displays geometry dependence, with elongated NPs and subsequent apoptosis [135]. Finally, STNMs may be inher-
allowing greater uptake due to enhanced cellular membrane con- ently biocompatible and yet promote cellular toxicity upon liver
tact in comparison to spherical NPs [122]. In general, non- sequestration, suggesting that elimination must be considered
phagocytic cells preferentially endocytose positively-charged when designing self-therapeutic nanosystems [90]. STNM expo-
NPs due to electrostatic interactions with anionic cell mem- sure can lead to a combination of toxic and therapeutic effects.
branes, but this is counteracted by increasing cytotoxicity with For this reason, the dose–response for both the intended thera-
increasing charge [119]. Finally, NP surface functionalization peutic and undesired off-target effects must be examined closely.
can improve cellular uptake. Cell penetrating peptides conju- The range of toxicities and potential for adverse effects from
gated to the NP surface promote endocytosis while ligands such intrinsic nanotherapies reinforce the importance of rigorous
as RGD peptides improve specific targeting [122]. Moreover, design and delivery to avert poor outcomes.
Mizuhara et al. showed that migration to the acidic tumor
microenvironment (pH 6.5) can activate selective uptake of Applications of self-therapeutic
surface-modified AuNPs by shifting zwitterion functional groups Cancer therapy
from neutral to cationic [123]. Alternatively, while PEGylated Cancer therapy: noble metals
liposomes showed decreased uptake through prevention of non- Gold nanomaterials are well recognized for their anti-cancer self-
specific protein interactions, liposomes modified with hyper- efficacy. The primary mechanism of nanogold self-therapy is
branched polyglycerol displayed increased macrophage multi-pathway modulation of cellular interactions within the
ineractions independent of adsorbed proteins [124]. tumor microenvironment (Fig. 3, Fig. 4). AuNPs inhibit the acti-
After acting in a targeted location, STNMs must be cleared vation of cancer-associated fibroblasts (CAFs) by altering the
from the body, the majority of which occurs through hepatobil- expression of TGF-b1, PDGF, uPA, and TSP1 [136] and inhibit
iary elimination. This process includes transport through the the proliferation of cancer cells through downregulation of
liver sinusoid and the space of Disse and into hepatocytes, which MAPK signaling [137]. In one recent publication, we showed that
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RESEARCH: Review
FIGURE 3
Self-therapeutic nanomaterials (STNMs) in cancer therapy. Green upward arrows indicate upregulation; red octagons indicate downregulation. (a) STNMs
prevent cancer metastasis. (b) STNMs activate apoptosis in cancer cells by upregulating expression of pro-apoptotic proteins in the intrinsic and extrinsic
pathways. (c) STNMs inhibit angiogenesis by mitigating endothelial cell migration and blocking the effects of pro-angiogenic signals. (d) AuNRs and graphene
nanosheets inhibit cytoskeletal assembly and prevent cancer cell division. AgNP: silver nanoparticle; AuNP: gold nanoparticle; AuNR: gold nanorod; CNT:
carbon nanotube; CuO NP: cuprous oxide nanoparticle; CPNP: calcium phosphate nanoparticle; IONP: iron oxide nanoparticle; La2O3 NP: lanthanum oxide
nanoparticle; PtNP: platinum nanoparticle; SeNP: selenium nanoparticle; SLNP: solid lipid nanoparticle; V2O5 NP: vanadium pentoxide nanoparticle. Created
with BioRender.com.
20 nm AuNPs disrupt communication between CAFs, endothe- disrupting IGFBP2/mTOR/PTEN autoregulation [139]. AuNPs
lial cells, and cancer cells by inhibiting MAPK and PI3K-AKT acti- moreover prevent metastasis by altering endothelial SMAD2/3
vation and epithelial to mesenchymal transition (EMT) [138]. signaling [140] along with expression of matrix metallopro-
We also recently reported that AuNPs inhibit cancer growth by teinase 9 (MMP9) and intercellular adhesion molecule-1
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FIGURE 4
Self-therapeutic nanomaterials (STNMs) in cancer therapy. Green upward arrows indicate upregulation; red octagons indicate downregulation. (a) AuNPs
promote the quiescent fibroblast phenotype. (b) STNMs alter cancer cell metabolism. (c) STNMs regulate the cell cycle. (d) MSNs and SLNPs activate the
immune system to target cancer cells. (e) STNMs enhance the efficacy of alternative therapeutic strategies. (f) STNMs increase reactive oxygen species within
cancer cells, ultimately leading to cell death. (g) AuNCs prevent mononuclear cells from differentiating into osteoclasts in late-stage breast cancer. (h) IONPs
and CNTs reprogram macrophages from the M2 phenotype to the M1 phenotype. (i) AuNPs prevent cancer proliferation by inhibition of MAPK. (j) STNMs
scavenge cancer cells circulating in the blood. AgNP: silver nanoparticle; APC: antigen-presenting cell; AuNC: gold nanocluster; AuNP: gold nanoparticle;
AuNR: gold nanorod; CNT: carbon nanotube; CuO NP: cuprous oxide nanoparticle; IONP: iron oxide nanoparticle; La2O3 NP: lanthanum oxide nanoparticle;
MnO2 NP: manganese oxide nanoparticle; MoO3-x NP; molybdenum oxide nanoparticle; MSN: mesoporous silica nanoparticle; PtNP: platinum nanoparticle;
ROS: reactive oxygen species; SeNP: selenium nanoparticle; SLNP: solid lipid nanoparticle; SnO2 NP: tin oxide nanoparticle; STNM: self-therapeutic
nanomaterial; V2O5 NP: vanadium pentoxide nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with BioRender.com.
(ICAM-1) [141]. AuNPs are potent inhibitors of pathologic angio- disruption of TGF-b signaling and actin filament assembly
genesis via interruption of VEGF signaling [142,143] as well as [144]. Ultrasmall AuNPs have been reported to cleave caspase-3
198
and poly-(ADP-ribose) polymerase (PARP), activate JNK/p38, and and inhibit tumor growth by activating apoptosis and consum-
express the pro-apoptotic protein Bax [145]. Moreover, AuNP ing cellular glutathione [168]. Finally, core–shell Au@Pt nanopar-
alteration of cellular secretion prevents proliferation and migra- ticles exhibit cancer cell cytotoxicity via generation of reactive
tion of cancer cells and cancer-associated cells in pancreatic duc- oxygen and nitrogen species [169].
tal adenocarcinoma [146] and thyroid carcinomas [147,148]. Each of the discussed noble metals can treat cancers through
AuNPs enhance expression of lipogenic genes including FASN, mediation of cellular processes. Nanoscale gold represents an
SREBP2, and FABP3 to transform activated CAF into quiescence important tool for battling cancer due to its broad efficacy across
[149], and AuNPs also enhance lamin A/C expression to increase disease processes. AuNPs act on cancerous cells to promote
nuclear membrane stiffness and reduce cancer cell migration/in- healthy cellular processes, on cancer-adjacent cells to inhibit
vasion [150]. Finally, AuNP tumoral inhibition is size dependent, crosstalk and disease phenotype expression, and on extracellular
RESEARCH: Review
with 5 nm AuNPs exhibiting greater tumor inhibition than 13, biomolecules to inhibit autocrine and paracrine signalling. The
30, or 120 nm AuNPs in a C6 glioma model, whereas 20 nm ability of nanoscale gold to impact signaling in the tumor
AuNP inhibits tumor growth in preclinical models of pancratic microenvironment, modulate the cell cycle and cancer gene
as well as ovarian cancer [137,138,146,151]. expression, and reverse tolerance to alternative therapeutics sug-
Non-spherical colloidal gold exhibits further anticancer prop- gests that AuNPs could be foundation to next-generation anti-
erties. AuNRs down-regulate several genes critical to glycolysis cancer therapies. AgNPs show anticancer self-efficacy through
and oxidative phosphorylation, thus preventing ATP production mechanisms similar to nanoscale gold, including modification
and F-actin cytoskeletal assembly [152]. Consequently, AuNRs of gene expression, cell signaling, and the cell cycle. One limita-
prevent invasion by breast cancer, prostate cancer, and mela- tion of AgNP therapy is that hypoxia counteracts ROS-mediated
noma cells while showing no effect on viability or proliferation apoptosis, which could preclude its wider translation [161].
[152]. Additionally, AuNCs avert development of osteolytic bone Moreover, AgNP cytotoxicity must be accounted for in develop-
lesions in late-stage breast cancer by preventing RANKL- ing intrinsic therapies [170,171]. As such, we do not expect silver
precipitated osteoclast differentiation [153]. Gold has further nanomaterials to offer the same level of clinical efficacy against
been combined with other STNMs to promote synergetic ther- cancers as gold despite exhibiting similar therapeutic mecha-
apy: gold core-silver shell NPs attenuate the activity of CAFs nisms. Finally, though we know PtNPs inhibits cancer growth
[11] while Au@Pt “nanoseeds” alter several regulators of the G1 by stimulating expression of apoptotic proteins [168], the rela-
phase of the cell cycle including CDK2, CDK4, cyclin D1, cyclin tive dearth of studies utilizing platinum in comparison to gold
E, and p21WAF1 [154]. Additionally, nanoscale gold can or silver necessitates increased study to match our understanding
enhance the efficacy of alternative therapeutics. AuNPs alter of PtNP therapy with that of AuNPs and AgNPs. Consequently,
the uptake pathway of liposomal siRNA therapy to prevent lyso- we anticipate that self-therapeutic properties of noble metal
somal degradation [155], sensitize pancreatic cancer cells to gem- nanomaterials could be exploited to develop next-generation
citabine [156], and counteract cisplatin resistance in ovarian cancer therapies, with AuNPs taking the preeminent role.
cancer [157]. AuNP–conjugated quercetin exhibit synergetic
effects on EGFR/VEGF-mediated angiogenesis inhibition [158]. Cancer therapy: metal oxides, non-noble metals, and select reactive non-
Finally, AuNPs sensitize non-small cell lung cancer to tumor metals
necrosis factor-related apoptosis-inducing ligand (TRAIL) by Iron oxide is another widely-utilized nanomaterial that exhibits
increasing the mitochondrial recruitment of dynamin-related two distinct self-therapeutic properties useful in cancer therapy.
protein 1 [159]. The first is a shift in cell death towards ferroptosis, an iron-
As with AuNPs, AgNPs alter cellular signaling pathways to dependent pathway characterized by iron accumulation and
promote anti-cancer self-therapy. AgNPs induce caspase-9- lipid peroxidation [172]. The second is the Fenton reaction
dependent apoptosis [160] and reduce the cancer-promoting wherein iron facilitates conversion of hydrogen peroxide to cyto-
activities of CAFs in breast cancer [11]. Moreover, AgNPs induce toxic hydroxyl radicals in acidic environments [20]. Utilizing
G2/M cell cycle arrest in lung cancer by generating ROS [161] as these mechanisms, IONP-based designs have shown
well as reducing expression of anti-apoptotic gene BCL-2 and concentration- and geometry-dependent efficacy against a vari-
enhancing expression of Bax [162]. ROS-induced apoptosis and ety of cancers [173]. Shen et al. report the development of a
loss of mitochondrial membrane potential has also been reported brain-penetrant IONP-based hybrid system capable of targeting
in hepatocellular carcinoma and Ewing sarcoma, suggesting this orthotopic brain tumors through lactoferrin-mediated transcyto-
is a generalizable mechanism for cancer targeting [161,163]. sis [174]. Similarly, Gao et al. utilized Fe3O4 IONPs as a peroxidase
Lastly, AgNPs are useful for sensitizing gliomas and breast can- mimic in their design of a breast-cancer-targeted nanocatalytic
cers to radiotherapy [164,165]. tumor therapy [175] and Lee et al. applied Fenton chemistry in
PtNPs are the third noble metal with notable anti-cancer effi- SnFe2O4 NPs to treat colon cancer [176]. Other IONP-based
cacy. PtNP-induced apoptosis has been linked to upregulation of designs incorporate glucose oxidase or linoleic acid hydroperox-
p53 and caspase-3 [166]. Similarly, combination PtNP/retinoic ide to produce H2O2 for the Fenton reaction and uncouple anti-
acid therapy has shown efficacy against neuroblastomas by tumor effects from innate tumor peroxide concentration
upregulating Bax, activating transcription factors 4 and 6, [177,178]. Yet intrinsic IONP therapy is not based solely on fer-
inositol-requiring enzyme 1, and protein kinase RNA-like roptosis and Fenton reactions. For example, IONP-based
endopasmic reticulum kinase 2 [167]. PtNPs have also been nanosystems prevent cancer migration by regulating expression
observed to form in vivo from cisplatin, accumulate in tumors, of MT1-MMP and MMP2 metalloproteinases and by inhibiting
199
Src kinase [179]. PEI-functionalized Fe3O4 IONPs can scavenge invasion while promoting macrophage migration and activation,
tumor cells from circulation to prevent metastasis [180], and suggesting potential as immune-mediated brain cancer therapeu-
superparamagnetic IONPs coated in hyaluronic acid have been tics [192]. PEGylated graphene oxide nanosheets inhibit cancer
utilized to reprogram macrophages and induce an inflammatory migration though impairing oxidative phosphorylation [193]
response within the tumor microenvironment [181]. whereas aminated graphene oxide causes mitochondrial dys-
Several other metallic nanomaterials also display intrinsic function, demonstrates ROS-induced cytotoxicity, and damages
therapy against cancers. CuO NPs nanoparticles target mito- cell membranes [194]. Finally, carbon nanospheres have been
chondria in vivo to trigger release of cytochrome C and activate utilized in hybrid nanozymes capable of ROS regulation and
caspase-3/9-mediated apoptosis [27]. CuO NPs have also demon- tumor targeting [195]. As such, nanoscale geometry and func-
strated specific cytotoxicity against pancreatic cancer stem cells tionalization directly influence the self-therapeutic properties
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[182] and can generate hydroxyl radicals from hydrogen perox- of carbon nanomaterials.
ide via Fenton-like chemistry [183,184]. ZnO NPs induce While better known as carriers for small molecule and gene
PINK1/Parkin-mediated mitochondrial autophagy (mitophagy) therapeutics, some polymer NPs show cancer-targeted self-
[24] while SnO2 NPs, MnO2 NPs, and MoO3-x NPs exhibit therapeutic efficacy. Surface-modified polystyrene NPs prevent
Fenton-like ROS-generating properties [21–23]. MnO2 NPs have cellular migration by adsorbing cell membranes and promoting
been hybridized with PLGA to enhance the natural killer cell cancer cell aggregation [196]. Gu et al. designed an antibody-
response to cancer by decreasing expression of immunosupres- like polymer NP that collects intratumoral galectin-1 for delivery
sors through catalytic mitigation of tumor hypoxia [185]. Lead to antigen-presenting cells, thus provoking an antitumoral T-cell
borate nanoparticles show selective toxicity towards p53- response [197]. Polymers of essential amino acids can exploit the
mutated cancers [186], while selenium nanoparticles (SeNPs) amplified amino acid demand of cancer cells by targeting large
show antiproliferative activity by activating caspase-mediated neutral amino acid transporter SLC7A5 (LAT-1) and triggering
apoptosis and Fas-associated death domain protein [187]. Lan- apoptosis [198]. Alternatively, lipophilic compounds displaying
thanum oxide nanoparticles (La2O3 NPs) cross the blood brain anti-cancer activity have been formed into SLNPs with increased
barrier to target glioblastomas, enhance the efficacy of radiation cytotoxicity over non-NP controls [199]. Other lipid NPs pro-
therapy, and eliminate cancer cells through ROS-magnification mote lymph node accumulation of antigen presenting cells
and apoptosis induction [188]. Similarly, Ding et al. recently and enhanced CD8+ T cell responses resulting in tumor growth
reported that transition-metal-based upconversion nanoparticles inhibition [200]. Nanogels have been shown to exhibit other
induce pyroptosis by dissolving within cancer cells and releasing extracellular and/or intracellular activities for anti-cancer ther-
ions, altering cellular osmolarity and generating ROS. This results apy. For example, Zhao et al. repurposed a glucose oxidase-
in cellular swelling, pore formation, and cytolysis in addition to decorated nanogel previously applied in insulin delivery applica-
stimulation of dendritic cells and memory T-cells [189]. Finally, tions [201,202] to kill melanoma cells by reducing the intracellu-
vanadium pentoxide nanoparticles (V2O5 NPs) prevent angio- lar glucose level and increasing the concentration of hydrogen
genesis, upregulate p53, and downregulate survivin in mela- peroxide [79]. Similarly, Ma et al. fabricated polymeric nanogels
noma models [190]. comprised of gemcitabine subunits that produced active gemc-
From these examples we see that cancer-targeted intrinsic itabine monomer upon degradation, facilitating tumor cell death
nanotherapies exhibit material-dependence within mediation [203].
of cell signaling and gene expression, generation of ROS, and The remaining anti-cancer nanomaterials display several dis-
sensitization to other therapeutics. In addition to cell- tinct mechanisms of action. For example, NaCl NPs are endocy-
modulating properties shown by noble metal nanomaterials, tosed by cancer cells, thus bypassing ionic transport regulation
IONPs display unique properties for treating cancers that are aug- [204]. Once inside, the NaCl NPs release a surge of osmolarity
mented by superparamagnetic properties, providing potential to from dissolution into sodium and chloride ions, leading to rapid
construct self-theranostic systems. We expect that IONP-based cell lysis [204]. Similarly, CaCO3 NPs and b -tricalcium phos-
systems will eventually offer self-therapy in conjunction with phate CPNPs can cause apoptosis by disrupting the calcium bal-
MRI. The variety of NPs with Fenton-like properties allows tun- ance in cancer cells through selective uptake and overload
ability in addition to modulation of gene expression and apop- [205,206]. Temperature-responsive nanogels facilitate cellular
totic pathways. In contrast to noble metal NPs, these necrosis through rapid volume expansion upon external treat-
nanomaterials may offer more specific self-therapy and thus ment with a hypothermic stimulus [207]. In another strategy,
could carve out their own medicinal niche. b-carotene NPs synthesized by Dunaliella salina microalgae
induce apoptosis via ROS generation [208], while NPs of diphthe-
Cancer therapy: carbon-based, organic and inorganic nanomaterials ria toxin and Pseudomonas aeruginosa exotoxin promote destruc-
Non-metallic nanomaterials for cancer self-therapy are diverse. tion of tumor tissue when targeting CXCR4(+) cancer stem cells
Carbon-based nanomaterials display varying intrinsic anti- [209]. Lastly, sub-6-nm nanochelators can bind to and inhibit
cancer properties based on geometry (nanodiamonds, nan- the cellular functionality of copper, which has been linked to
otubes, nanosheets, nanospheres, etc.). Guo et al. synthesized angiogenesis inhibition in both breast and colon cancer [210].
carboxylated nanodiamonds capable of inhibiting the Further, there are broad applications of STNMs in cancer
epithelial-to-mesenchymal transition process through TGF-b sig- immunotherapy [211]. MSNs promote cancer immunotherapy
naling and reducing metastasis of murine B16 melanoma cells by enhancing both Th1- and Th2-mediated immune responses,
[191]. CNTs modified with CpG oligonucleotides inhibit glioma upregulating the secretion of antibodies and cytokines, and acti-
200
vating the TLR4-NFjB axis [212,213]. Protein nanogels com- posited as both monotherapies and co-administered with CAR-
prised of immunomodulatory cytokines have shown promise T and adoptive T-cell therapies. Self-assembled poly(hydrox-
for in vivo T-cell expansion [75] and modulation of the activity yethyl methacrylate) nanogels coated with a tumor antigen cor-
of regulatory T cells [214]. Roles for these nanogels have been ona have exhibited greater dendritic cell activation than soluble
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201
tumor antigen, leading to the successful activation of cytotoxic T teins in murine models of melanoma and lung carcinoma that
cells [80]. As such, STNM activation of the immune system can are undetectable in plasma analysis [219]. Lastly, in addition to
promote a favorable anti-tumor response. biomarker identification, protein coronas from both graphene
Our discussion of non-metallic STNMs in cancer treatment oxide and SLNPs improve the accuracy of staging pancreatic duc-
reveals both a consistency and diversity in mechanisms. We tal adenocarcinoma [220,221]. Consequently, the utilization of
observe modulation of cellular signaling pathways along with the protein corona as a means to detect scarce proteins in solu-
ROS generation in carbon-based materials, whereas polymers tion suggests potential for improved cancer outcomes.
perform cancer cell scavenging or trigger apoptosis. The diver- The anti-cancer STNM properties discussed in this section are
gent approaches employed by NaCl nanotherapeutics and nan- summarized in a collection of figures. Figs. 3 and 4 display the
otoxin particles suggests that many effective nanomaterials aforementioned nanomaterials and their mechanisms of action,
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have yet to be discovered. We expect that molecular mechanisms while Fig. 5 displays data supporting these claims, including how
of intrinsic anticancer STNMs will continue to be elucidated and AuNP size affects cellular proliferation [137], which lipid metabo-
that these will provide alternatives to and complement current lism genes are upregulated by AuNPs [149], how AuNPs and
cancer therapies. PtNPs sensitize cancers to chemotherapeutics [156,168], and
how CuO NPs treat melanoma [27].
Cancer biomarker detection
Along with direct cancer treatment, STNMs have also been uti- Antimicrobials
lized to combat cancer through identification and detection of Several nanomaterials display antimicrobial properties (Fig. 6).
cancer biomarkers (proteins specifically overexpressed in patho- Silver nanomaterials display intrinsic antimicrobial properties
logical processes). Metal-based STNMs can selectively adsorb can- through the combination of ion release, ROS generation, and
cer biomarkers within the protein corona [97]. AuNPs, AgNPs, bacterial membrane destabilization [222,223]. AgNPs destabilize
and IONPs all adsorb several triple negative breast cancer gram-positive and gram-negative bacterial cell walls [224], com-
biomarkers despite variations in corona quantity and composi- bat mycobacterial infection [225], reduce protozoal oocyst viabil-
tion [215]. Citrate ligand-capped AuNPs adsorb increased quanti- ity [226,227], disrupt biofilm formation [228], and sensitize
ties of human immunoglobulin G (IgG) in prostate cancer microbes to antibiotic treatment [229]. For example, Huma
patients in comparison to noncancer controls [216]. This has et al. describe how functionalized AgNPs and silver nanoclusters
been developed into a prostate cancer screening test, with (AgNCs) hinder Pseudomonas aeruginosa biofilm formation
AuNP-IgG aggregates detectable via dynamic light scattering through inhibition of FapC protein fibrillization, with both bio-
(DLS), potentially forming the basis for rapid and sensitive early film absorbance and bacterial viability decreasing with increasing
detection [217]. MSNs can also be used to detect prostate cancer AgNP and AgNC concentration [230]. Recent designs augment
biomarkers through selective adsorption of low molecular weight intrinsic AgNP therapy with functional ligands that target bacte-
proteins [218]. Likewise, SLNPs can adsorb tumor-specific pro- rial membranes [231–233] or promote formation of antibacterial/
3
FIGURE 5
Data from self-therapeutic nanomaterials in cancer therapy. (a) Inhibition of cellular proliferation is dependent on AuNP size. Serum-starved A2780 cells were
incubated with AuNPs for varying lengths of time with [3H]Thymidine incorporation represented as fold proliferation. Values are mean ± SD. *P < 0.05,
**P < 0.001. Reprinted with permission [137]. (b) AuNPs upregulate the mRNA levels of lipid metabolism genes (FASN, SREBP1a, SREBP2, PLIN1, PLIN4, FABP3,
and FABP4) and induce quiescence in CAFs (SCM: serum-containing media, SFM: serum-free media). Results were expressed as fold mRNA expression, with
respect to nontreated controls (NT), and represented as mean ± SD of three individual experiments (n = 3). Statistical analyses were performed using the
Student’s unpaired t-test (NT vs GNPs, ns = nonsignificant, *p < 0.05, and **p < 0.01). Reprinted with permission from Hossen, M. N. et al. Gold Nanoparticle
Transforms Activated Cancer-Associated Fibroblasts to Quiescence. ACS Applied Materials & Interfaces 11, 26060–26068, (2019) Copyright 2019 American
Chemical Society [149]. (c) PtNPs inhibit tumor growth and reverse daunorubicin (DNR) resistance of K562 and HepG2 cells (K562/DNR: daunorubicin-resistant
K562 cells, HepG2/DNR: daunorubicin-resistant HepG2 cells). a DNR-sensitive and DNR-resistant K562 cell tumor-bearing nude mice were treated with PBS
(ctrl), 0.1 mg kg 1 DNR (DNR), 1 mg kg 1 cisplatin (cisplatin), 1 mg kg 1 Pt NPs (Pt NPs), 0.1 mg kg 1 DNR combined with 1 mg kg 1 cisplatin
(DNR + cisplatin) or 1 mg kg 1 DNR-Pt NPs (DNR@Pt NPs). The tumors were excised and their volumes measured. b DNR-sensitive and DNR-resistant K562
cell (left, n = 5) or HepG2 cell (right, n = 3) tumor-bearing nude mice were treated as described in panel a and the tumor volumes were measured. * P < 0.05.
Data = Mean + / Standard deviation. Reprinted under Creative Commons [168]. (d) AuNPs sensitize pancreatic cancer cells to gemcitabine. The proliferation
of PANC-1 (i), AsPC-1 (ii), MIA-PaCa-2 (iii) and HPAF-II (iv) were measured with MTT and the IC50 were calculated with Prism. Values are means ± SD and
statistical analysis were performed using one-way ANOVA. Reprinted with permission [156]. (e) Anti-melanoma effects of CONP therapy. (i) Representative
images of stripped subcutaneous tumors. The diameters of the subcutaneous tumors of the CONP group were obviously smaller than the diameters observed
in the glucose group. (ii) Representative images of mice bearing subcutaneous melanoma from the same study at day 12. The tumors of the CONP group
were significantly smaller than the tumors of the glucose group. (iii) Plot of tumor mass versus time. Day 0 was the starting of the treatment. The mice bearing
subcutaneous tumors were euthanized when exhibiting signs of illness or death. The tumor masses of the deceased mice were not included after the day of
death. Each group initially contained six mice. The error bars represent ± S.D. The tumors of the CONP group were significantly smaller when compared with
the tumors of the control mice (*P < 0.05, for day 16; **P < 0.005, for days 4 and 12; and ***P < 0.001, for day 8; Student’s paired t-test, n = 6). (iv) Survival plot
of mice bearing subcutaneous tumors. The survival of mice treated with CONPs was significantly longer than the mice in the glucose group (*P < 0.05, log-
rank test, n = 6). Day 5 was the first day of CONPs injection. (v) TUNEL (terminal deoxinucleotidyl transferase-mediated dUTP-fluorescein nick end labeling)-
stained assay of the subcutaneous tumors of CONP-treated mice on day 8. The image shows that CONPs induced the apoptosis of the tumor cells in vivo (as
indicated by pink arrow). (vi) TUNEL-stained assay of the control mice in the glucose group. Reprinted under Creative Commons [27]. AuNP: gold
nanoparticle; CONP: copper oxide nanoparticle; Pt NP: platinum nanoparticle.
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FIGURE 6
Self-therapeutic nanomaterials (STNMs) for antimicrobial applications. (a) Mechanisms of AgNP antimicrobial properties. AgNPs kill bacteria through ion
leaching, ROS production, and direct AgNP-biomolecule interaction. International Journal of NanoMedicine 2020:15 2555–2562 (Adapted) Originally
published by and used with permission from Dove Medical Press Ltd. [223]. (b) STNMs with antimicrobial properties. Arrows indicate the microbe or virulence
factor targeted by each STNM. AuNP: gold nanoparticle; AgNP: silver nanoparticle; CPNP: calcium phosphate nanoparticle; ROS: reactive oxygen species; ZnO
NP: zinc oxide nanoparticle. Created with BioRender.com.
antifungal AgNP complexes [234]. Frequently, antibiotic- ing biofilm formation [236–238]. Huo et al. showed that
resistant microbes will respond to AgNP therapy, placing AgNPs zwitterion-conjugated AuNPs can be tuned by size and ligand
at a crucial junction in the war against drug-resistant bacteria composition to alter antimicrobial activity, emphasizing the
[235]. Like AgNPs, functionalized AuNPs are capable of eliminat- importance of these parameters on self-therapeutic properties
ing a broad-spectrum of multidrug-resistant bacteria and inhibit- [239]. Chitosan-conjugated AuNPs have been incorporated into
203
wound dressings to combat multidrug resistant infections [240] Viral infection

and Au/Ag core/shell NPs inhibit biofilm formation and display Intrinsic nanotherapies targeted at inactivation of viral particles
antileishmanial properties [241]. have gained attention prior to and following the outbreak of
As with noble metal NPs, metal oxides and inorganic com- SARS-CoV-2. Viral particles exist in the extracellular environ-
pounds show efficacy in mitigating microbial infection. The ment when seeking new host cells, making them susceptible to
antimicrobial properties of CPNPs are a consequence of elevated inactivation by STNMs. AgNPs prevent infection by altering
intracellular calcium, high charge density, and the transfer of cal- the surface proteins and damaging the structural integrity of sev-
cium phosphate clusters at the NP-solution interface [31]. eral viruses (Fig. 7a), but they must be utilized with caution due
Molybdenum-doped hydroxyapatite CPNPs exhibit antibacterial to cytotoxic effects [256–260]. To address these concerns, Ag-
activity by scavenging electrons from bacterial metabolic cir- silica NP hybrids have been developed to deactivate influenza
RESEARCH: Review
cuitry, thus altering membrane function and promoting cell A with reduced cytotoxicity compared to pure AgNPs [12]. ZnO
death [242]. ZnO NPs express antibacterial activity against NPs have shown ability to inhibit H1N1 influenza infection,
gram-positive and gram-negative bacteria [26,238] in addition though this mechanism has yet to be elucidated [261]. Many
to controlling the growth of Mycobacterium tuberculosis [243]. viruses promote their own cellular uptake through binding hep-
Finally, ferumoxytol (a superparamagnetic IONP coated with car- aran sulfate proteoglycans on cell membranes; Cagno et al.
bohydrate) has been observed to disrupt biofilm formation and exploited this mechanism to develop heparan sulfate-
prevent tooth decay via autocatalytic activity [244], while MSN- mimicking NPs that bind and deactivate viruses including herpes
Fe hybrids combat root canal biofilm formation through simplex virus, human papilloma virus, respiratory syncytial
Fenton-reaction-generated ROS and sonosensitive combination virus, dengue virus, and lentivirus [60]. Alternatively, PLGA poly-
therapy [245]. mers resist acid degradation, leading to inclusion in oral antiviral
The antimicrobial properties of non-metallic nanomaterials NP therapies to treat Zika virus [262]. In comparison to antibac-
are diverse. Machelart et al. report that b-cyclodextrin NPs exhi- terial and anticancer therapies, antiviral STNMs are relatively
bit intrinsic antibacterial properties against Mycobacterium tuber- underreported. While this could be partly due to an increased
culosis through direct antibacterial action and induction of focus on vaccination, it may speak more broadly to the challenge
macrophage apoptosis, thus depleting infected cells and elimi- associated with developing effective antiviral therapies. Viral par-
nating mycobacteria within [246]. Quaternized carbon nano- ticles are vulnerable when in solution, suggesting that STNM
spheres disrupt bacterial cell walls by insertion of quarternary scavenging strategies could be critical to assisting the immune
ammonium groups attached to long-chain alkyl groups [247]. system in combating viral infection, but intrinsic nanotherapies
Similarly, crosslinked micelles containing quarternary ammo- for viral infection require further development in upcoming
nium surface groups show antibiofilm and antibacterial activity years to match the strides made by STNMs in other areas.
[248], while trypanocidal activity is displayed by polyisobutyl-
cyanoacrylate NPs against Trypanosoma brucei brucei [249]. Vaccine development
Although nanogels have been applied extensively for antibiotic Advances of STNMs in vaccine development complement those
delivery, recent work has established nanogels as self- made in treatment of bacterial, fungal, and viral infections. Sev-
antimicrobials. Cationic nanogels comprised of 2- eral immunogenic nanomaterials, especially those based on alu-
(diethylamino)ethyl methacrylate, cyclohexyl methacrylate, minum, have been harnessed as vaccine adjuvants (Fig. 7b).
and PEG methacrylate exhibit PEG-dependent antimicrobial Different adjuvant nanomaterials induce different immune
properties against gram negative bacteria [250]. Nanogels com- responses, with aluminum hydroxide nanoparticles (AlOH NPs)
posed of carboxymethyl chitosan/poly(vinyl alcohol) [251], and CPNPs inducing Th1-mediated responses and chitosan NPs
guanidine [252], and other materials [253] have also shown inducing Th2-mediated responses [32]. Combinations of calcium
antimicrobial efficacy. Interestingly, Koide et al. recently pub- and aluminum phosphates allow tuning between Th1 and Th2
lished a report of hydrogel NPs that selectively adsorb histones responses [263]. Interestingly, the size of particle determines
(an inflammatory modulator released during bacterial sepsis) the immune response, with CaPO4 microparticles inducing a
and that histone sequestration results in near complete survival Th2 response and aluminum-compound microparticles inducing
in murine sepsis models [254]. Finally, hectorite nanoclays a Th1 response [263]. As with CPNP/AlPO4 NP combinations,
adsorb bacteria and promote aggregation while conjugation of PEI/PLGA copolymer nanoparticles can promote a dual Th1/
bactericidal peptides to hectorite prevents infection spread [255]. Th2-mediated immune response [264]. Furthermore, AlOH NPs
Each of these materials offer distinct opportunities for treating bound to repeating phosphoserine residues trigger B cell activa-
microbial infection. Antimicrobial AgNPs have been among the tion in lymph nodes through multivalent interactions, upregu-
earliest STNMs to be clinically translated. AgNPs exhibit a lating antigen processing and leading to more robust immune
breadth of therapeutic mechanisms; drawbacks precluding wider responses [265]. Interestingly, while ferritin NPs enhance protec-
use include cytotoxicity and off-target effects in vivo [170]. One tive immunity over alternative adjuvants [266], AuNPs employed
advancement provided by STNMs is the mitigation of drug- in SARS-CoV-2 vaccines promoted undesired eosinophil infiltra-
resistant microbes through intrinsic cytotoxicity or reversal of tion into the lungs while still inducing a strong IgG response
antibiotic resistance. Moreover, self-therapeutic antimicrobials [267]. Polymer-based adjuvants perform dual roles as antigen
work by several mechanisms, which may delay the development delivery systems and immune response triggers. In one in vivo
of bacterial resistance. We expect that translation of antimicro- study, an anthrax vaccine containing a chitosan-based NP adju-
bial STNMs will further expand in upcoming years. vant provoked elevated IgG responses and improved survival,
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RESEARCH: Review
FIGURE 7
Self-therapeutic nanomaterials (STNMs) as antivirals and vaccine adjuvants. (a) Intrinsic nanoparticle activity against viral particles. Arrows indicate the virus
against which each STNM has shown efficacy. (b) STNM vaccine adjuvants promote selective immune activation and tuning of nanoparticle adjuvants allows
rational selection of Th1- and/or Th2-mediated responses. (c) Chitosan-based nanoparticles (FUC-HTCC NPs) improved mouse survival in an i.p. anthrax toxin
challenge. (AVA: anthrax vaccine adsorbed, CpG: CpG oligonucleotide adjuvant) Reprinted from Carbohydrate Polymers 229, Chuang, C. C. et al. A fucoidan-
quaternary chitosan nanoparticle adjuvant for anthrax vaccine as an alternative to CpG oligodeoxynucleotides, 115403, Copyright 2020, with permission from
Elsevier [268]. (d) Cholesteryl-group-bearing pullan nanogels (cCHP) promote survival in botulin neurotoxin (BoNT)-challenged mice (BoHc/A: recombinant
non-toxic receptor-binding fragment (heavy-chain C terminus) of C. botulinum type-A neurotoxin subunit antigen Hc). IP: intraperitoneal; IN: intranasal.
Reprinted by permission from Springer Nature: Nature Materials. Nochi, T., et al., Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines.
Copyright (2010) [270]. AgNP: silver nanoparticle; AlOH NP: aluminum hydroxide nanoparticle; CPNP: calcium phosphate nanoparticle; CP/AlPO4 NP: calcium
phosphate/aluminum phosphate nanoparticle; PEI/PLGA NP: polyethylene imine/poly(lactic-co-glycolic acid) nanoparticle. PLGA NP: poly(lactic-co-glycolic
acid) nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with BioRender.com.
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FIGURE 8
Self-therapeutic nanomaterials for treating inflammatory conditions. (a) AuNPs and PAMAM/PEG dendrimers inactivate macrophages, microglia, and T cells
via several mechanisms. (b) b-cyclodextrin NPs inhibit migration of macrophages and neutrophils. (c) Nanogold (AuNGs) show similar efficacy as
methotrexate (MTX) in reduction of foot pad swelling in collagen-induced arthritis (CIA) models. * Significantly different from control; # significantly different
from induced group (p < .05); *** p < .05. Khan, M.A. and M.J. Khan, Nano-gold displayed anti-inflammatory property via NF-kB pathways by suppressing COX-2
activity. Artif Cells Nanomed Biotechnol, 2018. 46(sup1): p. 1149–1158. Reprinted by permission of the publisher (Taylor & Francis Ltd) [278]. (d) Bilirubin and
selenium NPs combat GI inflammation by preventing ROS-induced tissue damage. Created with BioRender.com.
with anthrax challenge survival curves showing improvements response [272–274]. This tunability offers the control necessary
over controls and alternative adjuvants (Fig. 7c) [268]. Addition- for customized vaccine development and may be a step towards
ally, chitosan has also been used as a carrier/adjuvant for an personalized medicine. As mechanisms of STNM immune activa-
influenza vaccine [269]. Formation of multi-layered protein com- tion are elucidated, we expect that STNMs could become cus-
plexes and protein nanogels offers another means of antigen tomized vaccine adjuvants that optimize each person’s
delivery for vaccination; while this work is early-stage, pre- response to a presented antigen.
clinical efficacy has been observed in an intranasal protein-
nanogel vaccine for Clostridium botulinum neurotoxin (survival Inflammation
curves shown in Fig. 7d) [270] and an intramuscularly- Intrinsic nanomaterial therapies can treat inflammatory and
administered influenza A vaccine [271]. autoimmune conditions through direct cell targeting and regula-
STNM adjuvants offer opportunities for tuning the immune tion of cytokine expression (Fig. 8). AuNPs regulate a number of
response. Research on NP-based adjuvants has led to new find- inflammatory pathways; Xu et al. describe how phagocytized
ings regarding the independent and synergistic roles of particle AuNPs dampen immune responses through inhibition of chemo-
composition, shape, and size on the nature of the immune kine receptor 5 [275], while Aghaie et al. show that PEGylated
206
AuNPs inhibit IL-23 and IL-27 signaling [276]. AuNPs can treat Tissue regeneration
psoriasis through downregulation of pathways downstream of Tissue regeneration encompasses wound healing, cell differenti-
IL-17 and show equal efficacy as vitamin D/steroid therapy with- ation, cell migration, angiogenesis, and extracellular matrix
out the side effects of wrinkling and hair loss [277]. Nanoscale deposition (Fig. 9). Incorporation of nanoclays into tissue scaf-
gold also suppresses Cox-2 activity and mimics the effects of folds promote rapid healing through improved cell migration,
methotrexate (MTX) in a collagen-induced arthritis mouse proliferation, and viability along with enhanced mechanical
model (Fig. 8c) [278]. Furthermore, AuNPs have been incorpo- properties [41,42]. These properties are advantageous in several
rated into therapies that inhibit cytokine production in dendritic areas, foremost of which is osteogenesis. Inclusion of 2D nanosil-
cells for the treatment of type-1 diabetes mellitus [4]. Finally, icates within hydrogels promotes attachment, differentiation,
AuNPs limit the damage of cerebral ischemia/reperfusion injury and proliferation of mesenchymal stem cells for calvarial bone
RESEARCH: Review
by promoting secretion of anti-inflammatory cytokines, inhibit- healing along with an increased modulus and decreased degrada-
ing activation of microglia and astrocytes, preventing neuronal tion rate [41]. Likewise, nanoclay-modified PEG networks
apoptosis, alleviating oxidative stress, and enhancing mitochon- improve cellular adsorption and osteogenic differentiation when
drial respiration [279,280]. compared to pure PEG hydrogels [294]. Mechanistically,
In addition to AuNPs, organic nanomaterials have shown effi- laponite-based hydrogels improve osteogenic differentiation
cacy against several immune-mediated conditions. PAMAM- and and cell adhesion by activating Wnt/b-catenin signaling through
PEG-based dendrimers display both anti-oxidant and anti- the laponite degradation products lithium and orthosilicic acid
inflammatory properties along with intrinsic targeting of acti- [295]. Fig. 9h shows the upregulation of osteogenic genes ALP,
vated microglia to combat neuroinflammatory conditions Runx2, and OCN along with b-catenin and a and b integrins in
[84,281]. Hydroxybenzyl alcohol-incorporating copolyoxalate the presence of nanoclay hydrogels [295]. Nanoclay-based thera-
NPs scavenge hydrogen peroxide in ischemia/reperfusion inju- pies for osteogenesis can be augmented by inclusion of bone
ries to prevent ROS-induced tissue damage [282]. Similarly, morphogenic protein 2 (BMP2), with nanoclay-BMP2 interac-
MSN-based nanocomposites can sequester zinc ions prevalent tions allowing extended protein release [296]. Similarly, incorpo-
in reperfusion injury and improve cell survival [283]. Hyaluronic ration of calcium-deficient hydroxyapatite nanocrystals within
acid nanogels have broad anti-inflammatory effects in circula- tissue scaffolds promote osteogenesis by allowing exogenous cal-
tion [284], and the nature of the inflammatory response to hya- cium phosphate to enter the bone remodeling cycle, thus match-
luronic acid is molecular weight dependent [285]. Likewise, ing bone formation with scaffold degradation [33].
hyaluronic acid NPs synthesized with pentosane polysulfate Nanoclays also exert therapeutic effects throughout the
sodium modulate the CD44-NFjB-catabolic gene axis and have wound healing process. Kaolinite nanoclays act as hemostatic
been applied in transdermal osteoarthritis therapy [286,287]. agents by promoting platelet aggregation and activating the
PEGylated bilirubin NPs protect cells from peroxide-based dam- intrinsic coagulation pathway [297]. Laponite has been com-
age observed in ulcerative colitis [288], and SeNPs similarly bined with self-healing polymers to create an injectable bioadhe-
reduce inflammation in inflammatory bowel diseases [289]. sive capable of sealing irregular geometries such as vascular
NPs synthesized from tea polyphenol also demonstrate radical anastomoses [298]. Once bleeding has stopped, nanoclay-
scavenging properties and have the benefit of an environmen- hydrogels promote fibroblast motility into the wounded area
tally sustainable synthesis process [290]. Cyclodextrin NPs treat [299] and injectable laponite and vascular endothelial growth
atherosclerosis and psoriasis through intrinsic ROS-scavenging factor (VEGF) nanocomposites promote regrowth of blood ves-
and anti-inflammatory activity [58,59], and these properties also sels [300]. Finally, wound dressings can be made from anisotro-
inhibit neutrophil and macrophage migration in peritonitis and pic hydrogels containing magnetic nanoclays that allow
acute lung injury [291]. Finally, SLNP protein corona analysis can asymmetric swelling to mitigate in-plane stress damage [301].
detect biomarkers useful for differentiating between non- Metal-based NPs also exhibit self-therapeutic properties appli-
infectious systemic inflammation and sepsis in emergent situa- cable to tissue regeneration. IONPs enhance expression of gap
tions [292]. junction protein connexin 43 in cardiomyoblasts, which is
Anti-inflammatory properties of nanomaterials will become essential for cellular crosstalk during healing following myocar-
increasingly crucial as the medical field shifts from treating acute dial infarction [302]. AuNP cellular mediation properties coun-
to chronic disease. The prevalence of antinuclear antibodies has teract benign prostatic hyperplasia and regenerate healthy
increased significantly in the United States over recent decades, prostate tissue by inhibiting TGF-b, IL-6, and VEGF-A [303].
suggesting that treatment of autoimmune and inflammatory AuNPs conjugated to a chitosan film improve its mechanical
conditions could be a notable challenge in upcoming years and antibacterial properties while sequentially promoting cell
[293]. AuNP modulation of cellular signaling and protein expres- adhesion and proliferation for rapid wound healing [304]. Simi-
sion can be exploited in treatment of immune-mediated condi- larly, branch-shaped ZnO NPs incorporated into a polymeric
tions analogously to how AuNPs disrupt communication matrix enhance the mechanical, adhesive, and antibacterial
between cancer cells and the associated tissues. Conversely, properties of the structure while promoting eukaryotic cell
organic materials scavenge ROS and mitigate cellular oxidative growth [305]. Interestingly, ZnO NPs have also been reported
stress. This targeting of the underlying cause of inflammation to attenuate proliferation in human tenon fibroblasts, which
on a cellular level is an advantage of nanomaterial self-therapy could reduce scar formation and subsequent surgical failure in
that could offer hope to those with ineffectively-managed ophthalmologic operations [306]. Titanium carbide quantum
autoimmune conditions.
207
RESEARCH: Review
208
dots have been incorporated into chitosan hydrogels to make intervention. STNMs treat these pathologies by interacting with
them non-immunogenic by reducing activation of CD4(+) IFN- offending agents on a macromolecular scale. Alzheimer’s disease
c(+) T cells and increasing activation of CD4(+) CD25(+) FoxP3 is characterized by the buildup of amyloid-b (Ab) plaques in the
(+) regulatory T cells [307]. brain; AuNPs prevent Ab formation by stabilizing the a-helix of
Tissue scaffolds can display intrinsic tissue regenerative prop- amyloid precursor proteins and preventing the transition to b-
erties alone or when doped with other nanomaterials. One con- sheet [314]. Alternatively, AuNP corona analysis can detect the
ductive hydrogel has been shown capable of being painted on an unique serum protein profile of Alzheimer’s disease [315]. NP-
area of myocardial infarction, bonding to the beating heart and enabled blood proteome analysis also reveals fluctuation in pro-
improving both revascularization and cardiac function [308]. tein levels by disease stage which could prove essential for early
Alternatively, self-therapeutic PEG hydrogels incorporating inte- detection [316]. The therapeutic action of nanoscale gold is
RESEARCH: Review
grin binding sites and protease-sensitive substrates imitate the geometry dependent: small AuNCs completely inhibit Ab forma-
extracellular matrix of natural tissue and enabled rapid incursion tion, whereas large AuNPs actually accelerate Ab fibrillation (for-
of native vasculature [309]. Incorporation of ionized or ionizable mation of linear aggregates from misfolded proteins) [317].
NPs within cellular scaffolds offers a means of complexing and AuNRs are more effective than AuNPs in fibrillation prevention
delivering growth factors for sustained periods. For example, due to promotion of a mild hydrophobic microenvironment
Pakulska et al. demonstrated that cationic cytokine adsorption favored by aromatic side chains [318]. Interestingly, casein-
onto anionic PLGA nanoparticles facilitated the sustained deliv- coated AuNPs cross the blood brain barrier and promote recovery
ery of stromal cell-derived factor 1 alpha, neurotrophin-3, and of cognitive and motor function in zebrafish exposed to Ab [319].
brain-derived neurotrophic factor [310]. Epitope-imprinted AuNPs are also effective against several other biomolecular aggre-
nanogels with selective affinity for TGF-b3 were similarly able gates. Vimal et al. developed PEGylated AuNPs that target tau
to sequester cell-secreted growth factor and guide differentiation protein aggregates and improve the learning ability of tau
of adipose derived stem cells [311]. Europium hydroxide nanor- P301L mice via protein remodeling and repair of aberrant pro-
ods promote endothelial cell proliferation and angiogenesis teostasis [320]. Polymer-functionalized AuNPs bind to insulin
through activation of MAPK and generation of ROS [312]. Lastly, monomers to combat insulin amyloid fibril deposition and disag-
graphene oxide NPs extend the self-renewal capacity of stem gregate mature insulin amyloid plaques [321,322]. Finally, islet
cells by promoting cell–cell and cell-matrix interactions while amyloid polypeptides (IAPPs) can be treated with citrate-capped
double-layered hydroxide NPs extend stem cell self-renewal by AuNPs through inhibition of local cytokine secretion [323].
activating the PI3K/Akt signaling pathway [52,313]. Non-gold metal nanotherapies for diseases of bioaggregation
Intrinsic nanotherapy is positioned to improve upon current include AgNPs, IONPs, and ZnO NPs. AgNPs inhibit protein
techniques to promote cell migration, angiogenesis, and wound aggregation by weakening interprotein interactions [13], and
healing. Integration of STNMs into tissue scaffolds offers oppor- magnetite IONPs hinder insulin fibrillation through protein-NP
tunities to improve mechanical properties and biocompatibility van der Waals (VDW) interactions [324]. As VDW forces are
while inhibiting bacterial growth. Intrinsic nanotherapeutics weak, fibrillogenesis suppression improves when maghemite
alter cellular signaling to reduce inflammation, promote stem IONPs are conjugated with dextran-based polymers [325]. Zinc-
cell regeneration, and counteract hyperplasia and could improve doped ferrite IONPs inhibit fibrillization in both insulin and
outcomes in stabilization of wounds sustained on the battlefield, albumin [326]. This occurs by dual mechanisms: zinc ion leach-
through natural disasters, and in traumatic accidents. We expect ing prevents fibrillogenesis and magnetic-field induced NP
that tissue-regenerative hybrid nanomaterials will continue to be “dancing” promotes amyloid degradation [326]. The surfaces of
developed and could be a boon for those suffering acute trau- ZnO NPs preferentially interact with amyloidogenic proteins to
matic injuries. produce non-toxic intermediates [327] and geometries with
higher surface area to volume ratios display greater therapeutic
effect than spheres of equivalent size [328]. ZnO NPs also exhibit
Biomolecule aggregation
seemingly contradictory effects: preferential ZnO NP-protein
Diseases of biomolecule aggregation such as amyloidosis and Alz-
binding generates non-amyloidogenic intermediates [329],
heimer’s disease typically respond poorly to small-molecule
3
FIGURE 9
Nanoclays as intrinsic therapeutics in tissue regeneration. (a) Nanoclay-embedded tissue scaffolds promote bone healing. (b) BMP2-nanoclay complexes
promote extended BMP2 release and improved bone regeneration. (c) Nanoclays in conjunction with VEGF promote angiogenesis. (d) Nanoclays promote
mesenchymal stem cell differentiation into osteoblasts through Wnt/ b-catenin signaling. (e) Nanoclays promote platelet activation and platelet plug
formation. (f) Nanoclay-infused hydrogels promote fibroblast migration and activation to promote wound healing. (g) Structure of layered silicate nanoclay.
Reproduced from Beyer (2002) [37] and Pavlidou & Papaspyrides [38]. Reprinted from Progress in Polymer Science, 33(12) Pavlidou, S. and C. Papaspyrides, A
review on polymer–layered silicate nanocomposites. 1119–1198, Copyright 2008, with permission from Elsevier. (h) Gene expression of cell-encapsulated
supramolecular hydrogels. (i) Osteogenic genes ALP and Runx2 were tested at day 1, 7, and 14. OCN was evaluated at day 1, 14, and 21 (n = 3, *p < 0.05,
**p < 0.001 by one-way analysis of variance, ANOVA). (ii) Wnt/b-catenin signaling markers Gsk3 and b-catenin and (iii) cell adhesion markers Integrin a and
Integrin b were evaluated after incubation for 1, 7, and 14 days (n = 3, *p < 0.05, **p < 0.001 by one-way analysis of variance, ANOVA). Reprinted with
permission from Zhang, X. et al. Supramolecular Hydrogels Based on Nanoclay and Guanidine-Rich Chitosan: Injectable and Moldable Osteoinductive Carriers.
ACS Appl Mater Interfaces 12, 16088–16096, https://doi.org/10.1021/acsami.0c01241 (2020). Copyright 2020 American Chemical Society [295]. ALP: alkaline
phosphatase; BMP2: bone morphogenic protein 2; VEGF: vascular endothelial growth factor. Created with BioRender.com.
209
whereas the presence of ZnO NPs has also been reported to another strategy, poly(2-hydroxyethyl acrylate) nanostars pro-
increase insulin fibrillation [130]. Interestingly, while ZnO NPs mote fibril formation with the aim of eliminating toxic IAPP
exhibit reportedly mixed properties, CuO NPs promote expres- intermediates responsible for poor glycemic control in type 2 dia-
sion of amyloid precursor proteins, activate NFjB, and contribute betes mellitus [339]. As such, polymer-based nanomaterials pre-
to redox stress and are thus anti-therapeutic [330,331]. vent the progression of amyloidosis and potentially reverse its
Polymeric NPs are effective against diseases of proteostasis and course through a variety of mechanisms.
exhibit properties distinct from those discussed above. The nan- Alternative STNMs effective for treating protein aggregation
otherapeutic effect of some polymer NPs is dependent on protein disorders include GQDs, silica nanoparticles (SiNPs), and nan-
stability, with NPs improving stability of inherently unstable oclays. GQDs prevent formation of IAPP toxic intermediates
proteins while destabilizing intrinsically stable proteins [332]. through hydrogen bonding, electrostatic interactions, and
RESEARCH: Review
Zwitterionic polymers act as molecular chaperones by enhancing hydrophobic interactions [340]. Likewise, tramiprosate-
hydrophobic interactions within proteins, resulting in reduced functionalized GQDs hinder Ab fibrillation through synergistic
protein structural abnormalities and maintained protein func- covalent bonding [341]. Nanoscale graphene and CNTs inhibit
tion [91,333]. Additionally, zwitterionic polymers electrostati- prion aggregation through p-p stacking between aromatic side
cally stabilize the a-helix and create a “kinetic trap” that chains and the carbon NPs [342], while pristine and hydroxylated
prevents b-sheet formation [91,333]. Hydrophobic moiety- C60s prevent IAPP fibrillation through hydrophobic/aromatic
modified pullulan nanogels similarly inhibit the formation of stacking and hydrogen bonding/aromatic stacking interactions
amyloid fibrils through a chaperone effect [334,335], and nano- respectively [50]. In contrast, SiNPs exert self-therapeutic efficacy
gels comprised of epigallocatechin gallate and/or curcumin- at the nucleation phase of fibrillation, leading to formation of
modified hyaluronic acid similarly reduce the size and quantity short, thin fibrils or clusters rather than long, thick fibrils [343].
of amyloid aggregates [336]. Liu et al. showed that poly(carboxy- A wide selection of nanoclays have been identified to inhibit pro-
betaine) NPs treat Alzheimer’s disease by attracting Ab to micro- tein aggregation, though bentonite and MMT K-10 act at the
glia and ensuring degradation by shifting pathways from nucleation phase to exert the most notable effects [36]. Finally,
lysosomal degradation to proteasomal destruction [337]. G2 nanoliposomes prevent microvascular endothelial dysfunction
PAMAM dendrimers are also recognized for preventing amy- in light-chain amyloidosis by increasing the bioavailability of
loidogenic transthyretin (ATTR) fibril formation and eliminating NO and enhancing expression of antioxidant enzymes [344].
pre-formed ATTR fibrils through b-sheet destabilization [338]. In
FIGURE 10
Self-therapeutic nanomaterials (STNMs) for treatment of diseases of biomolecular aggregation. STNMs inhibit the transition from a-helix to b-sheet critical for
protein aggregation, inhibit protein–protein interactions, and promote amyloid protein degradation and plaque breakdown. Green upward arrows designate
upregulated processes whereas red octagons designate downregulated processes. AgNP: silver nanoparticle; AuNC: gold nanocluster; AuNP: gold
nanoparticle; AuNR: gold nanorod; C60: fullerene; IONP; iron oxide nanoparticle; SiNP: silica nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with
BioRender.com.
210
RESEARCH: Review
FIGURE 11
Nanoparticles as biomimetic enzymes and nanoparticle toxicities. (a) Electron spin resonance spectra of 3-carbamoyl-2,5-dihydro-2,2,5,5-tetramethyl-1H-
pyrrol-1-yloxyl (CTPO) in absence or presence of catalysts in a closed chamber. Samples contained 0.1 mM CTPO, 0.5 mM H2O2 mixed without or with AuNPs
(0.1 mg/mL) or 5 U/mL catalase in pH 11.0 buffer. Spectra were collected after 4 min of incubation. Hyperfine splitting loss indicates the presence of
molecular oxygen. Reprinted from Biomaterials 34, He, W. et al. Intrinsic catalytic activity of Au nanoparticles with respect to hydrogen peroxide
decomposition and superoxide scavenging, 765–773. Copyright 2013, with permission from Elsevier [345]. (b) Catalytic activity of self-therapeutic
nanoparticles. (c) Cuprous oxide nanoclusters (CuxO NCs) rescued memory deficits in mice with Parkinson’s Disease. (i) Escape latency, (ii) swimming speed,
and (iii) relative time spent on the target quadrant where the escape platform used to be located. Statistical analysis was performed using a one-way ANOVA
test, with ** indicating p < 0.001 and * indicating p < 0.05 compared with the OA group (n = 8 per group). (iv) Representative path tracings of different
groups. Reprinted with permission from Hao, C. et al. Chiral Molecule-mediated Porous CuxO Nanoparticle Clusters with Antioxidation Activity for
Ameliorating Parkinson’s Disease. Journal of the American Chemical Society 141, 1091–1099. Copyright 2019 American Chemical Society [346]. AuNP: gold
nanoparticle; CuO NP: cuprous oxide nanoparticle; GeNP: germanium nanoparticle; IONP: iron oxide nanoparticle; MnO2 NP: manganese oxide nanoparticle;
MSN: mesoporous silica nanoparticle; PAMAM: poly(amidoamine); SLNP: solid lipid nanoparticle; ZnO NP: zinc oxide nanoparticle. Created with
BioRender.com.
Diseases of protein fibrillation and aggregation present special helix structures, inhibition of fibril nucleation, or prevention of
challenges to conventional therapies, but STNMs offer an effec- toxic intermediate buildup (Fig. 10). Each of these mechanisms
tive solution. Several organic and inorganic STNMs treat these is characteristic of intrinsic nanotherapy and is not readily repli-
conditions through selective protein binding, stabilization of a- cated by alternative therapeutic strategies. Due to the dearth of
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212
RESEARCH
TABLE 2
Clinical trials incorporating self-therapeutic nanomaterials.
NCT Number Title Status Conditions Interventions Outcome Measures Phases Enrollment Start Last Locations
Date Update
Posted
NCT03752424 Topical Silver Unknown Foot Infection Fungal | Drug: Silver The antimicrobial Phase 30 11/ 10/11/ Buraidah Clinic,
Nanoparticles for status Infection, Bacterial nanoparticles | Drug: activity of silver 1 13/19 19 Buraidah, Al
Microbial Activity [355] Topical approved anti- nanoparticles in the two Qassim, Saudi
microbial gel groups of control and Arabia
an infected patient will
be determined. Each
group will be of 6
volunteers, each one
will be controlled for the
CTCAE. | Stable topical
anti-microbial silver
nanoparticles
NCT02400957 Addition of Silver Unknown Tooth Demineralization Other: Silver Enamel Phase 40 9/1/ 3/27/15 Gabriela Moreno
Nanoparticles to a[n] status nanoparticles | Other: demineralization 3 14 Meraz, San Luis
Orthodontic Primer in Placebo (Diagnodent-pen Potosi, Mexico
Preventing Enamel evaluation)
Demineralization
Adjacent Brackets [365]
NCT01975545 Fluor Varnish With Silver Unknown Down Syndrome Drug: Fluor varnish | Remineralization Phase 20 9/1/ 3/7/14 Universidad
Nanoparticles for Dental status Drug: Fluor varnish with 2 12 Autónoma de
Remineralization in nanoparticles San Luis PotosÍ,
Patients With Trisomy San Luis PotosÍ,
21 [366] Mexico
NCT04332796 Chlorhexidine Scrub, Not yet Foot Dermatoses Drug: Chorhexidine The number of patients Phase 72 4/3/ 2/25/21 Department of
ZnO Nanoparticles recruiting scrub | Device: ZnO-NPs who had improvement 4 20 Dermatology
Socks and the socks | Combination of pitted lesion after Siriraj Hospital,
Combination for Product: Combination of treatment | The Bangkok,
Treatment of Pitted chorhexidine scrub and percentage of patients Thailand
Keratolysis [361] ZnO-NPs socks develop[ing] any side
Materials Today
effect such as erythema,
burning
NCT04337749 Chlorhexidine Scrub, Not yet Foot Dermatoses Drug: Chorhexidine The number of patients Phase 316 11/5/ 2/25/21 Department of
ZnO Nanoparticles recruiting scrub | Device: ZnO-NPs who had pitted 4 21 Dermatology
Socks and the socks | Combination keratolysis after Siriraj Hospital,
Combination for Product: Combination of treatment | The Bangkok,
d
Volume 62
Prevention of Pitted chorhexidine scrub and percentage of patients Thailand
Keratolysis [360] ZnO-NPs socks | Device: develop[ing] any side
Placebo socks effect such as erythema,
burning
d
NCT01167985 A Clinical Study: the Unknown Endodontic Treatment | Device: IABN In vitro evaluation | Phase 200 7/1/ 7/23/13 Hadassah
January/February 2023
Antibacterial Effect of status Irreversible Pulpitis | Radiological evaluation 2 13 Medical
Insoluble Antibacterial Healthy Pulp | Infected of the root canal sealer | Organization,
Nanoparticles (IABN) Pulp Clinical and in vitro Jerusalem, Israel
Incorporated in Dental evaluation of the root
Materials for Root Canal canal sealer
Treatment [364]
Materials Today
TABLE 2 (CONTINUED)
Date Update
Posted
NCT04645147 Safety and Recruiting EBV | Epstein-Barr Virus Biological: EBV gp350- Local and systemic Phase 500 3/29/ 7/12/22 National
d
Immunogenicity of an Infection | Infectious Ferritin Vaccine | Other: reactogenicity; 1 22 Institutes of
Volume 62
Epstein-Barr Virus (EBV) Mononucleosis Matrix-M1 unsolicited adverse Health Clinical
gp350-Ferritin events; serious adverse Center,
Nanoparticle Vaccine in events; change in Bethesda,
Healthy Adults With or neutralizing antibody Maryland,
d
Without EBV Infection responses to EBV | United States
[368] Change in antibody
responses to EBV gp350;
change in CD4 + T cell
responses to EBV gp350
NCT04887389 Cariostatic and Active, Dental Caries in Drug: Nano Silver Clinical evaluation using Phase 115 8/1/ 6/8/22 Faculty of
Remineralizing Effects not Children | Cariostatic Fluoride varnish | Drug: international caries 4 21 Dentistry /
of Three Different recruiting Agent | Resistance, nano-hydroxyapatite detection and Mansoura
Dental Varnishes [367] Dental Caries | Fluoride varnish | Drug: sodium assessment system University,
Varnishes Fluoride Varnish (ICDAS II visual scoring Mansoura,
criteria | Enamel biopsy Dakahlia, Egypt
for detecting Calcium
and Fluoride content.
NCT03993171 31P-MRS Imaging to Recruiting Relapsing Remitting Drug: gold nanocrystals The change from Phase 30 12/ 1/26/22 University of
Assess the Effects of Multiple Sclerosis baseline to week 12 in 2 19/19 Texas
CNM-Au8 on Impaired CNS metabolic changes, Southwestern,
Neuronal Redox State in based on 31P-MRS Dallas, Texas,
Multiple Sclerosis. [369] Redox Ratio. United States
NCT05442359 Effect of Nano-Bio Recruiting Free Gingival Graft Drug: Nano-bio fusion Wound healing | Post- Phase 22 6/1/ 7/5/22 Cairo University,
Fusion Gel on Palatal gingival gel | Device: operative Pain 4 22 Cairo, Egypt
Wound Healing After Acrylic stent Assessment | Patient
Free Gingival Graft Satisfaction
Harvest. [373]
NCT04701320 Clinical Evaluation of Active, Dental Restoration Drug: Conventional Clinical restorative Phase 20 7/7/ 1/8/21 Faculty of
Nano Hydroxyapatite not Failure glass ionomer | Drug: performance Service 1 19 dentistry, Cairo,
Reinforced Glass recruiting Nano hydroxyapatite (USHPS) Egypt
Ionomer in Treatment of reinforced glass
Root Caries in Geriatric ionomer
Patients [374]
NCT04298151 Clinical Performance of Active, Geriatric | Performance Drug: Zirconomer Clinical performance Phase 28 9/1/ 11/15/ Doaa Abdou,
Zirconia Reinforced GI not Improved | Drug: Ketac 2 21 21 Giza, Egypt
Versus Conventional recruiting Molar Aplicap
Viscous GI in Geriatric
Patients [375]
(continued on next page)
RESEARCH
213
RESEARCH: Review
RESEARCH: Review
214
RESEARCH
TABLE 2 (CONTINUED)
Date Update
Posted
NCT05221749 The Antibacterial Effect Not yet Primary Teeth | Drug: Nanosilver Antibacterial effect in Phase 50 2/3/ 2/3/22 Faculty of
of Nanosilver Fluoride recruiting Microbial Colonization | Fluoride (NSF) | Drug: active dental caries 3 22 Dentistry,
on Primary Teeth [376] Caries | Dental Caries in Silver diamine fluoride lesions | The relation Alexandria
Children between the Univeristy,
antibacterial activity and Alexandria,
the caries activity in Egypt
dental caries lesions |
Antibacterial effect in
unstimulated saliva
samples
Completed Clinical Trials
Date Update
Posted
NCT02033447 Magnetic Nanoparticle Complete Prostate Cancer Other: Magnetic Number of Participants Early 12 12/1/ 5/10/17 University
Thermoablation- Nanoparticle Injection with Adverse Events as Phase 13 College London
Retention and a Measure of Safety and 1 Hospital,
Maintenance in the Tolerability | The London, United
Prostate: A Phase 0 anatomical distribution Kingdom
Study in Men [372] of magnetic
nanoparticles
NCT04793074 Transforming Complete Chronic Venous Combination Product: Time to complete Phase 60 7/1/ 3/11/21 Helwan
Nanoparticle Dressing Hypertension With Transforming healing (weeks) 4 19 University,
For Management of Ulcer nanoparticle dressing | Helwan, Egypt
Chronic Venous Ulcers Combination Product:
[377] Conventional
compression dressing
NCT00337714 Comparison of Central Complete Central Venous Procedure: CVC The primary end-point Phase 472 7/1/ 5/16/11 UCSC, Policlinico
Venous Catheters With Catheter Related impregnated with silver is the difference in raw 4 06 Universitario A.
Materials Today
Silver Nanoparticles Infections nanoparticles (AgTiveÒ) percentage occurrence Gemelli, ICU,
Versus Conventional | Procedure: CVC of central venous Rome, Italy
Catheters [378] cannulation catheter related
infections (CVCRI) (on a
patient basis) between
groups A and B. | The
d
secondary end-point are
Volume 62
the infection-free time
and the probability of
CVCRI as a function of
multiple predictors.
d
NCT02668536 A Sunscreen Based on Complete Melanoma|UV Ray Skin Drug: Standard Skin Reaction Phase 13 7/17/ 3/13/18 Yale University,
Bioadhesive Damage Sunscreen | Device: BNP 1 17 New Haven,
Nanoparticles Connecticut,
United States
Materials Today
TABLE 2 (CONTINUED)
Date Update
Posted
NCT03692286 Assessment of Complete Postoperative Pain Combination Product: Change in post- Phase 30 6/1/ 10/19/ Cairo University,
d
Volume 62
Postoperative Pain After Silver nanoparticle/ operative pain | 4 19 20 Cairo, Manial,
Using Various Intracanal Calcium hydroxide | Intracanal Bacterial Egypt
Medication in Patients Drug: Silver count reduction |
With Necrotic Pulp Nanoparticles in gel Number of analgesic
d
form | Drug: Calcium tablets taken by the
Hydroxide Intracanal patient after endodontic
medication treatment
NCT04481945 Evaluation of Complete Endodontic Disease Drug: bioceramic sealer Antibacterial efficacy Phase 30 6/1/ 1/27/22 Misr
Antimicrobial Efficacy Measuring antibacterial 4 21 International
and Adaptability of effect of sealers | university,
Bioceramic Sealer adaptability Faculty of Oral
Containing and Dental
Nanoparticles Medicine, Cairo,
Egypt
NCT03669224 Effect of Nano Care Complete Caries Class Ii Other: Nano Care Gold | Marginal adaptation | Phase 57 11/1/ 3/23/21 Aya Abd El-
Gold on Marginal Other: No intervention | Marginal staining | Post 1 19 Fattah
Integrity of Resin Other: Chlorhexidine [-]operative sensitivity Mohammed
Composite [379] Nemtallah,
Maadi, Cairo,
Egypt
NCT01950546 Nanosilver Fluoride to Complete Dental Caries Drug: nanosilver Initial biofilm collecting Phase 30 9/1/ 6/10/15 Escola Municipal
Prevent Dental Biofilms fluoride before applying the 1 14 Anita Trigueiro
Growth [380] product and after do Valle,João
nanosilver fluoride Pessoa, Paraíba,
application. | Evaluation Brasil
of effectiveness of
nanosilver fluoride on
bacterial growth in the
dental biofilm
NCT04365270 Antibacterial Effect and Complete Reversible Pulpitis | Drug: Glass Ionomer | Antibacterial | Clinical Phase 65 1/15/ 1/12/21 Faculty of
Clinical Performance of Pulpitis | Caries, Dental | Drug: Chitosan Low performance 3 19 Dentistry, Ain
Chitosan Modified Glass Caries Class I | Caries; Molecular Weight (20– Shams
Ionomer [363] Dentin | Caries 200 Mpa.S) | Drug: University, Cairo,
Chlorhexidine Diacetate Egypt
| Drug: Titanium Dioxide
NCT01405794 In-Vivo Assessment of Complete Healthy Drug: 32 ppm Silver Changes in standard Phase 12 7/1/ 7/4/16 University of
Silver Biomaterial Nano- Particle | Drug: Placebo blood labs 1| 11 Utah, Salt Lake
Toxicity 32 Ppm [371] Phase City, Utah,
2 United States
NCT02755870 A Phase I SAD and MAD Complete Healthy Volunteers - Other: CNM-Au8 | Other: Treatment emergent Phase 86 4/1/ 6/3/19 Centre for
Clinical Trial of CNM- Male and Female Placebo adverse and serious 1 15 Human Drug
Au8 in Healthy Male and adverse events | Tmax | Research
Female Volunteers CL/F | t1/2 | Cmax | (CHDR), Leiden,
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216
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TABLE 2 (CONTINUED)
Date Update
Posted
Changes in cytokine Netherlands
levels
NCT03186261 Antibacterial Effect of Complete Dental Caries Drug: Nano silver Bacterial Count of Phase 44 4/1/ 9/16/21 Faculty of
Nano Silver Fluoride vs fluoride solution | Drug: Streptococus Mutans 3 18 Dentistry, Cairo
Chlorhexidine on Cavity Cleanser University., Cairo,
Occlusal Carious Molars Egypt
Treated With Partial
Caries Removal
Technique [381]
NCT01243320 In Vivo Assessment of Complete Healthy Drug: 10 ppm Oral Silver Changes in standard Phase 36 12/1/ 8/25/15 University of
Silver Biomaterial Nano- Particle | Drug: 32 ppm blood labs 1| 10 Utah Hospital
Toxicity [370] Oral Silver Particle Phase and Clinics, Salt
2 Lake City, Utah,
United States
NCT04098406 Therapeutic Complete Amyotrophic Lateral Drug: CNM-Au8 | Drug: Electromyography Phase 45 12/ 3/10/22 University of
Nanocatalysis to Slow Sclerosis Placebo measures of disease 2 19/19 Sydney Brain
Disease Progression of progression. | Mean and Mind
Amyotrophic Lateral change in the average Centre, Sydney,
Sclerosis (ALS) difference between New South
active treatment and Wales, Australia |
placebo from Baseline Westmead
for respiratory function Hospital, Sydney,
as measured by forced New South
vital capacity (FVC). | Wales, Australia
Mean absolute change
of the average
difference between
active treatment and
placebo from Baseline
through Week 36 for the
Materials Today
MUNIX score (4).
NCT03815916 31P-MRS Imaging to Complete Parkinson's Disease Drug: Gold Nanocrystals Change in 31P-MRS Phase 13 12/ 11/22/ UT
Assess the Effects of Redox Ratio (NAD+/ 2 19/19 21 Southwestern,
CNM-Au8 on Impaired NADH) Dallas, Texas,
Neuronal Redox State in United States
Parkinson's Disease
d
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NCT04147091 Nano-hydroxyapatite Complete Caries, Dental Other: ApaCare & Repair Remineralizing effect | Phase 92 2/1/ 10/31/
and Ozone - Effect on Remineralizing effect - 2| 12 19
Approximal Initial Caries follow-up Phase
3
d
NCT02895321 Nano-hydroxyapatite Complete Dentin Sensitivity Other: Cavex Bite&White Evaluation of change of Phase 35 3/1/ 10/26/ Complex
With Potassium Nitrate ExSense | Other: baseline VAS score at 4 16 16 Operative Unit
in the Therapy of the Colgate, Protection 4 weeks, and 8 Weeks of Dentistry,
Dental Sensitivity Caries | Other: Placebo after the treatment Sassari, Italy
gel
Materials Today
TABLE 2 (CONTINUED)
Date Update
Posted
NCT01243320 In Vivo Assessment of Complete Healthy Drug: 10 ppm Oral Silver Changes in standard Phase 36 12/1/ 8/25/15 University of
d
Volume 62
Silver Biomaterial Nano- Particle | Drug: 32 ppm blood labs 1| 10 Utah Hospital
Toxicity [370] Oral Silver Particle Phase and Clinics, Salt
2 Lake City, Utah,
United States
d
NCT03980847 Evaluation, the Complete Bone Resorption Drug: Alendronate New bone formation Phase 20 2/23/ 6/11/19 Amirhossein
Histomorphometric 20 mg | Procedure: (bone area as percent) 2 18 Farahmand,
Study of Nanocrystalline Nanocrystal Tehran, Iran,
Hydroxyapatite (Nano hydroxyapatite Islamic Republic
Bone) Wif Alendronate of
in the Preservation of
the Tooth Socket
NCT04213716 Comparison of the Complete Retreatment | Root Combination Product: Postoperative pain Phase 120 6/15/ 1/2/20 Endodontic
Efficacy of Calcium Canal Retreatment | silver nano particulate using a pain-measuring 2 15 Department,
Hydroxide With Silver Nonsurgical solution mixed with scale Faculty of
Nanoparticle and Retreatment | calcium hydroxide Dentistry, Cairo
Conventional Calcium Endodontic Failure | powder | Combination University, Cairo,
Hydroxide Intra Canal Symptomatic Product: conventional Egypt
Medications on Post- Endodontic Failure | calcium hydroxide
Operative Pain in Nanosilver | Intracanal
Symptomatic Root Medicament | Intracanal
Canal Treatment Failure Dressing | AgNPs |
Cases. [382] Calcium Hydroxide | Ca
(OH)2 | Discomfort | Pain
| Flare up |
Postoperative | Ache |
Post-operative | Post
Obturation
NCT02936830 Effectiveness of Complete Dentin Hypersensitivity Drug: 5% Sodium Sensitivity measured by Phase 63 10/1/ 3/11/20 Riyadh colleges
Nanohydroxyapetite Fluoride Varnish | Drug: a visual analog scale 4 16 of dentistry and
Paste on Reducing 15% pharmacy olaya
Dentin Hypersensitivity Nanohydroxyapetite campus, Riyadh,
paste | Drug: Glycerol ArRiyadh, Saudi
Arabia
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TABLE 2 (CONTINUED)
Date Update
Posted
NCT02918617 Clinical Efficacy in Complete Dentin Sensitivity Drug: Control Percentage Change Phase 203 5/1/ 11/16/ School of
Relieving Dentin toothpaste containing From Baseline in VAS 2 15 18 Dentistry,
Hypersensitivity of Novamin technology | (Visual Analog Scale) University of
Nanohydroxyapatite- Drug: Control With Air Stimulation | Texas Health
Containing Toothpastes toothpaste containing Percentage Change Science Center,
and Cream 1500 ppm fluoride as From Baseline in VAS San Antonio,
MFP | Drug: Test (Visual Analog Scale) Texas, United
toothpaste with nano- With Cold Stimulation | States
HAP (high Percentage Change
concentration) | Drug: From Baseline in DPS
Test toothpaste with (Dental Pain Scale) With
nano-HAP (low Air Stimulation |
concentration) | Drug: Percentage Change
Test toothpaste with From Baseline in DPS
nano-HAP and (Dental Pain Scale) With
(Potassium Nitrate) Cold Stimulation
KNO3 | Drug: Control
toothpaste without
nano-HAP | Drug: Test
toothpaste with nano-
HAP (medium
concentration) | Drug:
Test cream with nano-
HAP (higher
concentration) | Drug:
Control cream without
nano-HAP
NCT02108535 Comparative Analysis of Complete Second-degree Burn Drug: Nanocrystalline Complete Phase 100 11/1/ 5/18/21 Clinic of the Burn
Cost-effectiveness of silver | Drug: Silver epithelialization of the 4 13 Treatment of
Silver Dressing in Burns Sulfadiazine wound | Number of Sorocaba's
Materials Today
dressing changes | Hospital
Direct medical and non- Complex,
medical costs of Sorocaba, Sao
treatment | Level of pain Paulo, Brazil
| Sugery | Infection |
Adverse reactions
d
Volume 62
d
comparable alternatives, we predict that STNMs will contribute shifting paradigms in human trials (Table 2). Recent and ongoing
notably to the treatment of diseases of protein aggregation and clinical trials involving STNMs rely heavily on the antimicrobial
fibrillation. properties of metallic NPs, though several other features of
STNMs are now being clinically investigated. Several clinical
Enzymatic activity studies have investigated the effect of AgNPs on drug resistant
Nanomaterials catalyze bioreactions by stabilizing the transition bacteria [354], fungal infections [355,356], nosocomial infec-
state of adsorbed reactants. These nanocatalysts can be used to tions [357], and hand flora [358]. Additionally, ZnO NPs have
augment existing chemical pathways or overcome enzyme defi- been incorporated into socks to counteract foot odor [359] and
ciencies. Whereas prior discussion emphasized interactions pitted keratolysis [360,361] while polymer NPs have been uti-
lized to irrigate root canals, eliminate oral bacteria, and treat den-
RESEARCH: Review
between STNMs and macromolecules, here STNMs interact with
small molecules in biological contexts. Catalase and superoxide tal caries [362–364]. In terms of tissue regeneration, AgNPs are
dismutase degrade toxic ROS within cells [345]. Metallic nano- currently under investigation to prevent enamel demineraliza-
materials exhibit activity similar to these enzymes and thus can tion and promote remineralization in Phase 2, 3 and 4 trials
mimic their ROS-reduction capabilities (Fig. 11a) [345,346]. [365–367]. Immunogenic STNMs are being investigated in a
Hao et al. described the synthesis of CuxO NP clusters exhibiting Phase 1 trial utilizing a ferritin NP adjuvant in an Epstein-Barr
intrinsic peroxidase, superoxide dismutase, catalase, and glu- virus vaccine [368], and gold nanocrystals are being investigated
tathione peroxidase activity that prevented ROS-associated neu- for value in modulating the impaired neuronal redox environ-
rotoxicity in vitro and rescued memory loss in mice with ment in multiple sclerosis [369]. Finally, NP toxicity, safety,
Parkinson’s disease (Fig. 11c) [346]. Arginine-Pt NPs can mimic and tolerability has been studied in AgNPs [370,371] and in
multiple enzymes including uricase, catalase, and superoxide dis- IONPs [372]. Though we know STNMs offer potential for broad
mutase [347]. MnO2 NPs rescue cells from ROS-induced damage therapeutic application, few have been translated into human
without altering endogenous anti-oxidation mechanisms, sug- studies, a discrepancy which highlights the novelty of the self-
gesting that MnO2 NPs suppress oxidative stress parallel to cellu- therapeutic paradigm. Consequently, we expect that clinical tri-
lar processes [348]. Magnetite IONPs exhibit catalase activity as als involving STNMs will increase over the coming decade.
well, which can counteract the damage from ROS induced by
magnetite IONPs in cancer cells. Interestingly, hematite IONPs
do not exert catalase activity, and thus are more effective at
Concluding remarks and future perspective
inducing cell death in pheochromocytoma cells [349]. Both The self-therapeutic paradigm both juxtaposes and complements
AuNPs and germanium nanoparticles (GeNPs) exhibit peroxidase broadly accepted therapeutic strategies throughout the biomedi-
activity as evidenced by enhanced dopamine oxidation in the cal field. We have seen intrinsic nanotherapy treat cancers, viral
presence of AuNPs and H2O2 [350] and the oxidation of infections, and autoimmune conditions through an array of
3,3,5,5-tetramethylbenzidine (TMB) in the presence of GeNPs mechanisms. STNMs can serve as the foundation for vaccines,
and H2O2 [351]. Carbon-based nanomaterials exert enzymatic promote tissue regeneration, and supplant cellular enzyme defi-
activity as well, with polyhydroxylated fullerenes (fullerenols) ciencies. Whereas some drug discovery methodologies rely on
catalyzing thrombolysis [51] and copper ion-doped carbon dots uncovering key regulators to disease processes before identifying
exhibiting peroxidase activity [352]. Finally, AuNPs can improve molecular modulators, STNMs can isolate and regulate disease-
the catalytic activity of proteins. Chymotrypsin bound to amino associated proteins simultaneously [295]. Moreover, STNMs can
acid-functionalized AuNPs display a three-fold increase in sub- augment conventional therapies by mitigating cellular degrada-
strate specificity and improved kcat in comparison to free chy- tion or enhancing chemotherapy and radiotherapy efficacy,
motrypsin, with the amino acid layer augmenting the transport and some STNMs can even wield therapeutic synergy by exerting
of substrates and products [353]. their own medicinal effect while amplifying the effects of con-
Both metallic and carbon-based STNMs exert biomimetic ventional or alternative therapies [155,164]. Finally, simultane-
enzymatic activity. The effects of these catalytic actions vary ous STNM modulation of several cellular pathways offers
from protection against ROS-induced cellular damage to clot unique functionalities. For example, laponite nanoclays facilitate
breakdown and interference with anti-cancer properties. NPs osteogenic differentiation and cell adhesion through ALP,
are currently utilized in photocatalysis, and the aforementioned Runx2, OCN, b-catenin, and a/b integrin expression [295]; and
self-therapeutic catalytic activities could be potentially aug- Au@Pt “nanoseeds” alter CDK2, CDK4, cyclin D1, cyclin E, and
mented by light application via surface plasmon resonance. p21WAF1 expression [154]. These coincident effects offer advan-
Few other therapies offer opportunity to augment or replace defi- tages over single-mechanism therapeutics and could suggest that
cient enzymes, and we accordingly expect that intrinsic biocatal- only limited reduction in efficacy may occur with extended use.
ysis will continue to evolve to include tunable enzyme kinetics, Despite their recent development, STNMs have already
allowing physicians a degree of interventional control that has revealed complexities within the tumor microenvironment.
been heretofore absent. Crosstalk between cancerous and somatic cells contributes to
the natural history of cancer, and inhibition of this crosstalk
reduces expression of cancer-associated phenotypes [149]. We
Clinical trials have utilized self-therapeutic AuNPs to identify and target
Having summarized pre-clinical investigations of STNMs across biomolecular signaling pathways that contribute to poor disease
the biomedical field, we now observe intrinsic nanotherapeutics outcomes. CAFs are transformed to a quiescent phenotype by
219
AuNPs through the simultaneous amplification of FASN, essential for expansion of self-therapeutic strategies to combina-
SREBP1a, SREBP2, PLIN1, PLIN4, FABP3, and FABP4 [149]; tion therapies.
AuNPs also inhibit CAF activation through TGF-b1, PDGF, uPA, Self-therapeutic nanotherapies are still in their infancy. Selec-
and TSP1 signaling [136]. Consequently, AuNPs bifunctionally tive delivery of STNMs remains challenging. The magnitude of
provide insight into localized cellular crosstalk and highlight tar- the EPR effect and NEL vary, making it difficult to passively rely
gets for molecular mediation. Further STNM modulation of on these mechanisms for consistent results [94]. Active targeting
cancer-adjacent crosstalk can be seen in mitigation of tumor- can be hindered by protein corona interference with targeting
associated angiogenesis through VEGF, EGFR, TGF-b, and actin ligands, and increased design intricacies amplify costs and com-
filament assembly inhibition [142–144,158] and in preventing plicate manufacturing processes [94]. Moreover, the long-term
RANKL-precipitated osteoclast differentiation in late-stage breast effects of STNMs have not been studied in vivo. The limited num-
RESEARCH: Review
cancer [153]. This strategy of altering cellular crosstalk could ber of clinical trials utilizing STNMs suggests that potential side-
prove effective for reducing tumor growth while reducing the effects are still being investigated in preclinical studies. Whereas
risk of selecting for therapy-resistant cancer cells. protein and nucleic acid therapeutics can be degraded by cellular
STNMs can be utilized to elucidate molecular targets and machinery and small molecule drugs are commonly metabolized
mechanisms of disease beyond the tumor microenvironment by the cytochrome P450 superfamily, STNMs can be challenging
through formation of a protein corona. Each STNM exposed to to clear from the body. Though inherently biocompatible,
a biological environment develops a coat of adsorbed proteins, accummulation of STNMs could produce toxic effects or stimu-
the composition of which is codependent on the host proteome late organ damage [90]. A significant portion of injected NPs
and the intrinsic properties of the NP [101]. In this way, STNMs accummulate in the liver, which reduces the fraction of STNM
function as tunable nanoconcentrators, allowing for early detec- in circulation and may promote hepatocellular toxicity [90]. Reg-
tion of disease states and offering hope for improved clinical out- ular dosing of STNMs could result in marked liver sequestration if
comes [101,315]. Analysis of NP coronas can provide improved hepatobiliary excretion is insufficient to match the rate of system
information about previously diagnosed conditions, allowing input [125]. There is also limited information on how STNMs
physicians to tailor treatments to individuals with improved interact with polypharmacy. Further studies must determine
accuracy. Similarly, the STNM protein corona can be utilized as the extent to which intrinsic nanotherapeutics can be combined
a diagnostic differentiator between dissimilar diseases with paral- with other drugs and devices to treat chronic or complex dis-
lel clinical presentations to prevent improper use of antibiotics in eases, as the same mechanisms by which they promote coinci-
non-infectious diseases [292]. Moreover, numerous human ill- dent and synergistic therapy may detrimentally impact
nesses have no known inciting cause, leaving clinicians without concurrent medications. Finally, while we are gaining under-
information central to the disease process. The insight provided standing into which cellular pathways STNMs modulate, the pre-
by intrinsic nanotherapy-facilitated proteome analysis could be cise molecular mechanisms by which they achieve this effect are
essential to solving the riddles posed by idiopathic disorders. poorly understood. Studies investigating how primary, sec-
The mechanisms governing protein corona formation are also ondary, and tertiary protein structure, exposed residues, and
central to nanomaterials self-therapeutic properties. Proteins can charge influence NP-protein interactions will help in deciphering
undergo a conformational change when adsorbing to an STNM. precise molecular interactions that lead to self-therapeutic
These adsorbed proteins can subsequently be incorporated into properties.
the “hard” corona and sequestered from the microenvironment, These challenges are not without recourse. We will be better
or they can desorb from the STNM, potentially retaining the able to predict how STNMs affect the pharmacokinetics of co-
altered conformation induced by adsorption [100]. Altered pro- administered medications with continued study into molecular
tein conformation can alter protein function and impact numer- mechanisms. Additionally, clearance challenges could be
ous cellular pathways [100]. Unfortunately, we are still relatively addressed by creating degradable materials that promote renal
ignorant about the details of these interactions and have been clearance and prevent liver sequestration [89], and additional
generally relegated to identifying upregulated or downregulated study into the retention of STNMs within stellate macrophages
intermediates rather than elucidating how those intermediates will elucidate the design parameters critical for sufficient removal
and modulated mechanistically. from the body. Further molecular modeling and computational
Currently, STNMs comprise a limited portion of clinically simulations of the interactions between distinct nanomaterials
approved nanomedicines, but they are well-suited for new thera- and biomolecules at the nano-bio interface could assist our
peutic applications. Combining self-therapeutic nanotherapy understanding of how STNMs interact mechanistically in a com-
with small-molecule pharmacotherapy, biologic therapy, or pho- plex biological environment. Finally, there is a plethora of data
totherapy can expand the impact of STNMs while supplement- currently being generated on nanomaterials for delivery pur-
ing other therapeutic strategies. Surface modifications that poses, diagnostic imaging, photothermal/photodynamic ther-
enable active targeting can promote efficiency and reduce off- apy, and theranostics. While these reports do not emphasize
target effects to a greater degree than the passive targeting com- the inherent therapeutic properties of the materials involved,
monly exhibited by STNMs [93]. Moreover, combinations of the insights into interactions between biomolecules and nano-
organic and inorganic materials can form hybrid nanosystems materials could assist in smart design of nanomaterials with
capable of enhanced therapeutic benefits over similar non- enhanced activity and minimized side effects.
hybridized systems [5]. Protocols for STNM augmentation are As observed, intrinsic nanoparticle therapy offers opportuni-
ties for disease diagnosis and treatment distinct from traditional
220
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Materials Today d Volume 62 d January/February 2023 RESEARCH

Keywords: Self-therapeutic nanomaterials; Intrinsic nanotherapy; Biomolecule-nanoparticle interaction; Bioactive

190 1369-7021/Ó 2022 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.mattod.2022.11.007

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