Polydopamine-Based Nanostructures A New Generation of Versatile, Multi-Tasking, and Smart Theranostic Tools

Nano Today 55 (2024) 102151
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Nano Today
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Polydopamine-based nanostructures: A new generation of versatile,

multi-tasking, and smart theranostic tools
Matteo Battaglini a, *, Melis Emanet a, Alessio Carmignani a, Gianni Ciofani a, *
a
Istituto Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, Pontedera 56025, Italy
A R T I C L E I N F O A B S T R A C T
Keywords: Smart nanomaterials, thanks to their stimuli-responsive properties, represent a promising class of nanostructures
Polydopamine nanostructures for biomedical applications. Their ability to undergo structural or functional changes in response to specific
Theranostics external cues has been exploited for the manipulation of cellular activities as a potential treatment for various
Smart nanomaterials
health disorders. Despite their rather interesting properties and applications, most smart nanostructures are
Antioxidant nanoparticles
Photothermal therapy
composed of inorganic materials, thus limiting their translatability in clinical applications due to potential
Photoacoustic imaging toxicity and long-term accumulation concerns. Polydopamine nanostructures can overcome the limitations posed
by inorganic smart nanomaterials thanks to their high biocompatibility, biodegradability, antioxidant effects,
pH-responsiveness, tunability, surface reactivity, photothermal conversion properties, and the ability to act as
photoacoustic contrast agents. In this review, we will present a general analysis of the properties of polydop
amine nanostructures and of their biomedical applications. Our aim is to provide the reader with the state of the
art concerning the use of polydopamine nanostructures as smart organic nanoplatforms in nanomedicine, also
providing an analysis of the current limitations connected to the translation in clinical applications and the
potential solutions to these challenges.
Introduction: The potential of polydopamine nanoparticles as an nanoparticles [9]. The rationale behind the use of smart nanomaterials is
organic theranostic smart nanoplatform to exploit their ability to respond to external stimulation to achieve a
desired biological effect that can range from a controlled tuning of
Theranostic refers to the possibility of combining diagnosis and specific cellular activity, such as neuronal activation [6] or muscle cell
therapy into a single platform [1,2]. Since the introduction of the term in contraction [9], to the inhibition of cancer cell proliferation and in
1998 by John Funkhouser, theranostic nanomaterials have gained great duction of apoptosis [5]. The desired biological effects can also be
attention as a potentially revolutionary tool in medicine, promising to achieved by combining external stimulation with specific molecular
bypass the limitation of conventional diagnostic and therapeutic ap cargos, like in the case of drug-loaded nanoparticles for the magneto
proaches and being able to provide a faster, cheaper, safer, and more thermal or photothermal therapy (PTT) of various forms of cancer [5,
effective intervention on health disorders [1,2]. 10].
Smart nanomaterials represent one of the most promising classes of The diagnostic components of smart theranostic nanoplatforms are
nanomaterials among the various types of theranostic nanoplatforms [3, linked to the possibility of exploiting inorganic nanostructures as
4]; they are able to change their structural or functional properties in contrast agents in various detection techniques: for example, magnetic
response to specific external stimuli such as temperature, pH, light, nanostructures in magnetic resonant imaging (MRI) [11] or noble metal
magnetic fields, and electrical or mechanical stimulation [3,4]. Some of and barium titanate nanoparticles through computed tomography (CT)
the most representative examples of smart nanomaterials include [12,13]. However, the diagnostic potential of smart nanomaterials can
iron-based magnetic nanoparticles such as superparamagnetic be improved with the labeling with specific compounds like fluorescent
iron-oxide nanoparticles (SPIONs) [5], piezoelectric nanostructures dyes, MRI contrast agents (for example Gd-based compounds), or ra
such as barium titanate nanoparticles [6,7] or boron nitride nanotubes dioisotopes for single photon emission computed tomography (SPECT)
[8], and light-responsive noble metal nanomaterials like gold or positron emission tomography (PET) [14].
* Corresponding authors.
E-mail addresses: [email protected] (M. Battaglini), [email protected] (G. Ciofani).
https://doi.org/10.1016/j.nantod.2024.102151
Received 12 October 2023; Received in revised form 4 December 2023; Accepted 3 January 2024
Available online 9 January 2024
1748-0132/© 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
M. Battaglini et al. Nano Today 55 (2024) 102151
Despite their interesting properties, the adverse health effects related 5) PDNPs can convert light irradiation at specific wavelengths (in
to the use of inorganic nanomaterials have raised concerns among the particular in the near infrared -NIR-) into heat, enabling their
scientific community. The potential toxicity of inorganic nanomaterials exploitation as platforms for PTT [27];
is an extremely complicated problem that is highly dependent on several 6) PDNPs have antioxidant properties, being able to scavenge a vast
factors, including the size and physical/chemical properties of the variety of reactive oxygen species (ROS) from the surrounding
exploited nanostructures [15–17]. Moreover, the inability of most environment, because of the previously mentioned functional groups
inorganic nanomaterials to be biodegraded and excreted from tissues present on their surface [28,29];
has been linked to the onset of potential adverse health effects [15–17]. 7) PDNPs are inherently pH-responsive, and this property can be
Lastly, the fabrication of inorganic nanomaterials usually involves the exploited to achieve the targeted delivery of active molecules (e.g.,
use of organic solvents and other potentially toxic compounds able to drug release from PDNPs triggered by the acidic pH environment
induce adverse effects in cells and tissues if not properly removed after typical of the tumor niche) [30];
the nanostructure synthesis [18]. A possible solution to overcome the 8) Lastly, it has been observed that PDNPs can be used as label-free
limitations of inorganic nanomaterials would be the development of photoacoustic (PA) contrast agents, enabling the imaging of biolog
organic biodegradable smart nanostructures able to be synthesized ical structures [31].
without the need for toxic reagents. In this view, polydopamine nano
particles (PDNPs) represent an extremely promising candidate as a The interest in polydopamine-based nanomaterials is demonstrated
smart organic, biodegradable, and highly biocompatible nanomaterial by the ever-increasing number of scientific articles present in the liter
[19,20]. Described for the first time in 2007 by Lee et al., polydopamine ature discussing the synthesis and exploitation of PDNPs. Moreover,
is a material derived from the self-polymerization of dopamine, inspired several reviews already discussed the properties and potential applica
by the adhesive components excreted by the mussel Mytilus edulis and tions of PDNPs [19,20,26], however focusing either on specific appli
commonly used as a coating material due to its adhesive properties and cations of PDNPs or on their potential use in combination with inorganic
relatively high biocompatibility [21]. In the following years, the syn nanomaterials (for example SPIONs or gold nanostructures) [19,20,26].
thesis of nanostructures composed of polydopamine, primarily PDNPs, In this review, we aim to provide a complete analysis of PDNP proper
catalyzed great attention because of their several interesting features ties, synthesis procedures, and biomedical applications focusing our
(Fig. 1): discussion on studies exploiting completely organic formulations of
PDNPs. Our goal is to demonstrate how polydopamine represents to date
1) PDNPs are completely organic and can be synthesized without using one of, if not the most, promising candidate for the development of
organic solvents or other potentially toxic compounds. Moreover, organic biocompatible and biodegradable smart nanoplatforms, able to
they have been shown to be highly biocompatible even at relatively overcome the limitations posed by inorganic smart nanomaterials. With
high doses [19,20]; this work, we hope to further trigger the scientific community towards
2) PDNPs are biodegradable and can be easily excreted from tissues new and clinically translatable applications of PDNPs, paving the way to
[22]; their realistic exploitations in human healthcare.
3) PDNP size, porosity, and shape can be tuned with relative ease by
changing specific parameters of their synthesis procedure, including Fabrication procedures and properties of polydopamine
temperature, pH, or monomer concentration [23–25]. nanostructures
4) due to the functional groups present on their surface (catechol,
imine, and o-quinone), PDNPs can be easily functionalized with a Synthesis of polydopamine nanostructures
vast variety of molecules [20,26];
There are currently three main ways to fabricate polydopamine-
based materials, namely solution oxidation [32],
Fig. 1. An overview of the “smart” properties of PDNPs.

Image prepared with www.Biorender.com.
2
electro-polymerization [33], and enzymatic oxidation [34]. The solution proposed polymerization model for polydopamine formation is based on
oxidation procedure is based on the polymerization of dopamine under the synthesis of melanin in living organisms, where dopamine undergoes
alkaline conditions (pH>7.5) [20,35]; electro-polymerization exploits a series of oxidative reactions generating 5,6-dihydroxyindole that, in
the generation of polydopamine from the direct deposition of dopamine turn, undergoes a series of covalent polymerization processes [36]. As
on electrodes [33], while the enzymatic oxidation procedure is based on depicted in Fig. 2, under alkaline conditions in solution, dopamine is
the preparation of polydopamine by using enzymes such as urease [34]. oxidized in dopaminequinone, which is then subjected to intramolecular
Among these synthesis procedures, the solution oxidation method rep cyclization and oxidation to form dopaminechrome; the latter eventu
resents the easiest to set up, fastest, and most versatile, thus resulting by ally undergoes an intramolecular rearrangement to form 5,6-dihydrox
far the most widely exploited approach [20,35]. yindole [36]. It was supposed the covalent oxidative polymerization of
Despite the relatively easy synthesis procedure involved in the 5,6-dihydroxyindole being the only process at the basis of polydop
preparation of PDNPs, the molecular mechanisms at the base of poly amine formation; however, it has been later on demonstrated that the
dopamine polymerization are still largely unknown [36]. The first physical self-assembly of non-covalently bonded molecules such as
Fig. 2. The two main proposed mechanisms for the formation of polydopamine. A) covalent bond-forming oxidative polymerization; B) physical self-assembly of
dopamine and 5,6-dihydroxyindole (DHI).
Image reproduced with permission from Ref. [36].
3
(dopamine)2/5,6-dihydroxyindole, due to intermolecular interactions the synthesis reaction. The added Pluronic is able to self-assemble into
like π − π stacking or hydrogen bonding, could also participate in the micelles acting as templates for the polymerization of mesoporous
formation of polydopamine [36]. Currently it is accepted that both PDNPs of various shapes while being easily removable at the end of the
processes are involved in the final formation of polydopamine, yet the synthesis through centrifugations and washing procedures [47]. Hollow
precise molecular mechanisms and the final chemical composition of PDNPs can instead be obtained through various methods such as
polydopamine-based nanostructures would need further clarifications mini-emulsion templating with organic solvents or by exploiting soft
[36]. templates such as Pluronic F127 or 1,3,5-trimethylbenzene (TMB) [48,
Regarding the solution oxidation procedure for PDNP preparation, 49]. Polydopamine-based nanostructures of different morphologies can
several parameters of the synthesis process can affect the reaction ki also be obtained through oxidation-based synthesis. For example, Sun
netics and the properties of the obtained nanostructure: pH, solution et al. described a detailed protocol to fabricate polydopamine nanobowls
buffer, temperature, dopamine concentration, and presence of external of various shapes and diameters obtained through the collapse of hollow
oxidants [19]. Our group recently demonstrated that by varying the pH polydopamine nanostructures, by exploiting an oxidation-base synthesis
of the synthesis solution it is possible to control the size of the obtained in presence of tris(hydroxymethyl)-aminomethane. Hollow bowl-shaped
PDNPs, with more alkaline pH yielding nanostructures with smaller nanostructures of different diameter and wall-thickness were also ob
diameters [24]. Moreover, changing the pH of the synthesis solution has tained by simply changing the reaction time [50]. As another relevant
been shown to affect also the kinetics and the yield of the fabrication example, Yu et al. proposed the synthesis of polydopamine nanofibers by
process, with a more alkaline pH leading to a faster reaction and conducting an oxidation-based fabrication of polydopamine in presence
increasing the yield in terms of obtained PDNPs [37]. The solvent used of folic acid [51].
in the synthesis procedure is commonly just water added with dopamine
and a basis; however, it has been shown that buffer solutions such as Biocompatibility, degradation, surface reactivity, and functionalization of
TRIS-buffer, phosphate, and bi-carbonate can also be exploited, with a polydopamine nanostructures
direct effect on the size of the obtained nanostructures [38].
Temperature plays also an important role in the synthesis of PDNPs, PDNPs, being derived from polydopamine and mimicking the
with temperatures higher than 40 ◦ C increasing the nanoparticle yield structure of melanin, are highly biocompatible, and most studies present
but reducing their diameter [39,40]. Dopamine concentration is also an in the literature confirm the absence of toxic effects after exposure to
important parameter affecting the kinetic and yield of polydopamine PDNPs even at relatively high concentrations both in vitro and in vivo
formation; however, most studies in the literature currently describe the [52]. Indeed, polydopamine is commonly exploited to perform a coating
effects of dopamine concentration on the formation of films or coating of and thus to improve the biocompatibility and reduce the toxicity of
other kinds of nanostructures rather than in the fabrication of PDNPs other compounds like gold nanostructures [53] or zinc oxide nano
[41]. particles [54]. The biodegradation of PDNPs is still a controversial point:
The most common oxidant used for the synthesis of PDNPs is oxygen it has been observed that melanin films (analogous to polydopamine)
dissolved in the reaction solution; however, other oxidant compounds implanted in rats were completely degraded after 8 weeks from the
have been tested in the polydopamine fabrication process such as Cu2+, implant [55]. Moreover, several external stimuli, including exposure to
KMnO4, Fe3, (NH4)2S2O8, NaIO4, and CuSO4 [19,42,43]. Despite their ROS or alkaline and acidic pH, have been shown to degrade PDNPs [22,
exploitability, the use of these alternative oxidants is still limited to the 24,56]. For example, our group recently demonstrated that the exposure
deposition and production of polydopamine films, with oxygen still of PDNPs to acidic pH (4.5) and H2O2 was able to cause PDNP degra
being the far most used oxidative agent in PDNP preparation [19,42,43]. dation [24]. Furthermore, the degradation kinetic of PDNPs is once
The diameter of PDNPs is a key factor in determining their proper again highly dependent on the properties of these nanostructures, i.e.,
ties: for example, it has been observed that smaller PDNPs have a higher their size, with smaller nanoparticles being able to degrade faster than
antioxidant ability compared to larger nanostructures, a phenomeno due larger ones when exposed to high levels of ROS [24]. Our analysis was
to the increased surface-to-volume ration at smaller sizes [24]. performed by exposing PDNPs to a solution of 5% hydrogen peroxide
Conversely, PDNPs with larger diameters have been observed to perform (H2O2), demonstrating a significant reduction of the average nano
better as photothermal conversion agents, being able to generate higher structure size and light absorption properties after 72 h of exposure
increments in temperature compared to smaller nanostructures irradi [24]. Other external stimuli have also been shown to be able to induce
ated at the same experimental conditions [24]. This difference is PDNP degradation: for example, it has been demonstrated how poly
essentially due to a higher light absorbance extent by larger nano dopamine can be degraded through exposure to glutathione (GSH). Dai
particles [24]. The size of PDNPs has been shown to also affect their et al. showed how the exposure of PDNPs to 5 mM of GSH for 24 h was
stability in aqueous solutions, with larger nanostructures being overall able to significantly reduce their average diameter [57]. Del Frari et al.
less stable and having the tendency to aggregate and precipitate [24]. demonstrated how polydopamine films could be degraded by exposure
Lastly, PDNP size can affect their interaction with biological structures; to sodium hypochlorite, and how this degradation process is highly
for example, it has been observed that smaller PDNPs are more easily influenced by the film thickness and fabrication process [58]. Even
internalized by cells compared to larger nanoparticles [24]. Moreover, physical stimulation, like the exposure to ultrasounds, has been shown
PDNP diameter also plays a pivotal role in cellular uptake mechanism, to induce PDNP exfoliation, and this process has been used to produce
with smaller PDNPs (180 nm) being internalized through micro ultrasmall PDNPs (with an average diameter below 10 nm) [29]. How
pinocytosis, while larger PDNPs (520 nm) being uptaken through ever, despite these preliminary results, very little is known about the
caveolae-mediated endocytosis [44]. molecular processes guiding PDNP degradation and the presence and
Other features of PDNPs, including shape or porosity, can be tuned composition of polydopamine degradation products. Moreover, an
by changing their synthesis parameters. For example, mesoporous and in-depth analysis of the degradation kinetics of PDNPs inside living or
hollow PDNPs, recently proposed as alternatives to solid PDNPs due to ganisms is still lacking.
superior cargo-loading efficiency, can be easily obtained through the In addition to high biocompatibility and biodegradability, one of the
classic solution oxidation synthesis procedure of polydopamine by most interesting properties of polydopamine is given by the high reac
simply adding removable templates and emulsifiers to the reaction tivity of its constituent monomer dopamine, which makes the surface
mixture [45,46]. Huang et al. proposed an interesting protocol to obtain functionalization of polydopamine-based nanomaterials relatively fast
mesoporous PDNPs of various shapes and porosity through Pluronic and easy. As described in 2007 by Lee et al., the catechol groups present
micelle-guided polymerization [47]. The principle behind this method on the surface of polydopamine can react under oxidizing conditions
consists of adding various concentrations of Pluronic F127 and P123 to with thiols and amines via Michael addition or Schiff base reactions [21,
4
59]. This phenomenon can be exploited to functionalize PDNPs with hydrogen bonding) [35,66]. The drug loading efficiency of PDNPs can
proteins and other thiol or amine-rich molecules, without the need for be easily tuned by changing the physical parameters of polydopamine
any other reagent. An overview of the chemical processes involved in the nanostructures such as shape, size, and porosity. For example, as we
functionalization of polydopamine with thiol or amine-rich molecules is previously mentioned, it has been shown that mesoporous and hollow
provided in Fig. 3. PDNPs are able to outperform solid polydopamine nanostructures in
terms of drug-loading efficiency [46].
Polydopamine nanostructures as drug carriers In a recent example, PDNPs were exploited for the oral administra
tion of gambogenic acid (GNA@PDNPs), a traditional Chinese medicine
Traditional chemotherapy, despite representing one of the major well known for its anti-tumor activity. To improve the cancer-targeting
systemic treatments of cancer, is severely limited by its low targeting efficiency, folic acid was conjugated on the surface of the polydopamine
efficiency; the off-target distribution of classical drugs reduces the suc nanostructures (GNA@PDNPs-FA) [67]. Moreover, since orally admin
cess rate of chemotherapy even potentially leading to systemic toxicity, istered pharmaceutical agents are absorbed by the gastrointestinal mu
due to the tendency of commonly used drugs to accumulate in the cosa after passing through the esophagus, the authors coated
reticuloendothelial system and in other excretory organs [60]. These GNA@PDNPs-FA NPs with sodium alginate (GNA@PDNPs-FA-SA) in
considerations are not restricted to chemotherapy, yet they are also order to protect the nanostructures from the harsh physiological con
valid for other treatments, such as those ones for neurodegenerative ditions of the gastric tract. The authors tested the cumulative drug
diseases [61]. To overcome these limitations, the exploitation of nano release of GNA@PDNPs-FA-SA in simulated gastric fluid and intestinal
carriers has become one of the main strategies to improve the stability, fluid demonstrating the ability of the nanoplatforms to steadily pass
bioavailability, and targeting efficiency of drugs [62]. through the gastrointestinal environment via oral administration,
Smart nanomaterials loaded or functionalized with drugs, due to thanks to the protective effect of the sodium alginate coating. Moreover,
their previously mentioned ability to respond to external stimulation, in vivo tests on breast cancer-bearing mice showed the higher
have been proposed as platforms for the targeted delivery and controlled anti-cancer efficiency of GNA@PDNPs-FA-SA compared to free gambo
release of bioactive molecules [63]. In this view, PDNPs represent an genic acid [67].
obvious promising drug delivery tool because of the already described In another example, PDNPs were exploited for the delivery of reti
peculiar chemical and physical properties [64]. As previously noic acid (RA) [68]. RA, a metabolic intermediate of vitamin A, is widely
mentioned, thiol and amine-rich molecules can be easily functionalized used in the treatment of melanoma and squamous cell carcinoma;
on the surface of PDNPs through Michael addition or Schiff’s base for however, its application is severely limited by serious side effects,
mation [65]. Moreover, several drugs with anthraquinone structures especially in the case of intravenous administration [69]. In order to
like doxorubicin, mitoxantrone, epirubicin, idarubicin, and valrubicin avoid such issues, its intradermal administration through skin-specific
can be loaded inside PDNPs or adsorbed on the surface of polydopamine delivery strategies has been proposed. In this context, PDNPs have
nanostructures through weak molecular interactions (π-π conjugation or been exploited as potential candidates for intradermal delivery of RA,
Fig. 3. Surface reactivity of polydopamine: the reactive functional groups present on the surface of polydopamine-based structures can react through Michael
addition or Schiff’s base reactions with thiol and amine-rich molecules.
Reproduced with permission from Ref. [59].
5
considering their tissue adhesiveness and skin affinity [68]. In a recent epigallocatechin-3-gallate and functionalized with folic acid for the
study, free RA and RA-loaded solid and mesoporous PDNPs were tested potential treatment of breast cancer. In their study, the release of
on rat skin models, comparing the obtained RA deposition among the doxorubicin and epigallocatechin-3-gallate has been shown to be trig
three administration protocols. The skin depositions of RA in stratum gered by NIR irradiation and exposure to the acidic pH of intracellular
corneum and underlying skin were found to be lowest in the case of the compartments, like endosomes and lysosomes. Moreover, the authors
treatment with free RA; conversely, significantly higher amounts of RA reported the higher anticancer efficiency of the proposed nano formu
were accumulated in the case of the administration exploiting lation with respect to the treatment with free drugs, improving the
RA-loaded PDNPs. The authors also tested the RA delivery efficiency of survivability of breast cancer-bearing mice [71].
mesoporous and solid RA-loaded PDNP formulations presenting two Another interesting example is provided by the study of Ren and
different diameters (500 and 300 nm), showing that the treatment with colleagues, where mesoporous PDNPs loaded with doxorubicin and
mesoporous nanostructures led to a higher RA skin accumulation coated with platelet membranes were developed as anti-cancer thera
compared to the administration through solid PDNPs. According to the peutic agents (Fig. 4) [72]. Doxorubicin-loaded PDNPs were able to
findings of this study, solid and mesoporous PDNPs significantly target breast cancer cells in tumor-bearing mice thanks to the platelet
improved the RA delivery into the stratum corneum and in deeper skin membrane coating, outperforming the treatment with free doxorubicin
layers, highlighting moreover as the porosity and size of PDNPs influ in terms of drug delivery efficiency and therapeutic outcome. Moreover,
ence the drug penetration across the skin [68]. once again the authors reported how the doxorubicin release from the
PDNPs also represent an ideal platform for the design of smart PDNP carriers was enhanced by the irradiation of the nanostructures
organic stimuli-responsive drug delivery systems. The release of drugs with NIR light and the exposure to acidic pH [72].
associated with PDNPs can in fact be triggered by the exposure of pol Besides delivery of chemotherapy drugs, relevant examples of poly
ydopamine nanostructures to external stimuli such as NIR irradiation or dopamine nanostructures for the treatment of other pathological con
acidic pH. For example, PDNPs were exploited to develop a stimuli- ditions can be found in the literature.
responsive anticancer carrier platform for the delivery of bortezomib Acter et al. proposed the development of photothermally responsive
(BTZ) [70]. In particular, PDNPs were functionalized with BTZ through emulsions, composed of an oil core loaded with aspirin and stabilized by
the catechol groups of polydopamine with a pH-sensitive bond, and polydopamine nanobowls. The obtained Pickering emulsions showed
subsequentially decorated with glucosyl ligands targeting GLUT1, a the ability to release the loaded drug upon exposure to acidic pH or NIR
protein over-expressed by tumor cells [70]. The BTZ release from the irradiation [73]. Sun et al. developed hollow nanoparticles loaded with
obtained polydopamine nanostructures was found to be 10–20% at pH the peptide RL‑QN15 for the treatment of skin wounds, demonstrating
7.4, while reaching nearly 45–65% at pH 5.0 in the same time period the ability of the obtained peptide-loaded nanostructures to outperform
(3 h). Moreover, a burst release of BTZ (90%) was observed after free RL-QN15 in terms of pro-healing potency on keranocytes, macro
exposing the BTZ-loaded PDNPs to NIR irradiation at pH 5.0, most phages, mice model of skin wounds and skin scald, rat models of oral
probably induced by the temperature increment caused by the photo ulcers, and swine models of full-thickness injured wounds [74]. Park
thermal mediated by PDNPs [70]. In another example, Fan et al. et al. developed hollow polydopamine nanoparticles functionalized with
developed PDNPs loaded with doxorubicin and N-diazeniumdiolates acting as nitric oxide (NO) generators as
Fig. 4. Schematization of the development and testing of platelet membranes-coated and doxorubicin-loaded mesoporous PDNPs as multi-functional smart drug
delivery systems for breast cancer treatment.
Reproduced with permission from Ref. [72].
6
antibacterial agents. The authors showed the ability of the obtained Commonly plasmon resonant noble metal nanostructures such as
NO-generating hollow polydopamine nanoparticles to be highly gold nanoparticles have been the most widely exploited class of nano
biocompatible while eliciting an antibacterial effect upon E. coli and materials for PTT in past decades [10,87]. When metal nanomaterials
P. aeruginosa [75]. Lastly, Han et al. proposed mesoporous polydop are photoexcited with electromagnetic radiation at a specific wave
amine nanoparticles loaded with prunetin and coated with hyaluronic length, for instance within the NIR range, their valence electrons un
acid as a potential treatment for UV-induced inflammation. The authors dergo coherent oscillations, named surface plasmon resonance, and
demonstrated the ability of the developed nanostructures to reach the consequently generate heat [88]. PDNPs, thanks to their previously
skin inflammation site on in vivo mice model, leading to an accumula mentioned photothermal conversion properties, represent a promising
tion of puretin and to consequent anti-inflammatory and antioxidant tool for the development of organic PTT nanoplatforms. This phenom
effects on skin cells [76]. enon has been associated to the light absorption of polydopamine in a
wide range of wavelengths, from ultraviolet to NIR light; however, the
Polydopamine nanostructures in photothermal therapy precise molecular mechanism behind this phenomenon still remains
poorly described [89]. Many studies have already demonstrated that
NIR light-based stimulation has emerged as a powerful and versatile PDNPs can achieve excellent results as NIR photothermal conversion
approach to generate highly localized temperature increments within agents, comparable to those obtained with traditional inorganic nano
tissues and biological structures. NIR light occupies a unique spectral particles [90–92]. In a study conducted by our research group, we
window in the electromagnetic spectrum, with wavelengths ranging investigated the size-dependency of various PDNP properties using a
from 700 to 1400 nm [77]. This spectral range holds significance in library of eight nanoparticles with different sizes, ranging from 145 to
biomedical research due to its ability to penetrate biological tissues with 957 nm in diameter, demonstrating how larger nanostructures were
minimal absorption [78–80]. able to perform as better NIR photothermal conversion agents compared
NIR-responsive nanostructures have been thus proven to be effective to smaller ones [93].
tools for PTT, a therapeutic strategy that allows the localized heat- In 2016, Wang et al. developed PDNPs functionalized with poly
induced treatment of tumors while minimizing damage to surrounding (ethylene glycol) (PEG) and loaded with doxorubicin and 7-ethyl-10-
healthy tissue [81]. NIR-induced hyperthermia has the potential to hydroxycamptothecin (SN38) as a multifunctional anticancer platform
induce apoptosis in cancer cells [82], and has been shown to enhance [94]. The anticancer efficiency of the obtained drug-loaded PEG-PDNPs
the sensitivity of cancer cells to chemotherapy [83] and ionizing radi was tested in vitro on PC9 lung carcinoma and MCF-7 breast cancer cells
ation therapy [84]. Moreover, it has been demonstrated that the high and in vivo on lung carcinoma-bearing bice [94]. The authors demon
metabolic activity and proliferative rate of cancer cells make them more strated the ability of these nanostructures to accumulate at the tumor
sensitive to temperature increments with respect to their healthy site through passive targeting, and to release their molecular cargo in
counterparts [85,86]. response to external stimuli like pH, ROS, and NIR irradiation (808 nm)
Fig. 5. Drug-loaded PDNPs as anticancer multifunctional platform. A) A scheme showing the NIR- and pH-triggered drug release from PDNPs and the synergistic
treatment of the tumor; B) tumor-site temperature evolution of mice irradiated by NIR laser and treated with drug-loaded PDNPs; C) the tumor volume evolution in
different experimental groups during the treatment period; D) overview of the excised tumors after the various treatment protocols; E) body weight trend of mice
treated with and without drug-loaded PDNPs and NIR irradiation along the therapeutic period.
Reproduced and adapted with permission from Ref. [94].
7
[94]. Moreover, the authors reported how the treatment with guanidine group of L-arginine present in the peptide chain associated
drug-loaded PDNPs and NIR irradiation was able to induce cancer cell with the nanostructures permitted the ROS-induced production of NO.
death and reduce tumor volume, outperforming the treatment with free The NO produced by the nanostructures promoted the growth of
drugs and plain nanostructures (Fig. 5) [94]. vascular endothelial cells leading to the restoration of damaged blood
In 2018, Zhang et al. proposed PDNPs functionalized with a pH- vessels. Moreover, the NIR irradiation of the PDNPs was able to induce
sensitive camptothecin (CPT)-containing polymeric prodrug (PCPT) the ablation of the thrombus and further promote the growth of vascular
for the treatment of ovarian carcinoma [30]. PCPT-loaded PDNPs were endothelium cells owing to the pro-angiogenic effects of the released NO
tested as drug carriers and PTT platforms both in vitro on HeLa cells and [100].
in vivo on HeLa-bearing mice. The authors reported that the release of Acter et al. developed polydopamine nanobowls loaded with doxo
CPT from PDNPs could be triggered both by exposure to acidic pH and rubicin for combined drug delivery and PTT treatment of ovarian can
by the irradiation of the nanostructures with a NIR laser source cer; they demonstrated the ability of the developed nanoplatforms to be
(808 nm) [30]. Moreover, the authors demonstrated the synergic effect internalized by HeLa cancer cells, release the loaded doxorubicin, and
of PCPT and PDNPs-mediated PTT both in vitro and in vivo, where the act as PTT agents upon NIR irradiation inducing cancer cell death [101].
combinatory treatment with PCPT-PDNPs and NIR irradiation was able
to outperform the treatment with just plain PDNPs or free PCPT in terms Polydopamine nanostructures in photodynamic therapy
of induction of cancer cell apoptosis and reduction of tumor volume
[30]. PDNPs have been extensively studied as platforms for photodynamic
PDNPs have also been exploited for the development of NIR- therapy (PDT) in the treatment of various forms of cancer [102]. PDT is a
responsive hydrogels in the context of cancer treatment. Injectable non-invasive therapeutic approach based on the irradiation of specific
self-healing hydrogels are smart soft materials able to repair any damage molecules, called photosensitizers, with light at specific wavelengths.
to their structure, and that can be exploited as drug carriers to achieve a Photosensitizers, when irradiated, can pass from a ground molecular
sustained and localized release [95]. Wang et al. developed a thermo state to an excited (triplet) state and subsequentially release the accu
sensitive self-healing gel exploiting the reaction between poly(ether mulated energy to the oxygen molecules present in the surrounding
imide) (PEI) and the acetoacetate groups in the four-armed star-shaped environment [102,103]. This process can generate high levels of ROS
poly(2-(dimethylamino)ethyl methacrylate-co-2-hydroxyethyl methac such as singlet oxygen (1O2), that are highly toxic to cancer cells being
rylate) modified with tertbutyl acetoacetate (DMAEMA-co-HEMA-AA), able to cause damage to macromolecules and cellular structures.
loaded with PDNPs and doxorubicin [95]. The obtained PDNPs and Some of the most commonly used photosensitizers include chlorin e6
doxorubicin-loaded hydrogels were then injected in breast (Ce6) [104], porphyrin [105], and indocyanine green (ICG) [106,107].
cancer-bearing mice at the tumor site and exposed to NIR radiation. The The major problems related to the use of photosensitizers are their poor
NIR-induced photothermal conversion of PDNPs led to the shrinkage of water stability and rapid blood clearance [102], and to overcome these
the hydrogel with the consequent release of doxorubicin from its matrix. limitations, PDNPs have been proposed as potential carriers. Similarly to
The combination of PTT, drug release, and physical stress induced by the what discussed in the context of the functionalization of PDNPs with
hydrogel contraction was able to induce cancer cell death and reduction drugs, photosensitizers can be associated with PDNPs through chemical
of the tumor volume [95]. conjugation by exploiting the high reactivity of polydopamine, through
An in vivo evaluation of PDNP NIR-induced hyperthermia for the physical absorption strategies exploiting weak interactions, or through
ablation of central nervous system (CNS) cancers localized in deep brain encapsulation procedures [102]. Usually, PDNPs loaded with photo
tissue was performed by Liu and colleagues by analyzing PTT mediated sensitizers are exploited in anticancer strategies combining PDT and
by PDNPs injected in the hippocampus of rats [96]. After 30 min from PTT, due to the ROS generation ability of the loaded photosensitizers
the injection, the rat brain was exposed to NIR laser irradiation (808 nm) and the photothermal conversion properties of polydopamine [102].
for 10 min, with a the temperature increment exceeding 60 ◦ C after Zhang et al. conjugated Ce6 on the surface of PDNPs through the
6 min of irradiation, leading to a precise and localized ablation of deep reaction with 1-ethyl-3-(3-dimethylaminopropyl) (EDC) and N-hydrox
brain tissues (the authors reported an ablated tissue volume ysuccinimide (NHS); the developed PDNPs-Ce6 were tested as PDT/PTT
of~6.5 mm3) [96]. Moreover, PDNPs were found to not cause signifi combinatory platforms on mice bearing HepG2 liver cancer cells [108].
cant damages to brain tissues, with the exception of small scars or blood PDNPs-Ce6 showed the ability to generate ROS when irradiated with a
clots caused by the microinjection. PDNP NIR-mediated hyperthermia laser at 670 nm, and to generate localized temperature increments when
presented minimal to no damage to the non-irradiated brain tissues, irradiated with an 808 nm laser. The combination of the two effects was
demonstrating the feasibility of polydopamine nanostructures as PTT able to induce cancer cell death and reduce the overall tumor volume in
platforms in the context of CNS disorder treatment, and their potential the xenograft animal model [108].
suitability in place of other more harmful and less localized thermal Poinard et al. developed PDNPs loaded with Ce6 through π-π stack
ablation approaches, for example envisioning radiofrequency and ing, enabling a controlled release of Ce6 from the polydopamine nano
focused ultrasound [97,98]. structures [109]. PDNPs-Ce6 were tested on T24 carcinoma cells,
In an interesting study from 2022, Li et al. developed and compared showing the ability to act as a PDT/PTT platform when irradiated with a
the anticancer efficiency of solid and mesoporous doxorubicin-loaded laser at 665 nm [103].
and PEG-coated PDNPs [99]. In their study, they demonstrated that Still in the context of polydopamine nanostructures loaded with Ce6,
both nanostructures were able to act as stimuli-responsive drug carriers Chen et al. proposed a different approach involving the development of
and NIR-PTT platforms inducing apoptosis in 4T1 cancer cells [99]. bovine serum albumin (BSA) and polydopamine hybrid nanostructures
However, the authors reported how mesoporous PDNPs outperformed [110]. In their study, the authors co-precipitated BSA with Ce6 obtain
solid nanostructures in terms of drug loading and release efficiency, ing Ce6 @BSA nanostructures, that were subsequentially coated with
photothermal conversion abilities, and degradation speed [99]. polydopamine leading to the formation of PDNPs-BSA-Ce6 hybrid
PDNP-mediated PTT has also been used for other therapeutic pur nanostructures referred to as dual-mode therapeutic nanoparticles (CBP
poses beyond cancer therapy. For example, in an in vivo study per NPs). The obtained CBP NPs were tested on 4T1, MCF-7, HeLa, and
formed in 2021, Fang et al. exploited PDNPs as an effective thrombolytic MCF-10A cancer cells, and in mice bearing breast cancer cells, showing
treatment [100]. The authors developed PDNPs loaded with urokinase the ability to generate ROS when irradiated with a 660 nm laser and act
(UK) and functionalized with the Arg–Gly–Asp (RGD) peptide for the as a PTT platform when irradiated with an 808 nm laser, demonstrating
effective targeting and treatment of thrombosis. The functionalization high anti-cancer efficiency in all the tested conditions (Fig. 6) [110].
with RGD allowed the PDNPs to target the thrombus site, while the As previously mentioned, ICG is another commonly used
8
Fig. 6. Development of hybrid BSA polydopamine nanostructures loaded with Ce6 for combined PTT and PDT against cancer.
Image reproduced with permission from Ref. [110].
photosensitizer exploited for the functionalization of PDNPs for PDT cerium oxide [117], and platinum [118] nanoparticles. Inorganic anti
approaches. ICG is characterized by a light absorption peak at 780 nm oxidant nanostructures have been tested in the context of Parkinson’s
and the ability to act as a PDT and PTT conversion agent, besides being a disease [119], Alzheimer’s disease [120], ischemic stroke [121], meta
widely used fluorescent tracker in diagnostic applications [111]. bolic disorders [122], senescence [123], treatment of various forms of
Moreover, the NIR absorption of ICG makes it a more suitable candidate cancer [124], and even, by our group, in space biology [125].
for PDT and imaging applications with respect to other photosensitizers, PDNPs, presenting excellent antioxidant properties, represent an
indeed because of the previously discussed high tissue penetrability of ideal alternative to the just-mentioned inorganic nanostructures. The
NIR irradiation. However, its use is limited by aggregation and low antioxidant properties of PDNPs have been linked to their catechol-,
stability in water solution, quick clearance, and accumulation in quinone-, and imine-rich surfaces, which grants them the ability to act as
off-target organs [112]. To overcome these limitations, Liu et al. ROS scavengers against a vast variety of different free radicals. For
developed hybrid nanostructures composed of hyaluronic acid loaded example, Guo et al. in 2021 theorized that the polydopamine ability to
with ICG and coated with polydopamine [113]. The obtained nano scavenge alkyl peroxyl radicals (•ROOC, produced during autoxidation
structures showed the ability to generate ROS and act as photothermal of lipid substrates induced by hydroperoxyl radicals, •HOOC) could be
conversion agents when irradiated by NIR laser, thus being able to elicit due to a H-atom transfer mechanism involving the free radical and the
anti-cancer effects both in vitro on 4T1 cells and in vivo in mice bearing quinone groups of polydopamine [28].
breast cancer cells [113]. In 2017, Shi and co-workers demonstrated the multiple enzyme-
In another study, PDNPs were loaded with a new form of ICG (IR820) mimicking antioxidant activities of melanin nanoparticles (chemically
and tested as PDT/PTT platforms for the treatment of psoriasis [114]. analogous of PDNPs) for the treatment of ischemic reperfusion brain
The obtained PDNPs/IR820 were able to penetrate the psoriasiform skin injury [126]. The authors demonstrated how PEGylated melanin nano
of an imiquimod (IMQ)-stimulated murine model, and to act as ROS particles (PEG-MeNPs) were able to scavenge various types of ROS
generators and cause temperature increments upon NIR laser irradia including superoxide (O•− 2 ), hydroxyl ( OH), nitric oxide ( NO) and
• •
tion, leading to the removal of the psoriasis plaque and relive peroxynitrite (ONOO− ) radicals. The results obtained by Shi and col
psoriasis-induced inflammation [114]. leagues suggested that PEG-MeNPs may effectively neutralize these
radicals through a nitration and nitrosation mechanism involving the
Antioxidant properties of polydopamine nanostructures phenolic groups abundant in melanin structures. Moreover, the authors
showed how PEG-MeNPs could react with H2O2, indicating their
The overproduction of ROS has been associated with the onset and possible catalase-like activity [126]. Lastly, PEG-MeNPs were exploited
progression of several health disorders, ranging from neurodegenerative as a protective antioxidant platform to prevent ischemic-stroke-induced
diseases to various forms of cancer [115]. ROS are in fact able to induce damage, demonstrating their beneficial effects by reducing ROS accu
damage to macromolecules and cellular components such as proteins, mulation and inflammation in an in vivo rat model of ischemic stroke
nucleic acid, cellular membranes, and mitochondria, leading to severe [126].
impairments of cellular functions [115]. Therefore, the research in the In 2018, Bao et al. reported antioxidant PDNPs in the treatment of
development and exploitation of antioxidant molecules as counter periodontal disease [127]. In their study, the authors exploited PDNPs
measures for oxidative stress is a “hot” topic in nanomedicine: in this for the prevention of ROS accumulation both in vitro on HGE cells and in
context, in fact, antioxidant nanoparticles have been recently proposed vivo in a lipopolysaccharides (LPS)-induced animal model of peri
in the treatment of several pathologies [115]. Some of the most used odontal disease [127]. They reported the antioxidant effect of PDNPs
classes of antioxidant nanostructures include manganese oxide [116], against •O−2 and •OH, their capacity to reduce ROS levels both in vitro
9
and in vivo, and the ability of polydopamine nanostructures to reduce innovative therapies for the treatment of various health disorders.
the expression of inflammation-related markers such as tumor necrosis NIR-responsive gold nanostructures have been exploited for the
factor α and interleukin ß [127]. non-disruptive remote control of cellular activities such as the remote
Jia et al. demonstrated the potential of PDNPs as protective antiox control of muscle cell contraction [138], modulation of gene expression
idant platforms for the prevention of irradiation-induced intestinal [139,140], and the induction of neural activation [141,142]. However,
injury [128]. In their study, they tested PDNPs on mice models of total as we extensively discussed in the previous Sections, the use of noble
body irradiation. PDNPs showed a clear antioxidant activity against O•− 2 metal in biomedicine is limited by their potential toxicity and their lack
and •OH radicals, two of the main ROS species involved in oxidative of biodegradability.
stress-induced cellular damages [128]. Moreover, the authors reported In this view, polydopamine nanostructures are a suitable organic
how PDNPs were able to prevent the depletion of intestinal stem cells, platform for the remote modulation of cellular activities, due to their
promote the repair of intestinal structures and activities, suppress in previously discussed photothermal conversion properties. For example,
testinal cell apoptosis and pyroptosis, and alleviate DNA damage in a recent study, Li et al. designed PDNPs loaded with CpG oligodeox
induced by ionizing radiation [128]. ynucleotides (CpG ODNs), an immunostimulatory nucleic acid adjuvant
Our group previously reported the antioxidant properties of PDNPs able to induce the maturation of dendritic cells (DCs), and thus to
both on neuron-like cells and on skin fibroblasts derived from patients stimulate antitumor immune responses [143]. Conventional PTT ap
affected by autosomal recessive spastic ataxia of Charlevoix-Saguenay, a proaches have the potential to induce immunogenic cell death, which
rare neurological disease caused by congenital mitochondrial disorders can lead to the release of tumor-associated antigens and the recruitment
[129,130]. In our studies, we were able to demonstrate the protective of DCs [144–146]. However, a disruptive PTT is usually unable to pro
effects on both cellular models in terms of reduction of ROS levels in the vide a sufficient activation signal to DCs, and as a result, the immune
presence of a pro-oxidative stimulus (tert-butyl hydroperoxide), and the system ability to inhibit tumor recurrence and proliferation may be
prevention of ROS-induced mitochondrial impairments such as inadequate, eventually leading to tumor recurrence [147]. The combi
morphological aberrations and loss of membrane potential [129,130]. nation of the NIR irradiation with CpG ODNs resulted in a significant
Zhang et al. proposed PDNPs as antioxidant and anti-inflammatory synergistic treatment in a mouse model of melanoma. This combined
enhancers against UV-induced skin damage [131]. In their study, they therapy enhanced the maturation of DCs and the activation of T cells
exploited PDNPs for the development of anti-UV sunscreen, and tested with respect to PTT or CpG ODNs individually. Moreover, this approach
the efficiency of this formulation on mice models of UV irradiation addressed the issue of insufficient immune response at distant tumor
[131]. The formulation was able to prevent UV-induced damages on the sites, a limitation observed with PTT alone, besides alleviating the
skin of mice exposed to UV irradiation, being able to absorb UV, reduce immunosuppressive environment within the tumor [143].
ROS and inflammation, prevent UV-induced damages (epidermal hy PDNP photothermal conversion showed interesting applications also
perplasia, transepidermal water loss, and skin barrier disruption), and in the context of cell transfection and gene therapy. For example, Zhang
being able to counteract photoaging by maintaining the metabolism of et al. exploited PDNPs for the transfection of cancer cells both in vitro
collagen fibers and elastins [131]. (HepG2 cells) and in vivo in KB tumor-bearing mice [148]. In particular,
PDNPs have also been studied in the context of neurodegenerative the authors exploited PDNPs loaded with p53 DNA as a gene delivery
disorders [132]. For example, in 2023 Zhu et al. proposed PDNPs as a platform. PDNP transfection efficiency was compared to commercial
potential countermeasure for inflammatory depression [132]. PDNPs lipofectamine 2000, obtaining similar transfection efficiency but with
reduced oxidative stress in an LPS-induced animal model of inflamma lower cytotoxicity. Moreover, the application of NIR stimulation
tory depression, being also able to limit the production of serum in increased by 4.5 times the transfection level of p53, thanks to the quick
flammatory cytokines, inhibit microglia activation, restore synaptic loss, escape of gene complexes from the endosomes. The synergistic efficacy
and alleviate splenomegaly, thus improving the anxiety and depression of gene/PTT resulted in an almost completed depletion of the tumor
of the treated animals [132]. Still in 2023, Han et al. proposed PDNPs as mass in treated mice after only one intratumoral injection, and in a
an anti-senescence treatment. In this study, ultra-small PDNPs (3 nm) tumor inhibition efficacy of 99% [148].
were tested as an anti-age formulation on 293 T cells and on two in vivo Intracellular temperature increments in neuronal cells are known to
models of senescence (D-galactose-induced Drosophila melanogaster and cause the stimulation of nerve transient receptor potential (TRP) chan
doxorubicin-induced mouse model) [29]. The authors reported the nels, leading to membrane depolarization and neuronal activation
ability of the developed PDNPs to counteract the accumulation of [149]. In a study performed by our group, we showed the ability of
various forms of ROS, exert cytoprotective effects against oxidative PDNPs to act as an organic NIR-responsive platform for the modulation
stress-induced damages, restore senescence-impaired functions in mice of neuronal activities. We were able to demonstrate that PDNPs can be
(renal activity, tissue homeostasis, fur density, and motor ability), and used to finely tune the intracellular temperature of neuronal-like cells in
prolong the life span of the Drosophila senescence model [29]. a non-disruptive and non-cytotoxic manner, with a consequent incre
ment of the intracellular calcium concentration, suggesting neuronal
Polydopamine nanostructures as smart modulators of cellular activation [129]. In 2021, Derami et al. showed the possibility of PDNPs
activities to exert a reversible modulation of the electrical activity of neurons and
cardiomyocytes, thanks to NIR irradiation [150]. PDNPs have been
One of the most exciting applications of smart nanomaterials is exploited to modulate neuronal activity and cardiomyocyte beating
represented by the possibility of remotely stimulating cellular activities frequency. By calibrating NIR laser power and stimulus duration, the
in a non-disruptive, non-invasive, and highly localized manner. Some authors demonstrated the possibility of modulating the electrical ac
examples include the modulation of neuronal cell activation or the tivities of hippocampal neurons and of suppressing or enhancing the
remote control of stem cell differentiation by exploiting piezoelectric beating rate of induced pluripotent stem cells-derived cardiomyocytes,
nanoparticles [6,133]. Moreover, the literature has extensively docu demonstrating the potential of polydopamine nanostructures as a
mented how heat stimuli within physiological ranges can effectively minimally invasive photothermal transducer [150].
modulate various cellular behaviors, including gene expression [134],
stem cell differentiation [135], and neuron activation [136]. In this Polydopamine nanostructures in imaging applications: Towards
context, the application of photothermal stimulation exploiting NIR organic contrast agents
radiation stands out as a powerful tool for remotely manipulating cell
activities and maturation [137]. This technology holds great promise for As mentioned, a theranostic smart nanoplatform combines a thera
advancing our understanding of cellular processes and developing peutic effect with a diagnostic action, being thus generally able to be
10
imaged and localized inside tissues and cells and to provide information interaction and π-π stacking [171]. The obtained doxorubicin-loaded
about its surrounding biological environment [1]. Several approaches PDAC showed the ability to act as an excellent PA contrast agent out
have been proposed to visualize PDNPs inside living organisms; for performing solid PDNPs of the same size (approximately 200 nm) both
example, polydopamine nanostructures have been conjugated with MRI in vitro and in vivo [171]. Moreover, these nanocomplexes showed high
inorganic contrast agents such as Gd [151], iron oxide nanoparticles anticancer efficiency upon NIR irradiation both in vitro and in mice
[152], manganese oxide [153], and nickel [154]. PDNPs have been also bearing breast cancer cells, outperforming the treatment with free
radiolabeled with 131I for SPECT imaging [155] or functionalized with doxorubicin. It is worth mentioning that, like in the case of the examples
noble metal as gold nanoparticles for Raman spectroscopy analysis discussed in the previous Sections, even in this case the authors observed
[156]. Despite the potential of these nanostructures, we would like to a burst release of doxorubicin from the PDAC caused by NIR irradiation
drive our attention on studies exploiting completely organic formula and exposure to acidic pH [171].
tions, thus avoiding the already mentioned drawbacks of inorganic PDNPs have also been used in combination with other PA contrasts
nanoparticles [157,158]. agent to improve their overall PA signal. For example, Yim et al.
The visualization of completely organic PDNP formulations within developed PDAC loaded with different PA molecular contrast agents like
biological structures can be achieved mainly by means of fluorescence Nile blue and methylene blue for the direct detection of heparin in the
imaging and PA analysis. The fluorescence-based imaging of PDNPs is whole human blood [172]. The obtained dye-loaded PDAC showed a PA
usually achieved through the functionalization of polydopamine with signal higher than the free dyes and enabled the direct detection of
fluorescent moieties either through Michael addition, encapsulation, or heparin; moreover, the authors showed that the obtained PA signal of
weak molecular interactions [102]. PDNPs have been easily function dye-loaded PDAC from the blood of 17 patients linearly correlated with
alized with a vast variety of fluorescent tracers such as carbocyanine the heparin values obtained through other conventional methods like
dyes, rhodamine, cyanines, and fluorescein, enabling their visualization clotting time [172]. As a last very recent example, Ren and colleagues
through fluorescence microscopy in vitro and in vivo [159]. Previously developed a multifunctional polydopamine nanocomposite combining
discussed photosensitizers, Ce6, IR820, and ICG, can also be used as most of the polydopamine properties that we discussed in this review.
fluorescent tracers in addition to their ability to act as PDT/PTT plat The developed nanostructures were composed of mesoporous PDNPs
forms [111,160,161]. One notable example of a fluorescent tracer is also loaded with the photosensitizer IR780, the natural NO donor L-arginine,
represented by doxorubicin that, owing to its fluorescence properties, and functionalized with BSA [173]. The obtained polydopamine nano
can enable the direct imaging of doxorubicin-loaded PDNPs [162]. composites showed the ability to act as PDT and PTT platforms, PA
The use of fluorescent tracers for the visualization of PDNPs is contrast agents, and NO generators upon NIR irradiation [173]. The
however limited by several issues, including as the fluorescence synergic combination of these effects enabled the detection of tumors in
quenching effect of polydopamine and the pH-dependent detachment of osteosarcoma-bearing mice, and an overall anti-cancer efficiency far
the fluorescent molecule from the nanostructures [163]. PA imaging has superior than that one of the single plain treatments (Fig. 7) [173].
gained attention in recent years as a label-free imaging technique for
diagnostic purposes [164]. PA imaging is based on the PA effect Conclusions: Current limitations and future perspectives
generated by endogenous chromophores or exogenous contrast agents
when irradiated with an external laser source: briefly, when the chro As discussed in this review, PDNPs have been studied for various
mophores or the PA contrast agents are irradiated with a proper laser applications including drug delivery, PTT, PDT, antioxidant-based
source, they can absorb part of the irradiation and undergo a rapid therapies, remote stimulation of cellular functions, and imaging of
thermoelastic expansion [164]. The mechanical expansion of the biological structures (a summary of the articles discussed in this review
photo-absorber is then able to generate a wide-band ultrasound wave can be found in Table 1).
that can be detected by a transducer and converted to electric signals To the best of our knowledge, despite the promising properties of
that are then processed to form an image [164]. Commonly noble metal polydopamine nanostructures, no clinical trials employing PDNPs are
nanostructures such as gold [164] and silver [165], carbon nanotubes ongoing. In our opinion, several key points currently limit the applica
[166], and dyes like ICG [167] and methylene blue [168] are the most bility of PDNPs in human healthcare, as discussed in the following.
widely used contrast agents for PA imaging.
Several works however reported also the potential of PDNPs as PA 1) The precise molecular mechanism behind polydopamine formation,
contrast agents. For example, Li et al. developed PDNPs modified with as we previously discussed, remains largely unknown, opening po
the arginine-glycine-aspartic-cysteine acid (RGDC) peptide and loaded tential concerns for their applications [36]. For example, despite the
with doxorubicin for the treatment and PA imaging of cervical cancer synthesis of polydopamine does not usually involve the use of
both in vitro and in vivo. The obtained nanostructures, characterized by organic solvents or other toxic compounds, the presence of
a high targeting and anti-cancer efficiency, showed the ability to act as non-polymerized dopamine molecules in PDNP dispersions could
PA contrast agents enabling the localization of the PDNPs and the tumor potentially lead to adverse effects [36]. Moreover, as described, even
imaging even at concentrations as low as 15 μg/ml [169]. In another the overall molecular structure of polydopamine itself is still largely
example, Fu et al. compared the PA and PTT properties of PDNPs ob unknown [174]: the analysis of PDNP formation mechanism and the
tained through solution oxidation and of melanin nanostructures development of new models that describe their molecular composi
developed through bacteria-mediated synthesis [170]. The authors tion are thus pivotal points to be addressed before a successful
showed that the bacteria-derived melanin nanostructures outperformed implementation of polydopamine nanostructures in clinical
the PDNPs obtained through solution synthesis in terms of both PA applications.
signal and PTT effects in 4T1 tumor-bearing mice [170]. 2) The properties of PDNPs in terms of antioxidant capacity, photo
In another study, hyaluronic acid-coated PDNPs (HA-PDNPs) were thermal conversion abilities, drug loading efficiency, and overall
exploited for the PA-guided imaging of endometriosis (EM) lesions in interaction with tissues and cells are highly dependent on the
vivo, as an innovative tool for the diagnosis and monitoring of this nanostructure characteristics such as diameter, porosity, and shape
disease [31]. The obtained HA-PDNPs showed the ability to accumulate [24,68]. Currently, there is an evident lack of standardization among
at the boundary of EM lesions in mice models. Moreover, PDNP-based the studies exploiting PDNPs for biomedical applications, with pol
volumetric reconstruction obtained through PA imaging accurately ydopamine nanostructures of various sizes, shapes, surface chemis
assessed EM progress [31]. Zhuang and colleagues developed a rather try, and molecular cargo being investigated as countermeasures for
interesting PDNP theranostic formulation based on polydopamine hol various health disorders ranging from cancer therapy [52,175] to the
low nanocapsules (PDAC) loaded with doxorubicin through electrostatic treatment of neurodegenerative diseases [132]. To maximize the
11
Fig. 7. Mesoporous PDNPs loaded with L-arginine, IR780, and functionalized with BSA are able to act as a theranostic platform for PDT, PTT, PA imaging, and NO
generation upon NIR irradiation, enabling the visualization and treatment of osteosarcoma.
Image reproduced with permissions from Ref. [173].
therapeutic efficiency of PDNPs and facilitate their transition into products could potentially lead to unexpected biological outcomes or
clinical applications, a set of highly standardized and reproducible even adverse health effects. Therefore, there is a need to extensively
fabrication procedures should be developed, investigated, and investigate the biodegradation process of PDNP with particular
implemented. attention to their degradation products.
3) The high reactivity of PDNPs represents a double-edged sword, since 5) Literature studies focused on the analysis of the long-term effects of
from one side it grants the possibility to easily functionalize PDNPs PDNPs in living animals are still fairly limited, with most articles
with a vast variety of molecules [59], but it could also potentially focusing on in vitro tests or reporting in vivo short-term analysis [19,
lead to unexpected interaction with biological structures. As it has 20]. For a successful implementation of PDNPs in clinical applica
been extensively described in the literature, when nanostructures tions, the study of the effects of chronic exposure to polydopamine
come in contact with biological fluids they are almost immediately nanostructures using in vivo models is a pivotal necessity.
coated with biological molecules such as proteins, lipids, and nucleic 6) Most studies currently present in the literature describes the syn
acids, collectively referred to as “biomolecular corona” [176]. This thesis of PDNPs in relatively small quantities (commonly with a
phenomenon could be exacerbated by the previously described high PDNP yield in the order of hundreds of milligrams) [177]. The
reactivity of polydopamine, leading to the formation of a biomole scalability of the PDNP synthesis procedure and the large-scale
cular corona associated with PDNPs that could potentially cause production of polydopamine nanostructures is an essential point
unexpected interactions with tissues and cells and compromise PDNP for their exploitation in clinical applications. As discussed, the yield
properties or their colloidal stability. To date, there is no extensive of PDNP synthesis can be affected by several parameters such as the
analysis of the formation of biomolecular corona associated with reaction pH, the dopamine concentration, and the process tempera
PDNPs when exposed to biological environments, and neither of the ture [40,41]. A potential solution for the large-scale production of
potential strategies to prevent or at least reduce the corona forma PDNPs could be the development of batch reactors able to produce
tion. An extensive analysis of this phenomenon for the future clinical polydopamine nanostructures in large quantities. Flow reactors are
application of polydopamine nanostructures is needed, in particular for example commonly exploited for the fabrication of inorganic
in terms of parameters (size, porosity, shape, surface functionaliza nanostructures like SPIONs or silica nanoparticles [178,179]. A
tion) potentially affecting biomolecular corona. Moreover, strategies major obstacle to the large-scale production of PDNPs is represented
to prevent the opsonization of PDNPs need to be developed and by the relatively slow kinetics of the polydopamine synthesis reac
investigated, including the coating of polydopamine nanostructures tion [19]. Several strategies could be exploited to overcome this
with protective molecules such as PEG. limitation; for example, it has been demonstrated that the applica
4) The overall degradation process of PDNPs and polydopamine in tion of external stimuli such as microwave [180] or UV irradiation
general is still under investigation. It is known that external pa [181] can affect the formation speed of polydopamine films. A
rameters such as pH and exposure to ROS can affect the overall similar approach could be exploited to improve the kinetics of PDNP
degradation of PDNPs over time; however, both the molecular formation facilitating the large-scale production of polydopamine
mechanism behind this process and the products of PDNP degrada nanostructures.
tion are largely unknown [20,24,35], and PDNP degradation
12
Table 1
An overview of the studies discussed in this review showing the exploited nanostructure composition, along with their main features.
Reference Nanostructures Loaded molecules / Loading / encapsulation Size Application
functionalization data
[67] PDNPs Loaded with gambogenic acid and Encapsulation efficiency 185.3 ± 5.1 nm Delivery of gambogenic acid as a
functionalized with folic acid and about 86% treatment for breast cancer
sodium alginate
[68] Mesoporous and solid Loaded with RA Encapsulation efficiency 500 nm and 300 nm Delivery of RA to skin
PDNPs about 90%
[70] PDNPs Loaded with BTZ and Loading efficiency up to 150-200 nm Delivery of BTZ as a treatment for breast
functionalized with glucosyl 11 wt% cancer
ligands
[71] PDNPs Loaded with doxorubicin and Encapsulation efficiency up 436.77 ± 25.31 nm Delivery of doxorubicin and
epigallocatechin-3-gallate and to 93% epigallocatechin-3-gallate as a treatment
functionalized with folic acid for breast cancer
[72] Mesoporous PDNPs Loaded with doxorubicin and Loading efficiency 38 wt%; 184 nm Delivery of doxorubicin as a treatment for
functionalized with platelet Encapsulation efficiency breast cancer
membranes 98%
[73] Oil emulsion stabilized Oil emulsion loaded with aspirin N/A 180 nm Developing of a smart drug-delivery
by polydopamine system
nanobowls
[74] Hollow PDNPs Loaded with the peptide RL‑QN15 Approximately 80% 52 nm Treatment of skin wounds
encapsulation efficiency
[75] Hollow PDNPs Functionalized with N Up to 297 pmol of NO 45 nm Antibacterial action through NO
-diazeniumdiolates release per mg of PDNPs generation
[76] PDNPs Loaded with prunetin and N/A Approximately Treatment of UV-induced inflammation
functionalized with hyaluronic 200 nm
acid
[94] PDNPs Loaded with doxorubicin and 7- Loading efficiency of 98 nm Delivery of doxorubicin and 7-ethyl-10-
ethyl-10-hydroxycamptothecin approximately 33 wt% for hydroxycamptothecin (SN38) and NIR-
(SN38) and functionalized with DOX and approximately induced PTT as a treatment for lung
PEG 11 wt% for SN38 carcinoma and breast cancer
[30] PDNPs Functionalized with PCPT N/A 114 Delivery of PCPT and NIR-induced PTT for
cancer therapy
[95] Thermo-responsive Loaded with doxorubicin N/A 220 nm (PDNP size) Development of injectable
hydrogels (DMAEMA-co- thermoresponsive hydrogels for the
HEMA-AA) loaded with delivery of doxorubicin as a treatment for
PDNPs breast cancer
[96] PDNPs N/A N/A 145 nm Analysis of the potential of PDNPs as PTT
platforms for the thermal ablation of deep
brain tissues
[99] Solid and mesoporous Loaded with doxorubicin and Up to approximately 80% 160 nm Delivery of doxorubicin and NIR-induced
PDNPs functionalized with PEG encapsulation efficiency PTT as a treatment for breast cancer
[100] PDNPs Loaded with UK and functionalized RGD decoration 0.16 wt% 243 nm PTT and NIR-induced NO-generation as a
with RGD treatment of thrombosis
[101] Mesoporous Loaded with DOX Loading efficiency 30 wt% 180 nm PTT and DOX delivery as a treatment of
polydopamine ovarian cancer
nanobowls
[108] PDNPs Functionalized with Ce6 N/A 43 nm PDT/PTT as a treatment for liver cancer
[109] PDNPs Loaded with Ce6 14.2 μM of Ce6 loaded in 260 nm PDT/PTT as a treatment for urinary
1 nM PDNPs bladder cancer
[110] Hybrid BSA/PDNPs Loaded with Ce6 N/A 80.7 ± 6.6 nm PDT/PTT as a treatment for various forms
of cancer (breast, lung, and ovarian
cancer)
[113] PDNPs Loaded with ICG and Up to 8.6% loading 318 nm PDT/PTT as a treatment for breast cancer
functionalized with hyaluronic efficiency
acid
[114] PDNPs Loaded with IR820 Encapsulation efficiency up 200 nm PDT/PTT as a treatment for psoriasis
to 97%
[126] Melanin nanoparticles Functionalized with PEG N/A 120 nm Antioxidant treatment against ischemic
stroke
[127] PDNPs N/A N/A 160 nm Antioxidant treatment of periodontal
disease
[128] PDNPs N/A N/A Diameter ranging Antioxidant treatment of irradiation-
from 107 to 183 nm induced intestinal injury
[129] PDNPs Functionalized with DSPE-PEG N/A 200 nm Antioxidant protection of neuronal-like
cells and NIR-induced stimulation of
neuronal activity
[130] PDNPs N/A N/A 200 nm Antioxidant treatment of ARSACS
[131] PDNPs N/A N/A 119.4 nm Development of PDNPs-based antioxidant
sunscreen against UV-induced damage
[132] PDNPs N/A N/A 250 nm Antioxidant treatment of inflammatory
depression
[29] Ultrasmall PDNPs N/A N/A 3 nm Antioxidant treatment of senescence
[143] PDNPs Loaded with CpG ODNs N/A 70-90 nm Modulation of DCs maturation as anti-
cancer treatment
(continued on next page)
13
Table 1 (continued )
Reference Nanostructures Loaded molecules / Loading / encapsulation Size Application
functionalization data
[148] PDNPs Loaded with p53 DNA N/A 320 nm Gene delivery and PTT in the context of
liver cancer treatment
[150] PDNPs N/A N/A 465 nm NIR-induced modulation of neuronal
activation and cardiomyocytes beating
frequency
[169] PDNPs Modified with RGDC and loaded Up to 2 wt% loading 120 nm PA imaging and combinatory treatment of
with doxorubicin efficiency cervical cancer
[170] PDNPs and melanin N/A N/A 200 nm (PDNPs); PA imaging and PTT as a treatment of
nanoparticles 40 nm (melanin breast cancer
nanoparticles)
[31] PDNPs Coated with hyaluronic acid N/A 200 nm PA imaging of endometriosis
[171] Hollow PDNPs Loaded with doxorubicin Up to 50% of loading 200 nm PA imaging and combinatory treatment of
efficiency breast cancer
[172] PDNPs Loaded with various PA contrast Loading efficiency up to From 70 to 120 nm Detection of heparin
agents like Nile blue and methylene 81%
blue
[173] PDNPs Loaded with IR780, L-arginine, and L-Arg loading content of 180 nm PA imaging, NO generation, and PDT/PTT
functionalized with BSA approximately 11 wt% as a treatment for osteosarcoma
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T. He, W. Penny, B.R.I. Miller, J.V. Jokerst, Enhanced photoacoustic detection of the Smart Bio-Interfaces Research Line and Coordinator of the
heparin in whole blood via melanin nanocapsules carrying molecular agents, ACS Center for Materials Interfaces (Pontedera, Italy). His main
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M. Zhu, A multifunctional nanocomposite coated with a BSA membrane for altered gravity conditions. He author of about 180 papers on
cascaded nitric oxide therapy, Int J. Biol. Macromol. 238 (2023) 124087, https:// international journals, and coordinator or unit leader of several
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polymeric nature of polydopamine, Angew. Chem. Int. Ed. 58 (4) (2019) Grant in 2016, 2018, and 2022, respectively. Thanks to
1077–1082, https://doi.org/10.1002/anie.201811763. grants from the Italian Space Agency and the European Space
[175] B.F. Grześkowiak, D. Maziukiewicz, A. Kozłowska, A. Kertmen, E. Coy, Agency, he had the opportunity to carry out experiments on
R. Mrówczyński, Polyamidoamine dendrimers decorated multifunctional board the International Space Station in 2017, 2019, and 2022.
polydopamine nanoparticles for targeted chemo- and photothermal therapy of
18

Polydopamine-Based Nanostructures A New Generation of Versatile, Multi-Tasking, and Smart Theranostic Tools

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Polydopamine-based nanostructures: A new generation of versatile,

Fig. 1. An overview of the “smart” properties of PDNPs.

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