Polydopamine nanomaterials and their potential applications in the treatment of autoimmune diseases

Abstract

The conventional treatment methods used for the management of autoimmune diseases (ADs) have limited efficacy and also exhibit significant side effects. Thus, identification of novel strategies to improve the efficacy and safety of ADs treatment is urgently required. Overactivated immune response and oxidative stress are common characteristics associated with ADs. Polydopamine (PDA), as a polymer material with good antioxidant and photothermal conversion properties, has displayed useful application potential against ADs. In addition, PDA possesses good biosafety, simple preparation, and easy functionalization, which is conducive for the pharmacological development of PDA nanomaterials with clinical transformation prospects. Here, we have first reviewed the preparation of PDA, the different functional integration strategies of PDA-based biomaterials, and their potential applications in ADs. Next, the mechanism of action of PDA in ADs has been elaborated in detail. Finally, the application opportunities and challenges linked with PDA nanomaterials for ADs treatment are discussed. This review is contributed to design reasonable and effective PDA nanomaterials for the diagnosis and treatment of ADs.

Keywords:

• Polydopamine
• autoimmune diseases
• photothermal therapy
• immunomodulation
• antioxidant

1. Introduction

Autoimmune diseases (ADs) are a complex group of long-term medical conditions that typically develop when a person’s immune system cannot discriminate between self and non-self, which can result in an inappropriate immune reaction against the self-tissues and organs. The overall prevalence of ADs is approximately 3–5% in the general population and can result in tremendous suffering to patients and also impose a substantial economic burden on society as well as on affected individuals (Wang et al., 2015).

ADs can primarily be divided into organ-specific and systemic autoimmune diseases based on the lesions’ location. Organ-specific ADs, such as primary biliary cirrhosis (PBC), autoimmune thyroid disease, inflammatory bowel diseases (IBD), type 1 diabetes (T1DM), etc., suggest that the various lesions are exclusive to certain tissues or organs. Systemic autoimmune diseases indicate means that lesions can affect involve a wide variety of tissues and organs, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic vasculitis, autoimmune hemolytic anemia (AHA), etc. Even though numerous in-depth molecular, immunological, genetic, and clinical studies have contributed to the field a more sophisticated understanding of the various underlying mechanisms underlying some of the most frequently diagnosed ADs, the potential triggers of autoimmune diseases, such as environmental factors, and the ensuing pathogenesis remain unclear (Fugger et al., 2020). Therefore, the current clinically relevant treatments are primarily focus on the symptom management and control of disease to reduce the number of relapsing events. These treatment choices, however, are non-disease specific, have poor effectiveness, and are frequently accompanied by adverse side effects, including infection and malignant disease. Hence, there is a pressing need for innovative strategies to improve the therapeutic efficacy and safety compared to traditional treatments.

As an emerging and attractive field, nanomedicine has recently opened new avenues for diagnosing and treating ADs. Due to their unique features, some polymer nanoparticles (NPs), primarily polydopamine (PDA) NPs, have been successfully utilized for diverse biological applications. PDA is an artificial melanin-like biomimetic polymer obtained through the dopamine monomer’s covalent oxidative polymerization and physical self-assembly. It can display excellent adhesion to almost all types of materials (Hong et al., 2012). PDA’s active catechol groups and amine groups, in particular, can allow the attachment of numerous small compounds, biomolecules, and polymers on PDA surfaces.

Furthermore, PDA can result in effective drug loading through metal chelation, hydrogen bonding, electrostatic interactions, and other mechanisms. Compared to other nanomaterials, PDA NPs have superior biocompatibility, biodegradability, and hydrophilicity. They can degrade under acidic (lysosomal) or reduced (cytoplasmic) conditions, thereby resulting in responsive drug release (Huang et al., 2017). Moreover, in terms of the treatment, PDA NPs have been shown to exhibit anti-inflammatory and antioxidant properties, as well as photothermal conversion capacity. As a result, PDA NPs have emerged as promising agents for diagnosing and treating various ADs.

Most studies on PDA-based biomaterials have focused mostly on their potential involvement in cancer therapy, with little emphasis on their potential impact on ADs. As a result, the primary objective of the present article was to summarize the multifunctional integration of PDA NPs and highlight the most recent advances regarding managing various ADs. We proceeded by discussing the preparation and functional modification of PDA NPs. Thereafter, the application of PDA NPs in ADs has been discussed. Subsequently, diverse roles of PDA in the treating ADs have been elaborated, including anti-inflammatory and antioxidant properties, promoting bone repair, anti-angiogenesis, and immunomodulatory effects. In the conclusion section, we have also evaluated and identified the limitations and potential development directions of PDA-based biomaterials for ADs treatment (Figure 1).

Figure 1. Schematic illustration of functional, application, and mechanism of PDA NPs.

2. Preparation of PDA NPs

The most popular approach for producing PDA NPs is solution oxidation, which entails utilizing water and/or ethanol as the reaction media and allowing dopamine (DA) to self-polymerize in an alkaline environment. In addition, there several methods that have been developed, such as electropolymerization (Tan et al., 2021), photochemical polymerization (Du et al., 2014; Lemaster et al., 2019; Kaya et al., 2021), and enzyme catalyzed polymerization (Li et al., 2015; 2018). Based on their structural characteristics, PDA NPs are classified as solid PDA NPs, mesoporous PDA NPs, core-shell PDA NPs and hollow PDA NPs based on their different structural features. Compared to solid structures, mesoporous structures have a larger specific surface area, higher pore volume, adjustable pore size, and more active site, which can achieve higher drug loading, controllable drug release, and screening of guest sizes (Zhao et al., 2023). Based on a simple mesoporous structure, the hollow mesoporous structure can produce increased drug loading and faster environmentally responsive drug release by inserting an interior cavity structure internally (Yang et al., 2013; Ma et al., 2022). The PDA coating with a core-shell structure is mainly used for encapsulating nuclear drugs, increasing the biocompatibility and modifiability of core materials (Song et al., 2023).

Unlike solid PDA NPs, mesoporous PDA NPs necessitate the existence of appropriate templates. Currently, mesoporous PDA NPs mostly use pluronic F127 as a template, with 1,3,5-Trimethylbenzene (TMB) as a modifier, and were obtained through etching the template with solutions such as tetrahydrofuran, ethanol, or acetone after self-polymerization of DA under alkaline conditions (Shen et al., 2023). Along with the standard mesoporous structure, Li et al. constructed Janus double spherical mesoporous NPs, in which the pore size in the mesoporous silica compartment may be changed from 3 to 25 nm. The pore size in the mesoporous PDA compartment ranges from 5 to 50 nm (Zhao et al., 2023).

PDA can be deposited on the surface of other materials for producing PDA NPs, or other materials can be deposited on PDA to form PDA NPs with their core-shell structure (Yan et al., 2019). In addition to oxidative self-polymerization in conventional the alkaline environments, the self-polymerization of DA on the surface of certain core materials that are sensitive to alkaline environments can be accomplished primarily under pH neutral or physiological conditions employing photochemical synthesis, enzymatic catalysis synthesis, etc. (Li et al., 2018; Pozy et al., 2023).

Hollow PDA NPs are usually first constructed with a core-shell structure and then obtained by removing/not removing the core template. The core template includes colloidal particles (Zhou et al., 2021; Gong et al., 2022), droplets (Cui et al., 2010), bubbles (Wu, Sun, et al., 2021), etc. However, PDA capsules tend to collapse after drying due to their lower mechanical strength. Thus, Zhang et al. have sequentially synthesized an inorganic shell layer with titanium dioxide or silicon dioxide and a PDA shell layer outside the CaCO₃ core to improve the capsules’ mechanical stability through biomimetic mineralization and biological adhesion. They further successfully etched CaCO₃ with ethylenediamine tetraacetic acid (EDTA) to obtain inorganic/organic hybrid microcapsules (Zhang et al., 2011a). Notably, during the process of DA polymerization, hollow mesoporous PDA NPs could be obtained by further adding templates pluronic F127 and TMB, and then etching the templates of the core. Similarly, PDA NPs with doped structures could be potentially obtained by adding various ions, compounds or biomolecules in the process of DA polymerization (Zheng, Wu, et al., 2021; Li, Xiong, et al., 2022; Lv et al., 2022). Table 1 summarizes various structures of PDA NPs.

Table 1. Comparison of various structure of PDA NPs.

Structure	Synthetic methods	Materials	Reaction condition	References
Solid	Solution oxidation	Au@PDANPs/TCZ	Ammonia, ethanol	(Wei et al., 2021)
Solid	Solution oxidation	PDA NPs	pH 5.0	(Kong et al., 2016)
Solid	Enzymatic polymerization	PDA NPs	Urease, urea	(Li et al., 2015)
Solid	Solution oxidation	Ultra-small PDA NPs	NaOH	(Han et al., 2023)
Solid doping	Solution oxidation	HSD-Cu-DA	Ammonia	(Xiong et al., 2022)
Solid doping	Solution oxidation	AS-IV@PDA-HA	Ammonia, ethanol	(Xu et al., 2023)
Solid doping	Solution oxidation	iRGD-apoA-I-PDA/DOX	Tris-HCl buffer (10 mM, pH 8.5)	(Lv et al., 2022)
Solid doping	Solution oxidation	Fe3O4–PDA	Tris-HCl buffer (pH 8.5)	(Liu et al., 2016)
Solid/Coating	Photochemical polymerization/UV irradiation		UV: 254 nm, Tris buffer (pH 6.4 ∼ 7.0)	(Du et al., 2014)
Wave drum shaped (core)	Solution oxidation	PDA@hm	Ammonia, ethanol	(Shao et al., 2020)
Coating	Electropolymerization/Cyclic voltammetry	MIPDA/peptide /GNPs/GCE	−0.5 V∼ 0.5 V, Scanning speed: 20 mV/s, 8 cycles	(Tan et al., 2021)
Coating	Enzymatic polymerization		Laccase, sodium acetate buffer (0.05 M, pH 5.5)	(Li et al., 2018)
Core-shell (core)	Solution oxidation	PDA@UCNP-PEG/Ce6	Ammonia, ethanol	(Yan et al., 2019)
Core-shell (core)	Solution oxidation	C-LPNs	NaOH (pH 9.6)	(Yang et al., 2020)
Core-shell (shell)	Solution oxidation	Ag-pMSNs@Dex	Tris-HCl buffer (50 mM, pH 8.5)	(Wu et al., 2023)
Core-shell (shell)	Solution oxidation	CuS@PDA/Pd	Tris-HCl buffer (10 mM, pH 8.0), ethanol	(Zhao et al., 2022)
Core-shell (shell)	Solution oxidation	JQ-1@PSNs-R	Tris buffer (20 mM)	(Xue et al., 2022)
Core-shell (shell)/Janus(壳)	Solution oxidation	Janus tBT@PDA-CPT NPs	Ammonia, isopropanol	(Meng et al., 2023)
Core-shell (shell)	Photochemical polymerization	PDA–LtEc	Acr-Mes, PBS buffer (pH 7.4), 12 V, light	(Pozy et al., 2023)
Core-shell (shell)	Solution oxidation	LM@PDA	Tris buffer (pH 8.5)	(Xu et al., 2021)
Core-shell(Fe2+- doped shell)	Solution oxidation	Magnetic nanoenzyme(MNE)	Tris-HCl buffer (10 mM, pH 7.9)	(Li, Xiong, et al., 2022)
Mesoporous	Solution oxidation/Templating(F127)	MPD@DMV	Ammonia, ethanol	(Chen et al., 2023)
Mesoporous /Janus	Solution oxidation/Templating(F127)	MSN&mPDA	Tris buffer, ethanol	(Zhao et al., 2023)
Hollow	Solution oxidation/Templating(DMDES)	Drug loaded PDA capsules(Fe3O4/QDs/thiocoraline)	Tris buffer (10 mM, pH 8.5)	(Cui et al., 2010)
Hollow	Solution oxidation/Templating(Bubbles)	Oxygen loaded PDA microcapsules	Tris buffer (pH 8.5)	(Wu, Sun, et al., 2021)
Hollow	Sonochemistry/ Templating(Rapeseed oil or n-dodecane)	PDA capsules	Tris buffer (pH 8.5)	(Yeroslavsky et al., 2013)
Hollow	Solution oxidation/Templating(Alkane)	PDA capsules	NaOH (0.02 M, pH 8.2)	(Xu et al., 2011)
Hollow	Solution oxidation/Templating(CaCO3)	α-Amylase, β-Amylase and glucosidase loaded PDA microcapsules	Tris-HCl buffer (0.1 M, pH 8.5)	(Zhang et al., 2011b)
Hollow	Solution oxidation/Templating(ZIF-8)	AVPt@HP@M	Methanol	(Gong et al., 2022)
Egg yolk shell	Solution oxidation/Templating(BDT)	PDA capsules	Tris-HCl buffer (10 mM, pH 8.5)	(Zhou et al., 2021)
Egg yolk shell	Solution oxidation/Templating(PBDT-TA)	PDA capsules	Bicine buffer (10 mM, pH 8.5)	(Yim et al., 2022)
Hybrid hollow	Solution oxidation/Templating(CaCO3/TiO2 or SiO2)	PTi-PDA/PSi-PDA	Tris-HCl buffer (0.1 M, pH 8.5)	(Zhang et al., 2011a)
Doped hollow	Solution oxidation /Gas diffusion	PEGCaNMCUR+CDDP	NH4HCO3, ethanol	(Zheng, Ding, et al., 2021)
Doped hollow	Solution oxidation/Gas diffusion	Ce6@CaCO3-PDA-PEG	NH4HCO3, ethanol	(Dong et al., 2018)
Nanobottles	Solution oxidation	PDA-PCM-R6G	Tris-HCl buffer (10 mM, pH 8.5)	(Qiu et al., 2021)

Acr-Mes: 9-intermediate acyl-10-methylacridine tetrafluoroborate; BDT: 1,4-phenyldithiol polymer; PBDT-TA: 1,4-phenyldithiol and tannic acid polymer; DMDES: dimethyldiethoxysilane; QDs: quantum dots.

3. Functional integration based on PDA

Chemical bonding processes such as Michael addition and/or Schiff are made possible by the amine and thiol groups in PDA. Moreover, PDA can effectively combine with other materials via physical bonding, such as hydrogen bonding, chelation, metal coordination, and/or π–π stacking. Regardless of the material’s chemistry, these characteristics can support to the multifunctionality of PDA-NPs, including multimodal imaging, drug loading, targeting, and surface modification for the multimodal diagnostic and therapeutic platform.

3.1. Multimodal imaging

PDA can exhibit significant optical absorption characteristics and favorable photoacoustic imaging features in the visible and near-infrared spectrum. PDA can considerably improve the photoacoustic signal when wrapped around a perfluorocarbon droplet (Vidallon et al., 2022). PDA’s abundant catechol structural units of PDA can exhibit a strong affinity for various metal ions and metal oxides. In addition, nanoprobes with magnetic resonance imaging (MRI), computed tomography (CT), positron emission computed tomography (PET), and other performance can be constructed by chelating Gd³⁺, Mn²⁺,Cu²⁺, radionuclides, and other metal oxides, for multimodal diagnosis of diseases as well as the visual evaluation of therapeutic effects (Wang et al., 2017; Liu, Zhang, Zhou, et al., 2023; Wan et al., 2023). The incorporation of nucleophilic reagents, altering the morphology, and by attaching fluorescent molecular probes or ultrasound contrast agents, and so on, can also enable PDA to obtain fluorescence imaging and/or ultrasound imaging performance (Kong et al., 2016; Gu et al., 2018; Mou et al., 2019; Shang et al., 2020). For instance, Lee et al. synthesized fluorescent PDA NPs (FPNPs) using DA hydrochloride and ethylene glycol as raw materials under weakly alkaline conditions by promoting the degradation of non-fluorescent PDA NPs. Further, they prepared Mn-FPNPs via chelating with the metal ions. Finally, MnCO₃ mineralized fluorescent PDA NPs were synthesized by adding the carbonate ions (CO₃^2-) (Lee et al., 2022). Specifically, the fluorescence signal and MRI signal of FPNP could be sequentially ‘closed’ after the metal chelation and biomineralization, whereas MnCO₃ exposed to the surface of FPNP can be ionized into Mn²⁺ and CO₃^2- under acidic conditions, which can effectively inhibit the photoinduced electron transfer caused by catechol-metal coordination, thereby leading to the ‘opening’ of MRI signals and fluorescence signals (Figure 2). Several prior investigations have also shown that when carrying the fluorescent molecules, PDA has a substantial fluorescence quenching ability, which may be associated with the possibility that quinone residues on the surface of PDA could capture the majority of the excited electrons in fluorescent dyes when exposed to laser irradiation (Qiang et al., 2014). The suppressing fluorescence quenching effect is achieved when introducing a new coating (such as SiO₂) to increase the distance between the fluorophore and the PDA surface (Cho et al., 2017). And as the coating thickness increases, a higher fluorescence signal can be detected. Moreover, the influence of the distance between PDA and the fluorescent group on fluorescence quenching can facilitate the possible use of PDA as a molecular switch for fluorescence imaging (Mao et al., 2020). In another elegant study, Xie et al. used π–π stacking to graft coumarin 7 onto the surface of PDA in another exquisite investigation. No fluorescence signal of coumarin 7 has been identified in the fluorescence spectrum detection and laser confocal imaging because of PDA’s high fluorescence quenching capabilities (Xie et al., 2020). The fluorescence signal of coumarin 7 can be seen in the mixed solution of nanomaterials and bacteria after co-incubation for 3 hours. Additional studies into the state transition mechanism in the fluorescence imaging demonstrated that the organic acids produced by the resistant Klebsiella pneumoniae fermentation could contribute to a weak acid environment (Zeng et al., 2000). Since the pH value was much lower than the protonation constant of coumarin 7, it can increase the positive charge and hydrophilicity of coumarin 7 by promoting the protonation of coumarin 7. The enhanced hydrophilicity lead to further weakens of the π-π stacking interaction between coumarin 7 and the PDA surface, thus enabling coumarin 7 to detach from the PDA surface, which can lead to the recovery of fluorescence signals. A dual modal probe for near-infrared region II fluorescence imaging and photoacoustic imaging may be produced directly designed through PDA wrapped down the conversion materials and altering the distance (Ma, Huang, et al., 2020). In conclusion, PDA-based contrast agents can be employed to direct further treatment as both a single and multimodal imaging contrast agents.

Figure 2. (A) A brief overview of the synthetic methods and working principle of MnCO₃-FPNPs for activatable FL/MR dual-modality imaging. (B) Postulated mechanism of MnCO₃-FPNPs for FL/MR imaging-guided PTT of tumors after increased accumulation due to the enhanced permeability and retention (EPR) effect (Lee et al., 2022). Copyright 2022, Ivyspring International Publisher.

3.2. Therapeutic drug loading

The therapeutic drug can be loaded on the outer surface, pores, hollow structures, or in the form of doping of PDA, when employed as a drug carrier, and the structure can then be related to drug loading effectiveness (Xue et al., 2022). Due to the presence of pores, mesoporous materials have a significantly larger specific surface area, enhancing the presence of pores, resulting in an increase in the binding sites that contribute to achieving higher drug loading rates (Zhu et al., 2021). The rich functional groups present on the surface of PDA can enable such as small molecule drugs, proteins, and nucleic acids to be connected to the surface of PDA through non-covalent interactions bonds such as hydrogen bonds, π–π stacking (Deng et al., 2022; Zhuang et al., 2022), or coupled to the catechol functional groups of PDA through Michael addition or Schiff base reaction. Chen et al., for instance, coated plasma black gold nanoparticles with a mesoporous PDA coating. They subsequently loaded the deoxyribonuclease I (DNase I) into the pores of the mesoporous PDA to synthesize AuPB@mPDA-DNase I (AMD). Furthermore, when exposed to the near-infrared light in the second region, AMD can release DNase I in the PDA pore, which can then reduce the capture and shielding of the extracellular trap (NET) to the circulating tumor cells by effectively destroying NET, enhancing the therapeutic effect of tumor immunotherapy and inhibiting metastasis (Figure 3) (Chen, Hou, et al., 2022).

Figure 3. Synthesis and schematic illustration of the AuPB@mPDA-DNase I (AMD) for cancer treatment. (A) Schematic illustration for the synthesis and NIR-II-responsive drug delivery of AMD. (B) Illustration for the process of colorectal cancer liver metastasis. Schematic illustration of AMD-mediated neutrophil extracellular trap (NET) degradation for (C) enhancing anticancer efficacy of immunotherapy and (D) preventing liver metastasis. Reprinted with permission from Chen, Hou, et al., 2022. Copyright 2022 American Chemical Society.

Additionally, by cross-linking PDA nanoparticles produced by the self-polymerization at the oxygen/water interface with glutaraldehyde, Wu et al. constructed oxygen loaded PDA microcapsules (Wu, Sun, et al., 2021). Oxygen-carrying PDA microcapsules demonstrated good dispersibility and were stable in an aqueous solution for at least a week. In addition, the outcomes of numerous in vitro and in vivo studies have demonstrated the potential of oxygen-carrying PDA micro-capsules as superior oxygen delivery vehicles that can significantly raise the oxygen concentration in a solution, and have significant application value in reducing the hypoxic microenvironment of the tumors. Yeo et al. used mesoporous silica as a template, and sequentially loaded siRNA and PDA, and then removed the mesoporous silica core. Finally, hollow PDA nano-capsules loaded with siRNA were prepared (Kim et al., 2021). The gel electrophoresis of the nano-capsules after encapsulation did not show any siRNA bands, thus suggesting that the PDA shell can achieve stable siRNA encapsulation of siRNA. However, because of its abundance of functional groups, the PDA shell can be constructed as a molecularly imprinted polymer specific binding target protein for selectively detecting proteins in samples (Zhai et al., 2018; Chen et al., 2019).

Apart from the drug delivery mediated by shell, mesoporous, and hollow structures, PDA can also be used as the core and then generate functional coatings with substantial therapeutic effects on its surface, attaining efficiency similar to the combination of photothermal therapy and other therapeutic methods (Yu et al., 2022). For example, using PDA as a photosensitizer and bacterial membrane vesicles as immune adjuvants coated on the outer surface to construct a cancer vaccine with photothermal/immune effects can lead to promising anti-tumor results (Chen et al., 2023). Additionally, PDA NPs can be utilized as a bridge to link bacteria with antigens and antibodies to construct the bacteria modified with triple immune activators, resulting in developing a unique immunotherapy approach (Li, Xia, et al., 2022; Liu, Zhang, Wang, et al., 2023).

3.3. Targeting delivery

Sulfhydryl or amino group-terminated molecules can be coupled with catechol or amino groups on the surface of PDA through a Michael addition or a Schiff base reaction to change how PDA functions. For instance, Han et al. used PLGA as the core material to load baicalin and human melanoma antigen peptide fragments (Hgp (100) 25-33). They ultimately obtained nanocomposites with M2-type macrophage targeting by coupling the immune stimulator CpG fragment and M2-type macrophage targeting peptides, M2pep and α-Pep. The acidic environment of lysosomes in M2 type macrophages can effectively trigger the degradation of the nanocomposite PDA coatings, thereby releasing drugs to reshape the tumor microenvironment and enhance the immune response to tumor treatment (Han et al., 2021). In addition to directly targeting mediated drug delivery, PDA can also lock natural cells such as red blood cells, platelets, neutrophils, macrophages, or bacteria as the transit vehicles for drug delivery through its own adhesion ability or target molecule modification, and thereby achieve indirect drug delivery through the directional movement of natural cells present in the body (Wang et al., 2021). The modification of PDA nanoparticles by specific target molecules to deliver the drugs has been associated with several problems, such as complex preparation processes, high cost, and poor targeting efficiency. The development of biomimetic technology for the cell membranes provides a more convenient and effective novel option for the targeted modification of PDA nanomaterials (Gong et al., 2022).

For certain cells rich in dopamine receptors, an earlier investigation found that the uptake of PDA-modified nanomaterials in the cells was predominantly mediated by the various surface receptors, particularly D2 dopamine receptors (D2DR) (Figure 4) (Liu et al., 2021). The uptake of PDA-based NPs was reduced by ∼30 and ∼20%, respectively, following gene downregulating that reduced the expression of D2DR in Neuro-2a and SH-SY5Y cells. However, it was observed that in both Neuro-2a and HEK 293 cells overexpressed with D2DR, the uptake of PDA-based NPs increased by ∼30% and ∼38% compared to wild-type cells, respectively. Further investigation revealed that among three kinds of NPs (Au₂₅@PEG₁₀₀₀-DA NPs, Au₂₅@PEG₁₀₀₀-NE NPs and Au₂₅@PEG₁₀₀₀-DOPA NPs) containing the catechol group, the binding of NPs to D2DR containing pores was 3 ∼ 5 times more than that of the pores without D2DR. In contrast, other NPs without the catechol group could hardly bind to D2DR, thus indicating that the catechol groups can effectively mediate the specific binding of NPs to D2DR. Overall, it was found that Au₂₅@PEG₁₀₀₀-DOPA NPs (containing both amine and catechol groups) were observed to be the most prevalent in binding to D2DR pores, followed by Au₂₅@PEG₁₀₀₀-DA NPs and Au₂₅@PEG₁₀₀₀-NE NPs (containing only catechol groups) indicating that both amine and catechol groups could cooperatively promote NP binding of to D2DR. In addition, aside from receptor mediated endocytosis, Xie et al. labeled borophene nanosheets containing a PDA coating with Cy5 (Cy5-B@PDA) to examine its intracellular uptake. According to the findings, the intracellular fluorescence intensity in pH 6.5 and 7.4 pH 7.4 settings was comparable following treatment with Cy5-B@PDA for 15 minutes. After continued incubation for 3 hours, the fluorescence intensity of the pH 6.5 group was found to be significantly higher than that of the pH 7.4 group, thereby suggesting that PDA can promote the endocytosis of nanomaterials by cells in acidic tumor environments (Xie et al., 2022). Additionally, it has been demonstrated that PDA is unstable in acidic conditions, which can help achieve active medication release through pH response and substantially minimize the toxic side effects on healthy tissues and organs (Chen et al., 2021). It was also found that by modifying PDA with enzymes with internal environmental responsiveness, micro nanomotors can be constructed to enhance drug penetration into target tissues (Choi et al., 2022).

Figure 4. A schematic illustration of the role of dopamine receptors in mediating the cellular uptake of PDA-based nanomedicines. Reprinted with permission from Liu et al., 2021. Copyright 2021 American Chemical Society.

3.4. Surface modification

PDA has great biocompatibility as a melanin mimic. Interestingly, PDA NPs at a 100 μg/mL concentration exhibited no discernible cytotoxicity on H293T cells (Ma et al., 2022). In addition, the large amount of catechol and amino acids in PDA can enable it to adhere to almost all types of inorganic or organic matrix materials. Consequently, in order to avoid the systemic toxicity caused by some functional materials with biological toxins entering the body, PDA is frequently used to modify the surface of the materials to considerably improve their biocompatibility (Mengdi et al., 2022). For example, Wu et al. examined the biocompatibility of zeolitic imidazolate frameworks (ZIFs) after surface modification with PDA. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay showed that unmodified ZIF-8 had high toxicity, whereas PDA@ZIF-8 has good biocompatibility. Next, in vivo, the acute toxicity of ZIF-8 and PDA@ZIF-8 was also analyzed. It was discovered that mice injected intravenously with a dose of ZIF-8 exceeding 15 mg/kg died immediately, with a 60% survival rate. After dissection, hematoxylin and eosin (H&E) staining of the main organs exhibited significant liver damage, thus confirming that ZIF-8 exhibited substantially high toxicity in vivo. However, after 75 mg/kg of PDA@ZIF-8 was administered, the survival rate increased to 80%, and H&E staining revealed no major organ damage. This shows that PDA modification could significantly improve the biocompatibility of ZIF-8 (Wu et al., 2018).

Moreover, except for ZIF, PDA was wrapped on the surfaces of biomaterials such as polymers, metals, and ceramics. The findings indicated that PDA coating considerably reduced the water contact angles of various samples compared to the uncoated group. The reduction in water contact angle suggested that PDA coating could be an easy technique for enhancing the hydrophilic properties of the different implant surfaces. It has been established that hydrophilic surface could facilitate the optimal adsorption of extracellular matrix (ECM) proteins and exert important effects on cell adhesion, proliferation, and differentiation (Wang et al., 2019).

4. Application of PDA-based biomaterials in ADs

4.1. Rheumatoid arthritis

A persistent autoimmune condition known as rheumatoid (RA) causes bone loss and joint synovitis. It may also severely damage several bodily organs, such as the skin, eyes, lungs, and heart. It has been found that owing to the current problems of poor compliance and toxic side effects in patients receiving RA medication, it is extremely important to develop novel, safe, and effective new methods to significantly improve RA prognosis significantly. In an innovative study, Zhang et al. loaded methotrexate and PDA/manganese dioxide NPs and methotrexate into microneedles (PDA@MnO₂), which were then administered through the skin to achieve sustained drug release at the disease site, avoiding the first pass effects, and reducing the toxic and side effects on the digestive tract (Wu, Cheng, et al., 2021). Additionally, in vitro and in vivo studies have shown that the combination of PDA@MnO₂ mediated antioxidant therapy and methotrexate (MTX) mediated chemotherapy can effectively remove ROS, and inhibit inflammation, thus achieving effective control of RA.

Additionally, Pan et al. developed a metal-organic framework (MOF) loaded with PDA and perovskite quantum dots (QDs) as a nano hydrogen (H₂) generator (Pt-MOF@Au@QDs/PDA) to effectively limit the proliferation of fibroblasts like synovial cells and localized oxidative stress in RA joints. They used PDA, which exhibited excellent photothermal conversion efficiency for the photothermal therapy (PTT) of RA, and perovskite QDs with unique photophysical properties for facilitating the localization of Pt-MOF@Au@QDs/PDA NPs. In addition, by combining Au’s surface plasmon resonance excitation with Pt-MOF Schottky junctions, Pt-MOF@Au@QDs/PDA could display high photocatalytic H₂ generation under visible light irradiation. This work used PDA-mediated PTT was used to alleviate oxidative stress and inhibit synovial cell proliferation while bio-reducing H₂ can further enhance its antioxidant effect. The combination of hydrogen and thermal therapy exhibited excellent antioxidant stress and anti-inflammatory effects in collagen-induced RA model mice (Figure 5) (Pan et al., 2022). The significantly elevated cell-free DNA (cfDNA) in RA patients’ synovial fluid and peripheral blood has been closely related to autoimmune reactions and disease progression (Rykova et al., 2017), and can serve as a potential target for RA treatment. The surface of PDA NPs could be positively charged through dimethylamino modification or polyethylene imide coating, which can then couple with negatively charged cfDNA in the body to effectively inhibit inflammation induced by cfDNA, thus providing a new method based on cfDNA clearance both for the prevention and treatment of RA (Shen et al., 2023).

Figure 5. A schematic illustration of the synthesis route and the hydrogen-photothermal treatment therapeutic mechanism based on the Pt-MOF@Au@QDs/PDA; (I) optimal design and synthesis procedures of Pt-MOF@Au@QDs/PDA nanoregulator; (II) the enhanced permeation and retention effect can enable the Pt-MOF@Au@QDs/PDA nanoregulator to achieve distinctive targeting to the synovium region, and photocatalytic H₂ generation for selectively reducing the cytotoxic ROS and the PTT for effective RA therapy (Pan et al., 2022). Copyright 2022, Elsevier Ltd.

4.2. Inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic and refractory disease that can even lead to colon cancer in severe cases. The fundamental cause of tissue damage is the abnormal expression of inflammatory cytokines and the increased accumulation of ROS caused by abnormal intestinal immune response. Therefore, immune regulation and ROS clearance are crucial factors for treating intestinal inflammation. Nanocomposites (PCM) obtained by coupling PDA NPs with antimicrobial peptide mCRAMP and further encapsulating them with the macrophage membranes have been found to target inflammatory tissue effectively, downregulate the expression of pro-inflammatory cytokines, and promote the secretion of anti-inflammatory cytokines. The concentration of probiotics might increase, and the growth of pathogenic bacteria growth may be inhibited after oral administration of nano drugs, according to 16S rRNA sequencing of the fecal microorganisms. This suggests that the designed nano platform can play an important role in optimizing the intestinal microbiota (Figure 6) (Bao et al., 2023). Moreover, a study by Liu et al. reported that using PDA NPs alone can significantly inhibit the overactive immune response in IBD by upregulating the ratio of Treg/Th17. When PDA coating was combined with probiotics, it could not only inhibit overactivated immune responses, but also effectively modulate the microbiota of the inflamed gut (Li, Hou, et al., 2022). Based on immunological and intestinal microbial regulation, the findings mentioned above offer a novel approach to treating IBD. Additionally, PDA NPs loaded with interfering RNA (siRNA) can provide efficient antioxidant and gene interference ­therapy for IBD through promoting ROS clearance, downregulating the expression of pro-inflammatory cytokines, and increasing the production of the pro-inflammatory cytokines (Wang et al., 2022). When PDA was integrated with catalase and serum albumin, it could further modify the macrophage target molecules, and the obtained nanocomposites can achieve effective antioxidant therapy for IBD by clearing the broad-spectrum ROS from inflammatory sites (Li et al., 2021). Overall, it was found that in comparison to using only clinical conventional anti-inflammatory medicines, the delivery system using PDA as a carrier has higher biosafety, anti-inflammatory, and anti-angiogenic properties and can successfully treat IBD (Yan et al., 2022; Meng et al., 2023).

Figure 6. (A) The prepared PDA NPs were coupled with antimicrobial peptide mCRAMP to form PDA@mCRAMP NPs (PC NPs), and then extruded with extracted macrophage membrane to form PDA@mCRAMP@MM NPs (PCM NPs). (B) Oral administration of PCM NPs for the treatment of colitis in mice. PCM NPs can accumulate in inflamed colonic mucosa and then modulate intestinal inflammation by inhibiting the secretion of pro-inflammatory factors and elevating the expression of anti-inflammatory cytokines, whereas reducing RONS production to mitigate oxidative damage and optimizing the composition of the intestinal flora by markedly increasing the abundance of probiotic bacteria and inhibiting the various harmful bacterial communities (Bao et al., 2023). Copyright 2023, Elsevier Ltd.

4.3. Other ADs

Type 1 diabetes is a genetic condition that mainly affects the pancreas. Nguyen et al. successfully prepared PDA-coated and tacrolimus (FK506) loaded microspheres (PD-FK506-MS). Then the stable cell-particle complexes were constructed and synthesized via PDA-mediated adhesion between PD-FK506-MS and pancreatic islet cells. The cell-particle hybrids can markedly prolong the survival time of heterologous islet grafts by continuously releasing extremely low amounts of FK506, a novel approach to the local immunomodulation therapy of type I diabetes (Nguyen et al., 2019). Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system disease with no known etiology and no effective treatment. The primary pathogenic alteration occurs when activated immune cells cross the blood-brain barrier, resulting in localized demyelinating lesions. In order to reprogram an abnormally activated immune microenvironment into an immunosuppressive environment rich in Treg cells, Park et al. constructed a tolerant nano-vaccine (AbaLDPN-MOG) by using PDA NPs (PN) as the core, a lipid layer loaded with dexamethasone as the membrane, and further modified with abatacept and myelin oligodendrocyte glycoprotein (MOG) peptide on the surface. AbaLDPN-MOG can block the interaction between CD80/CD86 and CD28 in antigen-presenting cells and T cells, and inhibit T cell activation. In addition, the co-administration of abatacept with autoantigens can increase specific antigen presentation by dendritic cells (DC), stimulate the proliferation of autoantigen specific Treg cells, and remodel of the immune microenvironment (Figure 7) (Park et al., 2023). In MS model mice, subcutaneous administration of AbaLDPN-MOG has achieved its distribution in lymph nodes, increased the integrity of the myelin basic sheath, and reduced the infiltration of immune cells. In Table 2 are summarizes PDA NP’s application in ADs.

Figure 7. (A) Illustration of AbaLDPN-MOG tolerogenic nanovaccine composition. (B) The proposed working mechanism of antigen-specific tolerance induction in lymph nodes. (C) Reprogramming of immune microenvironments in the central nervous system. (Park et al., 2023). Copyright 2023, John Wiley & Sons, Inc.

Table 2. Examples for PDA NPs application in ADs.

ADs application	Materials	Functional components	Theranostic	Mechanism	References
RA	PDA/MTX@TSG	Methotrexate (MTX), thermosensitive lipid gel	Anti-inflammatory/Antioxidant	Hypoxia ameliorating, ROS scavenging, M1-M2 macrophage polarization	Tao et al., (2023)
RA	MTX-mSiO2@PDA	MTX	Anti-inflammatory	pH responsive drug release	Guo et al., (2021)
RA	PEI-PDA@C-176 NPs	C-176	Anti-inflammatory	Cell free double stranded DNA (dsDNA) clearance, inhibiting the (stimulator of interferon genes) STING pathway	Shen et al., (2023)
RA	Dimethylamino modified PDA NPs	Dimethylamino groups	Anti-inflammatory	cfDNA clearance	(Chen, Wang, et al., 2022)
RA	Pt-MOF@Au@QDs/PDA	Pt-MOF, Au, Perovskite QDs	Phototherapy/Antioxidant/ Fluorescence imaging	Ablation of proliferative synovial cells and photocatalytic generation of H2 for antioxidant stress	Pan et al., (2022)
RA	PDA@MnO2	MnO2	Antioxidant	ROS eliminating	Wu, Cheng, et al., (2021)
RA	Au@PDANPs/TCZ	Tocilizumab (TCZ)	Anti-inflammatory/Antioxidant	OFR eliminating, downregulating IL-6	Wei et al. 2021)
RA	CeO2-ZIF-8@PDA	CeO2	Phototherapy/ Antioxidant	Ameliorating hypoxia, scavenging ROS, ablation of proliferative inflammatory cells	Chen, Lu, et al., (2022)
IBD	EcN@PDNI	Escherichia coli Nissle1917(EcN)	Immune regulation/Microbiota regulation	Suppressing overactive immune response, regulating gut microbiota	Li, Hou, et al., (2022)
IBD	Thali@PDA	Thalidomide	Anti-inflammation/Anti-angiogenesis	Macrophage polarization, normalizing blood vessels	Meng et al., (2023)
IBD	CAT-BSA@PDA@PAH@DS MP	Catalase, dextran sulfate	Anti-inflammatory/Antioxidant	Targeting macrophages, scavenging ROS	Li et al., (2021)
IBD	LS@PDA	Loxoprofen sodium	Anti-inflammatory/Antioxidant	Reducing the production of pro-inflammatory cytokines and alleviating oxidative stress	Yan et al., (2022)
IBD	PCM	Antimicrobial peptide (mCRAMP), macrophage membrane	Anti-inflammatory/Antioxidant	Inflammation targeting, ROS clearance, immune regulation, and optimization of intestinal microflora	Bao et al., (2023)
IBD	PAA@MPDA-SAP NPs	Polyacrylic acid (PAA), sulfasalazine (SAP)	Anti-inflammatory/Antioxidant	pH responsive drug release, ROS eliminating	Guan et al., (2023)
IBD	MPDA-siRNA@CaP	Calcium phosphate, siRNA	Antioxidant/Gene interference	pH responsive drug release, ROS scavenging, TNF-α knocking down	Wang et al., (2022)
MS	AbaLDPN-MOG	Dexamethasone, myelin oligodendrocyte glycoprotein(MOG) peptide, abatacept	immunotherapy	Immune microenvironment reprogramming	Park et al., (2023)
MS	Ibudilast loded PDAM	Ibudilast	Anti-inflammation/Neuroprotection	Downregulating TNF-α, stimulate myelin sheath regeneration	Sharifian et al., (2023)
SLE	Functionalized AuNP-PDA	dansylamino phenylboronic acid, hairpin DNA molecular beacon (MB), montanic acid, CD63 aptamer	Clinical testing	Specific binding to extracellular vesicles	Zhou et al., (2022)
Lupus nephritis	Nec-1/PDA@Pt-Fe3O4	Nectostatin-1 (Nec-1), Pt NPs, Fe3O4	Anti-inflammation/antioxidant/photoacoustic imaging/magnetic resonance imaging	Inhibition of protein 1 kinase, ameliorating hypoxia, reducing neutrophil extracellular traps	Li, Wang, et al., (2022)
Psoriasis	PDA/IR820	IR820	Photothermal and photodynamic therapy	Inhibiting the proliferation of keratinocytes and downregulating the expression of pro-inflammatory cytokines	Nirmal et al., (2022)
Type I diabetes	PD-FK506-MS	Tacrolimus(FK506)	Immunotherapy	Immunosuppression	Nguyen et al., (2019)

5. The mechanism of PDA in ADs

5.1. Antioxidant and anti-inflammatory effects

Different metabolic alterations, including the development of oxidative stress and inflammation, are commonly observed in ADs. The efficient removal of ROS in vivo and in vitro could be primarily responsible for PDA’s anti-inflammatory and antioxidant properties (Bao et al., 2018; Lou et al., 2021; Wu, Cheng, et al., 2021). Specifically, PDA can donate electrons to the various oxidants to an exhibit antioxidant effect of quenching oxidative free radicals (Liu et al., 2019). PDA NPs were observed to significantly limit the production of oxygen free radicals, up to 80%, by about 40% when coupled with gold nanoparticles. For hydroxyl radicals, using PDA NPs alone resulted in achieved an inhibitory effect of up to 80%. According to the studies above, PDA can exert substantial antioxidant effects by inhibiting the formation of oxygen and hydroxyl radicals, especially hydroxyl radicals (Wei et al., 2021). PDA can also be used with other antioxidants agents to cause broad-spectrum scavenging of ROS, such as hydrogen peroxide, hydroxyl radicals, and superoxide anions (Li et al., 2021). Interestingly, signaling pathway studies have demonstrated that PDA NPs can ameliorate LPS-induced inflammation by regulating the TLR4/NF-κB signaling pathway (Zhu et al., 2023). Moreover, upon detection of the various inflammatory factors in bone marrow derived dendritic cells (BMDCs) treated with PDA NPs, it was observed that the level of IL-10 increased, but that of IL-1β, IL-6, and TNF-α reduced markedly, thus confirming their potent good anti-inflammatory ability in vitro. Additional studies on PDA degradation products revealed that it is capable of inhibiting the expression of pro-inflammatory cytokines in macrophages induced by LPS via downregulating TLR-4-MYD88-NFκB pathway, as well as playing an antioxidant role in cells by eliminating ROS in cells and upregulating the expression of heme oxygenase 1 (HO-1), thereby ultimately regulating inflammatory activation of macrophages (Jin et al., 2019).

5.2. Promotion of bone repair

Bone is a dynamic mineralized tissue that maintains homeostatic balance and structural integrity through continuous remodeling. Mild bone damage caused by transient external forces often has a unique self-healing potential, whereas sustained and large-scale bone damage caused by ADs is difficult to self-heal. For instance, Han et al. prepared a hydrogel of PDA, chondroitin sulfate and polyacrylamide (PDA-CS-PAM) and investigated its potential effect on cartilage repair. In vitro, investigations revealed that when compared to CS-PAM hydrogel, the tissue adhesion of PDA-CS-PAM hydrogel considerably improved tissue adhesion and elevated the expression level of various chondrocyte indicators (proteoglycan and collagen II). In addition, H&E staining results revealed that new cartilage tissue could be observed in the CS-PAM hydrogel group. However, the defect was not filled, and the fibrous tissue still existed in the new tissue. Interestingly, the defects were well filled with cartilage-rich regenerated tissue the PDA-CS-PAM hydrogel group, and the chondrocytes were placed in a way that matched the surrounding natural cartilage. Moreover, in vitro and in vivo results indicated that PDA-mediated cell adhesion has a positive effect on cartilage tissue regeneration, and it could combine with CS-PAM to achieve synergistic effects for facilitating cartilage repair without growth factors (Figure 8) (Han et al., 2018). Specifically, PDA coating could promote the adhesion, proliferation, and osteogenic differentiation of the bone marrow mesenchymal stem cells (BMSCs) through modulating the FAK signal pathway, p38 signal pathway, calcium signal pathway, Wnt signal pathway, and TGF-β signaling pathways (Wang et al., 2019; Sun et al., 2023).

Figure 8. (a) Pictorial representation of the cartilage defect created on the rabbit knee joint. (b) Gross appearance of the reconstructed cartilage after 3 months. (c) ICRS scoring of the gross appearance of the regenerated cartilage. H&E staining of (d) blank group, (e) PAM hydrogel, (f) CS–PAM hydrogel, and (g) PDA–CS–PAM hydrogel. The blank box showed the magnified view of the defect areas, and red arrows indicated the newly regenerated tissue. (h) Modified o’Driscoll scoring of the histological analysis of the regenerated cartilage. Reprinted with permission from Han et al., 2018. Copyright 2018 American Chemical Society.

In addition, the abundant functional groups (catechins, amines, and imines) in the PDA coating can provide sufficient active sites for biomimetic mineralization and the obtained rough surface was better than the smooth surface for cell adhesion, diffusion, proliferation, migration, and osteogenic differentiation than the smooth surface (Wu, Zhang, Wu, et al., 2022; Ma, Han, et al., 2023). It is worth highlighting that the immune system accurately controls the dynamic balance of differentiation between osteoblasts and osteoclasts in vivo. In another elegant study, Liu et al. treated macrophages with non-PDA-coated and PDA-coated biomaterials, and then collected the treated culture medium as the conditional medium for MC3T3-E1 cells. The expression of Runx5, Bmp1, ALP, and Smads genes in MC3T3-E1 cells of the conditioned culture group with PDA coating was found to be significantly upregulated, indicating that PDA may promote osteogenic differentiation by influencing the immune microenvironment (Xue et al., 2022). However, the pro-inflammatory phenotype M1 macrophages can produce a large number of proinflammatory cytokines, such as TNF-α, IL-6, etc., which can induce osteoclast differentiation and thus lead to bone resorption. The anti-inflammatory phenotype M2 macrophages can also release BMP-2, VEGF, and TGF-β to promote the recruitment of BMSCs, osteogenic differentiation, angiogenesis, as well as matrix deposition, and thus can increase the production of anti-inflammatory cytokines, such as IL-4 and IL-10 to promote inflammatory regression and cause inhibition of osteoclast differentiation (Zhou et al., 2019; Chai et al., 2022; Li, Yang, 2022). Mild thermotherapy has recently been revealed to promote osteogenic differentiation by boosting the expression of certain heat shock proteins, accelerating the local blood circulation, regulating immunity. Proper photothermal conversion ability, excellent biocompatibility, and ease of preparation can render PDAs attractive bone repair agents. The PDA hydrogel prepared by Liao et al. increased to 42.6 °C in vitro and 44.1 °C in vivo after irradiation with an 808 nm laser. The alkaline phosphatase (ALP) activity of BMSCs in the PDA hydrogel + laser group was 98.72 ± 4.86 units, which was observed to be significantly higher than 43.58 ± 2.35 units in the PDA hydrogel group and 6.43 ± 0.25 units in the control group, thereby indicating that PDA mediated mild PTT enhanced osteogenesis differentiation of BMSCs. In addition, micro CT analysis showed that in comparison with the hydrogel + mild PTT group at 8 weeks, the bone volume/tissue volume ratio of the control group and hydrogel group was 37.59 and 77.21% respectively, thus confirming that PDA can effectively mediate mild PTT further promote bone repair in vivo (Wu, Zhang, Tan, et al., 2022). Transcriptomic analysis demonstrated that the activation of PI3K-Akt1 signaling pathway may also be involved in the M1 to M2 type macrophage change driven by mild PTT. The paracrine factor of M2 type macrophage induced by mild PTT can further act on BMSCs, and promote their recruitment, bone differentiation, and ECM mineralization (Li, Liu, Ye, et al., 2022). Therefore, PDA mediated mild PTT could provide a favorable immune microenvironment for osteogenesis, stimulating bone damage repair. In summary, PDA can promote bone repair via increasing cell and protein adhesion, biomineralization, and regulating the expression of the immune microenvironment.

5.3. Anti-angiogenesis

Oxidative stress in ADs can promote neovascularization, which in turn can aggravate the progression of the disease. ROS can stimulate neovascularization by increasing VEGF levels as a major mediator of angiogenesis. In contrast, ROS scavengers such as PDA are expected to delay the disease progression through activating anti-angiogenesis pathways. For instance, all the treatment groups, especially the Thali@PDA group, were found to significantly inhibit the proliferation of HUVECs induced by VEGF, when PDA NPs, Thali NCs, and Thali@PDA were incubated with HUVECs. The above findings suggested that PDA NPs have anti-angiogenic properties and show synergistic effects when combined with Thali (Meng, Z, et al., 2023). In another study, Jiang et al. treated ARPE-19 cells with hydrogen peroxide to induce oxidative stress, and then added PDA, PDA + bevacizumab, and bevacizumab, respectively. The results of ELISA assay showed that in comparison with the blank control group, the VEGF levels in the oxidative stress group, the PDA group, the PDA + bevacizumab group, and the bevacizumab group were 116.70 ± 4.41%, 87.31 ± 1.99%, and 25.31 ± 1.45%, respectively. When coupled with VEGF, the tube length observed in the PDA NPs group was significantly reduced, which further decreased, according to the endothelial cell tube formation experiment results. The tube length in the bevacizumab group was similar to that in the combination group. However, the VEGF level in the bevacizumab group was found to be the lowest, which was inconsistent with the results of tube length. The above results suggested that PDA NPs can synergistically inhibit angiogenesis through both VEGF-independent and -dependent pathways (Jiang et al., 2020). Copyright 2020, Elsevier Ltd.

5.4. Immunomodulatory effects

PDA NPs have been reported to upregulate the ratios of Treg/Th1, Treg/Th2, and Treg/Th17 in monocytes in the lamina propria of IBD mice to inhibit the overactivated immune response at the inflammatory site. Furthermore, PDA NPs can suppress the expression of CD86 and MHC II on LPS-stimulated BM-DCs, implying that they can effectively inhibit the maturation and antigen presentation of BM-DCs (Li, Hou, et al., 2022). Moreover, it was found that compared to LPS, PDA NPs could significantly increase the percentage of M2 macrophages and the ratio of M2/M1, thereby indicating that PDA can induce macrophages to polarize to an anti-inflammatory M2 phenotype (Figure 9) (Meng et al., 2023). The above studies have shown that PDA nanomaterials reduce the inflammatory level of ADs by stimulating Treg cells, inhibiting the differentiation of immature T cells into effector T helper cells, promoting the polarization of macrophages to M2 phenotype, and suppressing the activation of the dendritic cells.

Figure 9. A schematic diagram figure showing the tissue damage and angiogenesis status in IBD lesions before and after treatment with Thali@PDA. The specific therapeutic mechanisms of Thali@PDA have also been depicted (Meng et al., 2023). Copyright 2023, Elsevier Ltd.

6. Summary and future perspectives

Although numerous studies have shown how efficient this PDA-based biomaterial is at treating ADs, many challenges must be overcome before it can be used in clinical settings.

The preparation methods of PDA NPs mainly include solution oxidation, electro polymerization, photochemical polymerization and enzyme catalyzed polymerization. Thus, by controlling the synthesis conditions, PDA NPs can be prepared into solid, mesoporous, core-shell, or hollow structures, etc. The functional integration strategies for PDA NPs include: (a) PDA as a photoacoustic imaging agent can usually be combined with other contrast agents to achieve multimodal imaging for ADs diagnosis and dynamic monitoring. Future real-time comprehension of treatment mechanisms and efficacy evaluation is anticipated to be facilitated by the multimodal imaging integration strategy of PDA-based biomaterials. (b) PDA possesses good biocompatibility, controllable microstructure, and abundant surface functional groups, thereby making it an ideal carrier for drug delivery. Furthermore, when combined with other drugs, PDA may serve as a photosensitizer with good photothermal conversion performance, effectively contributing to the synthetic treatment of diseases when combined with other drugs. (c) The rich functional groups on the surface of PDA can help it to transport target molecular drugs in both covalent and non-covalent manner to achieve the precise treatment of diseases. The responsive release of drugs can also be enhanced by accelerating the breakdown in the inflammatory site’s acidic microenvironment. (d) PDA is suitable for the surface modification of other materials due to its simple preparation, good adhesion and biocompatibility. However, up to now, no PDA nanomaterials therapy has been approved for human research. To achieve the clinical transformation of PDA-based biomaterials, it is necessary to fully understand the composition, structure, surface charge, hydrodynamic diameter, solubility, stability, etc., and decipher the delivery route, distribution, metabolism, clearance, and potential toxic effects by using appropriate preclinical models.

Regarding the mechanism of PDA in the treatment of ADs: (a) The widespread presence of oxidative stress in ADs can further aggravate inflammatory reactions, and the antioxidant properties of PDA could be conducive to controlling the disease. PDA-based biomaterials can also achieve spectrum clearance of ROS when coupled with other antioxidants. Further research has revealed that the degradation products of PDA can also have substantial antioxidant properties. (b) The rich functional groups on the surface of PDA and its photothermal conversion properties can aid it in promoting osteogenic differentiation and inhibit osteoclast differentiation through biomineralization, increase protein as well as cell adhesion, and modulate the immune microenvironment, thereby facilitating the repair of bone destruction in ADs. (c) High levels of oxidative stress in ADs lesions can lead to extensive neovascularization, which can further exacerbate the progression of the disease. As a potent ROS scavenger, PDA can synergistically inhibit angiogenesis through both non-VEGF-dependent and VEGF-dependent pathways, thereby significantly delaying the disease progression. (d) PDA can improve the inflammatory level of autoimmune diseases by stimulating regulatory T (Treg) cells, inhibiting the differentiation of immature T cells into effector T helper cells, promoting the polarization of macrophages into the M2 phenotype, and suppressing the activation of dendritic cells. ADs can also cause nerve damage, but current research on nerve repair is often based on the multifunctional compounds used with different neurotrophic factors, scaffolds, etc. Little is known, however, regarding the effect of PDA alone on nerve recuperation (Zheng, Wu, et al., 2021; Li et al., 2022). However, PDA-mediated antioxidant therapy can promote neuron healing by developing a favorable microenvironment (Ma, Li, et al., 2023). In addition, PDA based PTT primarily relies on near-infrared. Still, the penetration depth of the light tissue in the near-infrared region II relatively limited, and the spatial distribution of light energy is rather uncontrollable.

In conclusion, in the last ten years, tremendous progress has been made in applying PDA-based biomaterials as an effective diagnostic and therapeutic platform has made significant progress. The future challenges of rational design and application of PDA-based biomaterials mainly depend on the coordinated efforts of multidisciplinary teams consisting of chemists, pharmacists, biologists, physicists, engineers, and doctors.

Author contributions

M.W. and C·H. analyzed data and wrote the manuscript. C.S. and D.X. investigated and collated data, as well as claimed for permission. Q.L., A.W. and T.C. conceived and supervised this review. All authors discussed and commented on the manuscript.

Disclosure statement

No conflict of interest was reported by the author(s).

Data availability statement

Data sharing is not applicable to this article as no new data were ­created or analyzed in this study.

Additional information

Funding

This work was supported by the funding from Ningbo Natural Science Foundation [2021J019, 2023J386, 2023J021], Zhejiang Medical and Health Science and Technology Plan Project [2022RC251], Ningbo Clinical Research Center for Medical Imaging [Grant No.2021L003: 2022LYKFZD01, 2022LYKEYB02, 2022LYKFYB05], National Natural Science Foundation of China [32025021, 51873225], 2021Z054 Ningbo major science and technology task project [Nos.2021Z054], Ningbo Clinical Research Center for Ophthalmology and the Project of NINGBO Leading Medical&Health Disipline [2016-S05], Ningbo Science and Technology Public Welfare Project [2022S26, 2022S133], the Strategic Priority Research Program of Chinese Academy of Sciences [Grant No. XDB36000000], Key Scientific and Technological Special Project of Ningbo City [2017C110022], Provincial and Municipal Co-construction Key Discipline for Medical Imaging [No. 2022-S02].