Nanozyme-Engineered Hydrogels for Anti-Inflammation and Skin Regeneration

doi:10.1007/s40820-024-01323-6

Abstract

Abstract:

Inflammatory skin disorders can cause chronic scarring and functional impairments, posing a significant burden on patients and the healthcare system. Conventional therapies, such as corticosteroids and nonsteroidal anti-inflammatory drugs, are limited in efficacy and associated with adverse effects. Recently, nanozyme (NZ)-based hydrogels have shown great promise in addressing these challenges. NZ-based hydrogels possess unique therapeutic abilities by combining the therapeutic benefits of redox nanomaterials with enzymatic activity and the water-retaining capacity of hydrogels. The multifaceted therapeutic effects of these hydrogels include scavenging reactive oxygen species and other inflammatory mediators modulating immune responses toward a pro-regenerative environment and enhancing regenerative potential by triggering cell migration and differentiation. This review highlights the current state of the art in NZ-engineered hydrogels (NZ@hydrogels) for anti-inflammatory and skin regeneration applications. It also discusses the underlying chemo-mechano-biological mechanisms behind their effectiveness. Additionally, the challenges and future directions in this ground, particularly their clinical translation, are addressed. The insights provided in this review can aid in the design and engineering of novel NZ-based hydrogels, offering new possibilities for targeted and personalized skin-care therapies.

Key words: Nanozymes, Hydrogels, ROS scavenging, Anti-inflammation, Skin regeneration

Amal George Kurian, Rajendra K. Singh, Varsha Sagar, Jung-Hwan Lee, Hae-Won Kim. Nanozyme-Engineered Hydrogels for Anti-Inflammation and Skin Regeneration[J]. Nano-Micro Letters, 2024, 16(1): 110-.

Amal George Kurian, Rajendra K. Singh, Varsha Sagar, Jung-Hwan Lee, Hae-Won Kim. [J]. Nano-Micro Letters, 2024, 16(1): 110-.

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URL: https://www.qk.sjtu.edu.cn/nml/EN/10.1007/s40820-024-01323-6

https://www.qk.sjtu.edu.cn/nml/EN/Y2024/V16/I1/110

Figures/Tables 12

Fig. 1 Number of NZ-related articles published in the last 5 years according to Web of science (report acquired using the keyword ‘nanozymes’), indicating the scope and importance of this rapidly emerging platform

Fig. 2 Schematic showing the chemical design of NZ@hydrogels based on intrinsic enzymatic properties

Fig. 3 Design of NZ@hydrogels with dominant enzymatic performance profiting skin regeneration. a Schematic diagram showcasing the synthesis process and the dual enzyme-mimic activity of MoS₂@TA/Fe NSs aimed at enhancing wound repair [50]. Copyright 2021, Elsevier. b Synthesis of PFOB@PLGA@Pt/GelMA/ODex nanohybrid double network hydrogels with exceptional enzymatic and antibacterial attributes for advancing wound healing process [127]. Copyright 2023, American Chemical Society. c Synthesis of MoS₂@Au@BSA NS and the preparation of an injectable hydrogel using an O₂-supplying glucose-powered cascade reaction for the reconstruction of infected diabetic skin [133]. Copyright 2022, John Wiley and Sons, Inc

Table 1 List of various NZ platforms utilized to engineer hydrogels and their key catalytic properties analyzed

Classification	Nanozyme	Analyzed catalytic property	References
Ce-based	nCe	SOD, CAT	[49]
	CeNZ	SOD, CAT	[77]
	Ce-MOF	SOD, CAT, GO_x	[67]
	CeNZ	SOD, CAT	[45]
Mn-based	MnO₂	CAT, POD	[158]
	MnCoO	CAT	[159]
	GO_x-MnO₂	POD, GO_x	[160]
	EPL-MnO₂	SOD	[41]
Fe-based	Fe@HCMS/GO_x	POD, GO_x, GSH	[114]
	Mica-Fe₃O₄	POD	[63]
	Fe₃O₄@GO	POD, SOD	[161]
	Fe-MIL-88NH₂	POD, OXD	[162]
	FePO₄	POD, SOD, CAT	[64]
	GA/Fe@AP (GAP)	CAT	[163]
	Fe₂O₃-GO_x@ZIF-8	GO_x, CAT	[164]
Mo-based	MoS₂@TA/Fe	POD, CAT	[50]
	CNT@MoS₂	POD, SOD, CAT	[83]
	MoS₂	CAT	[86]
	Ag/MoS₂	POD	[90]
	MoS₂@Au@BSA	GO_x, POD, CAT, SOD	[133]
	MoS₂	POD	[165]
	MoS₂-PDA	CAT	[166]
	MoNP	POD, SOD, CAT	[167]
MOF-based	MOF-818	SOD, CAT	[75]
	Ni₃(HITP)₂ MOF	SOD	[89]
	MOF(Fe-Cu)/GO_x	POD, GO_x	[168]
	Zr-Fc MOF	POD	[169]
Cu-based	Au/Cu_1.6O/P-C₃N₅/Arg NSs	SOD, CAT, POD, GO_x, NOS	[88]
	Cu_5.4O	SOD, CAT, GP_x	[170]
	Cu₂O/Pt	POD, GO_x,	[171]
	Cu₂MoS₄	POD	[172]
	Ni₄Cu₂	SOD, CAT	[51]
Au-based	Au-Pt	POD	[80]
Au-based	Au@ZIF-8	POD	[115]
Ag-based	PDA-AgNPs	POD	[56]
Ag-based	TA-Ag NZ	POD	[65]
W-based	WS₂/CL	CAT	[82]
PB-based	PB NZ	SOD	[42]
PB-based	PB NZ/GO_x	POD, GO_x	[44]
Pt-based	PtNZ	OXD, POD, GO_x, NO_x, SOD, CAT	[127]

Fig. 4 Schematic showing the multifunctional roles of NZ@hydrogels for skin therapy

Table 2 Summary of various functional NZ@hydrogel platforms and their specific catalytic properties analyzed for skin therapy

Function	Hydrogel	Nanozyme	Analyzed catalytic property	Application	References
Antioxidant	PVA/SA	CNT@MoS₂	POD, SOD, CAT	Infected wound healing	[83]
	Gelatin	MoNP	POD, SOD, CAT	Diabetic wound healing	[167]
	PLGA-PEG-PLGA	MOF-818	SOD, CAT, GP_x	Diabetic wound healing	[75]
Antibacterial	HG	FePO₄	POD, SOD, CAT	Infected wound healing	[64]
	GM-DC	Fe-MIL-88NH₂	POD, OXD	Infected wound healing	[162]
	Silk fibroin	Fe₃O₄	POD	Infected wound healing	[63]
Anti-inflammation	HMP	MnO₂	CAT, POD	Infected diabetic wound healing	[158]
	Hep-PEG	Cu_5.4O	SOD, CAT, GP_x	Diabetic wound healing	[170]
	PAM	MOF(Fe-Cu)/GO_x	POD, GO_x	Infected wound healing	[168]
Photothermal therapy	Carrageenan	Zr-Fc MOF	POD	Infected wound healing	[169]
	PVA/Dex	MoS₂@TA/Fe	POD, CAT	Infected wound healing	[50]
	MeHA	Fe₃O₄@GO	POD	Bacterial biofilm infection therapy	[161]
Chemo-dynamic therapy	Chitosan thermogel	CuO₂ nanodots	GSH, GP_x	Melanoma therapy and infected wound healing	[207]
	Pluronic F127	TMB/Fe²⁺/GO_x	GO_x	Infected diabetic wound healing	[209]
	ALG-HA	Cu₂O/Pt nanocubes	POD, GO_x,	Infected wound healing	[171]
	Poloxamer F127	Cu₂MoS₄	POD	Infected burn wound healing	[172]
Oxygen generation	HA-HYD	MnCoO	CAT	Diabetic wound healing	[159]
	HA encapsulated L-arginine	Au/Cu_1.6O/P-C₃N₅/Arg NSs	SOD, CAT, POD, GO_x, NOS	Diabetic wound healing	[88]
	ODex/gC	MoS₂ NSs	SOD, CAT, POD	Diabetic wound healing	[133]

Fig. 5 Diabetic wound healing accelerated by NZ@hydrogels. a An illustration showing the fabrication process of PCN-miR/Col hydrogel for hastening diabetic skin regeneration. b Photographs of diabetic wounds at different periods after the hydrogel treatment. b Quantification of wound area obtained from photographs. d Masson’s trichrome staining of skin tissues after 28 days of treatment. Scale bars, 100 μm. e Fluorescent expression of VEGF and CD31 markers. Scale bars, 50 μm. f Quantification for VEGF expression and g Quantification of several blood vessels at 28 days [45]. Copyright 2019, American Chemical Society. h Representation of the accelerated wound healing coordinated by MnCoO@PLE/HA hydrogel. i An illustration showing the fabrication process of MnCoO@PLE/HA hydrogels for diabetic wound healing. j Photographs of diabetic wounds were evaluated up to 16 days after the hydrogel treatment. k A representation of relative wound healing at different time points. l Quantification of residual wound area from wound photographs. m Blood glucose levels in animals induced with diabetes for studying the wound healing process [159]. Copyright 2022, John Wiley and Sons, Inc

Fig. 6 Wound healing process accelerated by NZ@hydrogels with antibacterial properties. a Fabrication of a multifunctional anti-bacterial hydrogel based on PEGMA-GMA-Aam copolymer. b Photographs of infected wounds after hydrogel treatment. Scale bar: 1 cm. c Relative wound healing rates at different time points. d Number of days taken for complete wound healing. e Quantification of bacterial density in the infected wound [158]. Copyright 2022, Elsevier. f An illustration of the fabrication of FEMI hydrogel for infected diabetic wounds. g Photographs of the wound after hydrogel administration. h A representation of the wound closure at different time points. i Quantification of wound closure rates. j Blood glucose levels were examined in mice at different time points. k The fluorescent expression of ROS levels in wounds by dihydroethidium (DHE). Scale bar: 50 μm. l The fluorescence intensity of DHE for various hydrogel groups. m Histological examination of wounds following hydrogel treatment. Scale bar: 100 μm. n Epidermal thickness examined on the 7th day. o Blood vessel regeneration examined on the 7th and 14th days. p Hair follicle formation examined on the 14th day [41]. Copyright 2020, American Chemical Society

Fig. 7 Therapeutic properties of NZ@hydrogels in alleviating AD. a Illustration of the design of a nCe-based hydrogel patch to treat AD. b Schematic of in vivo experiments and timeline for animal experiments. c Photographs of dorsal skin of different groups following treatment. d Evaluation of dermatitis score. e Histology of mouse skin sections stained with H&E after treatment. Scale bars, 100 μm. f Comparison of epidermal thickness. g Histology of the samples revealed infiltrated mast cells. Scale bars, 100 μm. h Relative quantification of infiltrated mast cells. i Representative immunofluorescence images of oxidative DNA damage marker: 8-OHdG. Scale bars, 100 μm. j Relative 8-OHdG quantification [49]. Copyright 2022, American Chemical Society. k An illustration highlighting the capacity of Gel@ZIF-8 to suppress oxidative stress and alleviate inflammatory responses. l Photographs of mice dorsal skin following treatment. m Evaluation of dermatitis score. n Comparison of epidermal thickness between groups. Scale bars, 100 μm. o Relative quantification of epidermal thickness. p Histology of the samples showing infiltrated mast cells. Scale bars, 100 μm. q Relative quantification of mast cells [239]. Copyright 2023, Springer Nature

Fig. 8 NZ@hydrogels act as radioprotectants for skin therapy. a Graphical representation showing the skin radioprotection capacity of the nano-GDY@SH hydrogel. b The photos of the skin wound changes of mice after different treatments. c The examination of skin tissues by H&E and Masson staining Scale bars, 100 μm [258]. Copyright 2021, Elsevier. d Schematic depicting the fabrication of IFI6-PDA@GO/SA hydrogel for RISI. e Images showing medical device used to induce the RISI model in mice. f Photographs of the dorsal skin of mice during the treatment period. g H&E staining of skin tissues on the 14th day. Scale bars, 200 μm. h Relative quantification of the wound area, granulation tissue thickness, and density of wound micro vessels [259]. Copyright 2022, Springer Nature

Fig. 9 NZ@hydrogels act mechano-chemically in alleviating symptoms of AD. a Graphical illustration displaying inflammatory reactions of AD due to oxidative harm and the outcome of mechanical scratching on AD. It also depicts the synergistic action of NZ@hydrogels in treating AD by ROS scavenging and FAK phosphorylation inhibition. b Representation of in vivo experiments. c Photographs of the dorsal skin of mice on the 24th day. d Evaluation of dermatitis score. e H&E staining of skin sections. Scale bars, 100 μm. F Epidermal thickness quantified from H&E staining. g TB staining of the skin section. Scale bars, 100 μm. h Measurement of the density of mast cells for each group after treatments [238]. Copyright 2023, Springer Nature

Fig. 10 Design of advanced NZ@hydrogel platforms for skin therapeutics. a Making of MoS₂-aided gelling hydrogel scaffolds through a microfluidic-assisted in situ printing approach to expedite the healing of infected chronic wounds [86]. Copyright 2023, Elsevier. b Ultrasmall TA-Ag NZ-catalyzed hydrogel platform is a sticky, antibacterial, and implantable bioelectrode that detects bio-signals and accelerates tissue regeneration while preventing infection [65]. Copyright 2021, Elsevier

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[1]	CHEN Lu (陈露), CHENG Liying (程丽英), CHEN Tian (陈田), ZHANG Yuguang (张余光), ZHANG Jianming* (张建明). Macrophage Polarization in Skin Wound Healing: Progress in Biology and Therapeutics [J]. J Shanghai Jiaotong Univ Sci, 2022, 27(2): 264-280.
[2]	Wenchao Zhao, Haifeng Zhou, Wenkang Li, Manlin Chen, Min Zhou, Long Zhao. An Environment-Tolerant Ion-Conducting Double-Network Composite Hydrogel for High-Performance Flexible Electronic Devices [J]. Nano-Micro Letters, 2024, 16(1): 99-.

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