New Strategies for the Treatment of Diabetic Foot Ulcers Using Nanoenzymes: Frontline Advances in Anti-Infection, Immune Regulation, and Microenvironment Improvement

Abstract

Diabetic foot ulcers are one of the most serious consequences of diabetes, arising from vascular impairment of the skin and disturbances in the microenvironment. This condition involves pathological changes such as wound infection, hyperglycemia, hypoxia, oxidative stress, and cellular dysfunction, necessitating multifaceted interventions. Traditional treatments often target only the wound itself, resulting in limited effectiveness. In contrast, nanoenzymes offer a promising therapeutic option due to their excellent biocompatibility and tissue permeability. They exhibit higher catalytic efficiency, optimal size and structure, and improved stability compared to natural enzymes. Encapsulating various nanoenzymes within novel biomaterials can enhance therapeutic outcomes through antibacterial action, glycemic control, oxygen delivery, antioxidative effects, anti-inflammatory properties, and angiogenesis promotion. This approach represents a key direction for future diabetic wound treatment. This article summarizes the role of nanoenzymes in diabetic wound management and discusses the potential mechanisms of their action. We also provide an outlook on their application prospects, aiming to advance their clinical utilization.

Keywords: angiogenesis; antibacterial action; chronic wound; hyperglycemia; oxidative stress.

Graphical abstract

Figure 1

(A) A schematic diagram of the synthesis, mechanism, and functional overview of CSPDA in synergistic antibacterial therapy combining PTT and CDT. (B and C) TEM images of Cu2O-SnO2,CSPDA. (D) SEM imaging of Staphylococcus aureus after different treatments.(NIR: 1.4 W·cm−2·s-1, CSPDA: 50 μg∙mL−1, Scale bars: 2μm). Reprinted from Acta Biomater. Volume 173, Gao J, Yan Y, Gao S, et al. Heterogeneous Cu(2)O-SnO(2) doped polydopamine fenton-like nanoenzymes for synergetic photothermal-chemodynamic antibacterial application. 420–431, Copyright 2024, with permission from Elsevier.

Figure 2

(A) MoO3–x/Cu Nanobelts Antibacterial Mechanism. (B and C) TEM images of MoO3 nanobelts. (D) TEM images of MoO3–x/Cu nanobelts. (E) MoO3 and (F) MoO3–x/Cu nanobelts HR-TEM images and SAED patterns. (G) EDS elemental mapping of MoO3–x/Cu. Reprinted from Liu H, Zuo Y, Lv S, et al. Ultralow loading copper-intercalated MoO(3) nanobelts with high activity against antibiotic-resistant bacteria. ACS Appl Mater Interfaces. 2024;16(14):17182–17192. Copyright © 2024 American Chemical Society.

Figure 3

The schematic diagram of the bactericidal action of the antibody bioorthogonal catalytic nanoenzyme S-Ab and its successful construction is as follows. (A) The physical recognition bactericidal mechanism illustrates that the bioorthogonal catalytic nanoenzyme obtained through calcination possesses a specific morphology, enabling it to engage in selective binding with target bacteria. (B) Zeta potentials of S. aureus, S aureus@TA-Cu, S aureus@Cu0, and S. aureus@Cu0@SiO2,The metal ion-tannic acid (TA) system can be used for coordination and assembly on the surfaces of materials with different shapes or even at pore interfaces, where “@” denotes a coating of Cu-TA. (C) The SEM image of the half-shell antibody fragment catalyst S-Ab generated by ultrasonic treatment. Inset: TEM image of S-Ab. (D) UV–vis spectra of S. aureus, S aureus@TA-Cu, S aureus@Cu0, and S. aureus@Cu0@SiO2 solution. (E) The schematic diagram of S-Ab, the dark field TEM image of S-Ab, and the corresponding elemental mapping for Si-K, O-K, N-K, and Cu-L signals. Reprinted from Niu J, Wang L, Cui T, et al. Antibody mimics as bio-orthogonal catalysts for highly selective bacterial recognition and antimicrobial therapy. ACS Nano. 2021;15(10):15841–15849. Copyright © 2021 American Chemical Society.

Figure 4

(A) Schematic diagram of the bactericidal action of RCF. (B and C) Show the bacterial survival rates of Escherichia coli and Staphylococcus aureus in different groups after RCF treatment, determined by the plate counting method. (D) SEM images of Escherichia coli and Staphylococcus aureus after different treatments: (I) PBS, (II) H₂O₂, (III) NIR, (IV) H₂O₂ + NIR, (V) RCF, (VI) RCF + H₂O₂, (VII) RCF + NIR, and (VIII) RCF + RH₂O₂ + NNR. Scale bar: 1 μm. *p <0.05, **p<0.01, ***p< 0.001. Reprinted from Liu Z, Zhao X, Yu B, Zhao N, Zhang C, Xu F-J. Rough carbon-iron oxide nanohybrids for near-infrared-II light-responsive synergistic antibacterial therapy. Acs Nano. 2021;15(4):7482–7490. Copyright © 2021 American Chemical Society.

Figure 5

(A) Schematic diagram of the synthesis of AuPd nanoenzymes and composite nanomaterials (APGH), which enhances the water solubility of the nanoenzymes, making them suitable for biological environments. (B and C) are respectively electron microscopy images of Au nanorods (NRs) and AuPd nanoparticles (NPs). (D) XRD spectrum of AuPd NPs, where the X-ray powder diffraction results confirm the presence of Au and Pd in the bimetallic nanostructure. Reprinted from Acta Biomater. Volume 177. Tang Z, Hou Y, Huang S, et al. Dumbbell-shaped bimetallic AuPd nanoenzymes for NIR-II cascade catalysis-photothermal synergistic therapy. 431–443, Copyright 2024, with permission from Elsevier.

Figure 6

(A) Synthesis of oxidized dextran (OD) and CeO₂. (B) Preparation of OCE hydrogel. (C) Application of OCE hydrogel in the repair of MDR-infected diabetic wounds. Reprinted from Cheng F, Wang S, Zheng H, et al. Ceria nanoenzyme-based hydrogel with antiglycative and antioxidative performance for infected diabetic wound healing. Small Methods. 2022;6(11):e2200949. © 2022 Wiley-VCH GmbH. (D) Schematic diagram of the NPs/hydrogel local co-delivery system. The co-delivery system reverses the harmful effects induced by AGEs through local supplementation of NO and intracellular delivery of rosiglitazone (RGZ). Reprinted from Yang Y, Huang S, Ma Q, et al. Combined therapeutic strategy based on blocking the deleterious effects of AGEs for accelerating diabetic wound healing. Regen Biomater. 2024:11:rbae062. Creative Commons.

Figure 7

(A) Applications and Potential Mechanisms of Gel-HA-Se@CeO₂ Hydrogel in Promoting Wound Healing through Controllable PDT. (B) Working Diagram of the ROS Balance System (C) Corresponding oxygen release curves of CeO2 and Se@CeO2. Reprinted from Wang M, Liu Y, Yang S, et al. Collaboration in contradiction: self-adaptive synergistic ROS Generation and scavenge balancing strategies used for the infected wounds treatment. Adv Healthc Mater. 2024;14:e2402579. © 2024 Wiley-VCH GmbH.

Figure 8

(A) Schematic Diagram of MnO₂-CO@MPDA NPs Fabrication. (B) Mechanism of Macrophage Phenotypic Transformation Mediated by CO. (C) TEM images of different nanoparticles (scale bar: 50 nm). Reprinted from Wu J, Chen M, Xiao Y, et al. The bioactive interface of titanium implant with both anti-oxidative stress and immunomodulatory properties for enhancing osseointegration under diabetic condition. Adv Healthc Mater. 2024;13:e2401974. © 2024 Wiley-VCH GmbH.(D) Schematic Diagram of AM/CeO₂ Construction. (E) Mechanism of Macrophage Phenotypic Transformation Induced by Apoptotic Signals Through Exocytosis. (F) Representative TEM images of CeO2-NPs, AM, and AM/CeO2. Reprinted from Wang H, Zhang Y, Zhang Y, et al. Activating macrophage continual efferocytosis via microenvironment biomimetic short fibers for reversing inflammation in bone repair. Adv Mater. 2024;36(30):e2402968. © 2024 Wiley-VCH GmbH.