Recent advances and challenges in hydrogel-based delivery of immunomodulatory strategies for diabetic wound healing

Abstract

Chronic wounds associated with diabetes present considerable clinical hurdles, primarily due to delayed tissue repair and dysregulated immune activity. The imbalance in immune responses, including impaired macrophage polarization, excessive neutrophil activation, and oxidative stress, further hampers the healing process. The application of immunomodulatory biologics as a novel treatment method for diabetic wounds often yields limited results due to rapid degradation and lack of targeting. Hydrogels not only prevent rapid drug degradation but also allow for conditional responsiveness and targeted delivery. Therefore, hydrogels loaded with immunomodulatory biologics emerge as a promising strategy, offering the capacity to reshape the immune milieu and promote regenerative outcomes. This review first outlines the role of immune system during the healing processes in normal and diabetic wounds. It then discusses the latest advancements in hydrogel delivery systems as part of immune-modulatory interventions, wherein hydrogels serve as pivotal carriers for (i) cell delivery, such as stem cells and macrophages; (ii) extracellular vesicles derived from both cellular and tissue sources, as well as extracellular vesicle mimetics; and (iii) bioactive substances, including oxygen-releasing microspheres, nanomaterials, and cytokines. Finally, this review focuses on the limitations of modulating immune responses in diabetic wound healing and proposes potential future directions.

Keywords: biomaterials; diabetic wounds; extracellular vesicles; hydrogels; immunomodulation.

Figure 1

Immunomodulatory strategies of hydrogels for the treatment of diabetic wounds. Hydrogels act as versatile carriers to deliver (i) cells, including MSCs, macrophages, and iPSC-derived lineages; (ii) EVs from cellular, tissue, or other sources; and (iii) bioactive substances including oxygen-releasing microspheres, nanozymes, cytokines, peptides, and growth factors. These hydrogel-based platforms reshape the diabetic wound immune microenvironment by promoting macrophage polarization toward the M2 phenotype, reducing NETs, modulating T-cell responses, alleviating oxidative stress, and enhancing angiogenesis. Collectively, these strategies restore immune balance and accelerate tissue repair. MSC, mesenchymal stem cell; iPSC, induced pluripotent stem cell; EV, extracellular vesicle; NET, neutrophil extracellular trap. Created with https://BioRender.com.

Figure 2

Immunomodulatory hydrogel systems for delivering cell-derived EVs. (A) Preparation and application of the PEG/Ag/CNT-M+E hydrogel for diabetic wounds. Adapted with permission from . Copyright 2023, Elsevier. (B) Immunomodulation of the M2 macrophage-derived EV-encapsulated microneedles with PDA (MEs@PMN) for diabetic wound healing. Adapted with permission from . Copyright 2023, Elsevier. (C) Fabrication and therapeutic mechanisms of regulating the inflammatory microenvironment and promoting angiogenesis in diabetic wound healing by Ep/CSO hydrogels. Adapted with permission from . Copyright 2025, American Chemical Society.

Figure 3

Immunomodulatory hydrogel systems for delivering tissue-derived, plant-derived, and animals-derived EVs. (A) Preparation, merits, and mechanisms of dissolvable MN-based wound dressing (PLT-EVs@ADMMA-MN). Adapted with permission from . Copyright 2024, Elsevier. (B) Isolation and application of PA-EVs. Adapted with permission from . Copyright 2023, Springer Nature. (C) Beneficial role of HA-ADH/OSA@Mg@sEVs hydrogel. Adapted with permission from . Copyright 2023, Wiley. (D) Fabrication and therapeutic mechanisms of Saccharina japonica-derived EVs-functionalized conductive microneedles. Adapted with permission from . Copyright 2025, Wiley.

Figure 4

Immunomodulatory hydrogel systems for delivering EV mimetics and apoptotic EVs. (A) The fabrication of VEGF-aPMNEM-ECM hybrid hydrogel: preparation of activated PMN EV mimetics and vascular endothelial growth factor wrapping into aPMNEM. Adapted with permission from . Copyright 2023, Springer Nature. (B) MSC-derived apoptotic EVs converting macrophages towards the M2 phenotype and improving the functions of fibroblasts and endothelial cells. Adapted with permission from . Copyright 2020, Springer Nature. (C) The mechanisms of hUCMSC-derived apoptotic EVs inhibiting macrophage pyroptosis. Adapted with permission from . Copyright 2023, Springer Nature.

Figure 5

miRNAs promoting diabetic wound healing. Created with https://BioRender.com.

Figure 6

Immunomodulatory hydrogel systems for delivering bioactive substances. (A) The mechanisms of oxygen-release microspheres (ORMs) and accelerated wound healing by ORMs encapsulated in hydrogel. Adapted with permission from . Copyright 2021, American Association for the Advancement of Science. (B) The preparation and mechanisms of ADSC-derived exosome coated BSA-based oxygen nanobubbles. Adapted with permission from . Copyright 2024, Springer Nature. (C) The mechanisms of netrin-1 co-crosslinked hydrogel accelerated diabetic wound healing. Adapted with permission from . Copyright 2024, Elsevier. (D) The mechanisms of a thermo-responsive hydrogel and the wound healing process. Adapted with permission from . Copyright 2025, Royal Society of Chemistry.