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

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.