Controlled release of mesenchymal stem cell-derived nanovesicles through glucose- and reactive oxygen species-responsive hydrogels accelerates diabetic wound healing.

Wound healing is often impaired in patients with diabetes. Mesenchymal stem cells (MSCs) and MSCs-derived nanovesicles (MNVs) hold promise as therapeutic agents for managing diabetic wounds. However, efficient delivery and controlled release of MNVs within these wounds are essential for maximizing therapeutic effectiveness. In this study, we developed a dual-responsive hydrogel designed to respond to elevated levels of glucose and reactive oxygen species. This hydrogel combines polyvinyl alcohol with phenylboronic acid-grafted chitosan, referred to as PBA-CP, while MNVs were produced by shearing MSCs through membranes with varying pore sizes. The composite PBA-CP/MNVs hydrogel significantly accelerated wound healing in a diabetic wound model by promoting epithelialization, dermal reconstruction, hair follicle formation, and angiogenesis. MNVs were readily taken up by keratinocytes, fibroblasts, and endothelial cells, stimulating their proliferation and migration. Altogether, the chitosan-based PBA-CP/MNVs composite hydrogel presents a promising therapeutic strategy for diabetic wound treatment.