Diabetic wounds are characterized by persistent inflammation, endothelial dysfunction, impaired angiogenesis, and poor local retention of therapeutic agents, all of which hinder effective repair. Here, we combined Netrin-1-enriched exosomes (NTN-Exos) from genetically modified adipose-derived stem cells with a photo-crosslinkable phenylboronic acid-modified hyaluronic acid methacryloyl/polyvinyl alcohol (HAMA-PBA/PVA) hydrogel to create a diabetic wound-responsive exosome–hydrogel system. NTN-Exos@Gel enabled prolonged local exosome retention owing to its favorable injectability, biocompatibility, and pH- and reactive oxygen species-responsive degradation and release behavior. In vitro, NTN-Exos reduced high-glucose-induced endothelial apoptosis and restored endothelial migration, proliferation, and tube-forming capacity. Additionally, NTN-Exos reduced inflammatory reactions and promoted macrophage polarization toward a reparative phenotype. NTN-Exos@Gel dramatically accelerated wound closure, improved blood perfusion, boosted neovascularization, improved re-epithelialization and collagen deposition, and decreased local inflammatory cytokine production in a diabetic full-thickness wound model. Mechanistically, transcriptome and protein analysis showed that the pro-angiogenic action of NTN-Exos was associated with altered Hippo signaling, which is typified by higher YAP/TAZ expression, decreased phosphorylation of LATS1 and YAP, and increased expression of CD146. These results suggest that NTN-Exos@Gel is a viable cell-free approach for the healing of diabetic wounds.
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Chen et al. (2026) studied this question.
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