A Diabetic Wound Microenvironment-Responsive HAMA-PBA/PVA Hydrogel for Localized Delivery of Netrin-1-Enriched Adipose-Derived Stem Cell-Derived Exosomes Promotes Diabetic Wound Healing through Immunomodulation and Angiogenesis.

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.