Multiple dynamic crosslinked multifunctional hydrogels with glucose/pH dual-responsive adipose-derived stem cells-exosomes-releasing for diabetic wound healing

Background: Diabetic wounds feature a high-glucose and acidic microenvironment that impairs macrophage polarization and healing. Adipose-derived stem cell-derived exosomes (ADSC-exos) show therapeutic potential but suffer from rapid clearance. This study aimed to develop a smart hydrogel for glucose/pH-responsive ADSC-exos release. Methods: A dual-responsive hydrogel (HAP/OCS/PEG/Ag-E) was fabricated via dynamic triple cross-linking. Characterization included rheometry, mechanical tests, and microscopy. In vitro macrophage polarization was assessed via flow cytometry and Western blot. A diabetic mouse wound model evaluated healing rates, histology, angiogenesis, and inflammation. Proteomics and pathway inhibition studies explored mechanisms. Statistical analysis used t-tests and ANOVA. Results: The hydrogel exhibited excellent self-healing, adhesion, and controlled ADSC-exos release under high-glucose/acidic conditions. It promoted M2 macrophage polarization, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), and accelerated wound healing with enhanced angiogenesis and collagen deposition. Mechanistically, the hydrogel suppressed the Notch/NF-κB/NLRP3 signaling pathway. Conclusion: The smart hydrogel facilitates diabetic wound healing through microenvironment-responsive ADSC-exos release and Notch/NF-κB/NLRP3 pathway inhibition, offering a promising strategy for chronic wound treatment.