A self-adapting DNA-crosslinked hydrogel reprograms macrophage polarization and angiogenesis for synergistic repair...

Chronic diabetic wounds continue to be a major therapeutic challenge due to sustained inflammation, impaired angiogenesis, and disrupted extracellular matrix remodeling. Partial conventional dressings and growth factor therapies often act passively or release agents independently, lacking coordinated regulation of immune and vascular responses necessary for effective healing. In this study, we report a self-adapting DNA-crosslinked silk fibroin hydrogel designed to reprogram macrophage polarization and angiogenesis for coordinated diabetic wound repair. The hydrogel integrates L-arginine-loaded bone marrow mesenchymal stem cell-derived exosomes within a pH-responsive DNA conformational switch, in which cholesterol-modified DNA strands undergo an acidic pH-induced duplex-to-i-motif transition. This structural change disrupts hydrogen bonding between complementary strands, enabling precise release of therapeutic cargos in the acidic diabetic wound microenvironment. In vitro, the hydrogel effectively induced macrophage M1-to-M2 repolarization, enhanced endothelial cell proliferation, migration, and angiogenesis. In diabetic mouse models, it accelerated reepithelialization, enhanced CD31 and vascular endothelial growth factor expression, suppressed pro-inflammatory cytokines, and restored collagen deposition. This self-adapting, dual-modulatory hydrogel establishes a self-reinforcing "immune-vascular" feedback loop, enabling synchronized immunoregulation and angiogenesis. The findings highlight a programmable therapeutic strategy for reversing chronic inflammatory microenvironments and promoting functional tissue regeneration in diabetic wounds.