Sustained in situ exosome delivery reprograms the diabetic wound microenvironment to unlock immuno-angiogenic repair

Chronic diabetic wounds persist because inflammation, oxidative stress and impaired angiogenesis create a hostile microenvironment. We developed an exosome-functionalized, aligned poly(lactic-co-glycolic acid)/gelatin electrospun dressing (EE@PG) that serves as a local depot for sustained delivery of endothelial progenitor cell-derived exosomes. EE@PG scavenged hydroxyl and superoxide radicals and showed enzyme-mimetic antioxidant activity. Under lipopolysaccharide stimulation, EE@PG lowered intracellular reactive oxygen species, restored mitochondrial membrane potential and promoted RAW264.7 macrophage polarization toward a reparative phenotype while improving human umbilical vein endothelial cell viability and tube formation. In a splinted full-thickness STZ-induced diabetic rat model, EE@PG accelerated wound closure, enhanced re-epithelialization and collagen remodeling and increased neovascularization and vessel maturation. Transcriptomic analysis supported a shift toward immune resolution and tissue repair programs. Hemolysis, serum chemistry and organ histology indicated favorable biosafety. This work highlights a generalizable drug-delivering nanofibrous dressing that couples sustained exosome signaling with aligned structural cues for chronic wound management in clinically relevant settings.