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 PLGA/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 HUVEC 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.