SCAP-Exo-Integrated CA/HACC Hydrogel Promotes Diabetic Wound Repair via miR-122-Driven Macrophage Phenotypic Transition.

Chronic diabetic wounds are characterized by persistent inflammation and a disrupted transition from the inflammatory to the reparative phase, largely driven by macrophage dysregulation and metabolic imbalance within the wound microenvironment. Here, we developed an exosome-integrated hydrogel system based on citrate-crosslinked hydroxypropyltrimethyl ammonium chloride chitosan (HACC), incorporating exosomes derived from stem cells of the apical papilla (SCAP-Exo) to modulate immune responses and promote diabetic wound repair. The SCAP-Exo-loaded HACC hydrogel exhibited favorable physicochemical properties and enabled sustained local exosome release. In vitro studies demonstrated efficient uptake of SCAP-Exo by macrophages, leading to a pronounced shift toward an anti-inflammatory, pro-reparative phenotype. MicroRNA profiling and functional validation identified miR-122-5p as a key bioactive component enriched in SCAP-Exo, mediating macrophage reprogramming through the regulation of inflammatory signaling and metabolism-associated pathways. Consequently, the remodeled immune microenvironment enhanced fibroblast proliferation and migration. In a diabetic wound model, treatment with the SCAP-Exo-functionalized HACC hydrogel significantly accelerated wound closure, improved granulation tissue formation, and promoted collagen deposition. Collectively, this study demonstrates that SCAP-Exo-based HACC hydrogel therapy facilitates diabetic wound healing through miRNA-driven immunometabolic modulation, highlighting a promising strategy for the treatment of chronic wounds.