Endothelial cell-targeting aptamer-empowered exosomes accelerate wound healing by promoting specialized angiogenesis in type 1 diabetic mice.

BACKGROUND: The reduced angiogenesis in diabetes mellitus (DM) represents a critical barrier to effective skin wound healing. Therapeutic strategies involving mesenchymal stem cells (MSCs) and MSC-derived exosomes (EXOs) have demonstrated potential in promoting wound healing in diabetic contexts. However, each approach presents specific limitations. METHODS: Apt-PEG-DSPE was synthesized via amide condensation between DSPE-PEG-COOH and NH₂-Apt, followed by incubation with EXOs to yield Apt-EXOs, then mixed with HA to form Apt-EXOs-HA. C57BL/6 mice were injected intraperitoneally with 50 mg/kg STZ daily for 5 days to induce a type 1 diabetes (T1D) model. Under anesthesia, dorsal fur was shaved and full-thickness skin defects (1.0 cm diameter) were created. The therapeutic effect of Apt-EXOs-HA on skin wound healing in T1D was evaluated by assessing wound closure, vascularization and collagen deposition. The Student's t-test (two-tailed) was used to assess statistical significance. RESULTS: In this study, we identified that vascular structures, specifically CD31⁺EMCN⁺ vessels, are impaired in T1D, and this impairment contributes to delayed wound healing and aberrant collagen deposition. Following proteomic analysis and related vascular endothelial cell experiments (including cell migration and tube formation) demonstrating the superior angiogenic potential of EXOs compared to MSCs, we engineered endothelial-targeting EXOs by conjugating them with aptamers (Apt). The application of these Apt-conjugated EXOs in combination with a hyaluronic acid scaffold significantly enhanced angiogenesis under both physiological and DM conditions, thereby accelerating wound healing. CONCLUSIONS: Collectively, our findings emphasize the essential role of specialized angiogenesis in wound repair and propose a novel, advanced EXOs modification-based therapeutic approach to enhance wound healing in both normal and diabetes-related pathophysiological conditions.