Reactive Oxygen Species-Responsive Microgels Loaded with Vascular Endothelial Growth Factor─Engineered Endothelial Extracellular Vesicles for Diabetic Wound Healing via Microenvironment Reprogramming

Diabetic wound healing is hampered by a dysregulated pathological microenvironment characterized by excessive reactive oxygen species (ROS), persistent chronic inflammation, and impaired angiogenesis. To address these challenges, we developed an endogenously bioactive components-polymer matrix integration platform (P-MG@vEVs) via encapsulating vascular endothelial growth factor (VEGF)-stimulated endothelial extracellular vesicles (vEVs) into ROS-responsive microgels (P-MG). Endothelial cells were preconditioned with VEGF, and the resultant vEVs were isolated via differential centrifugation, with enhanced vesicle production and enriched angiogenic factors (e.g., VEGFA) that effectively promote endothelial cell migration and tube formation. P-MG@vEVs microgels composed of phenylboronic acid-modified sodium alginate were fabricated using microfluidic technology. Moreover, the microgels exhibited ROS-triggered degradation, enabling targeted and sustained vEVs release in the oxidative wound microenvironment. In vitro, P-MG@vEVs efficiently scavenged ROS, modulated macrophage polarization toward the anti-inflammatory M2 phenotype, and enhanced angiogenesis. In streptozotocin (STZ)-induced diabetic mice, P-MG@vEVs efficiently reprogrammed the damaged cutaneous microenvironment via regulating key signaling pathways (e.g., HIF-1, IL-17, NF-κB), thereby alleviating inflammation, restoring redox homeostasis, and facilitating neovascularization. These multifaceted effects significantly accelerate wound closure and skin repair, as evidenced by enhanced re-epithelialization and improved collagen deposition. Collectively, this platform integrates the intrinsic bioactivity of VEGF-preconditioned vEVs with the ROS-responsive delivery capability of the microgel carrier, offering a highly promising strategy for diabetic wound management.