Hydrogel microneedles loaded with engineered extracellular vesicles accelerate diabetic wound healing by promoting angiogenesis and modulating macrophage polarization.

Oxidative stress, impaired angiogenesis, and persistent inflammation contribute to delayed diabetic wound healing. In this study, ALDH2-loaded liposomes were associated with extracellular vesicles derived from human amniotic mesenchymal stem cells to generate an ALDH2@Lipo/EV hybrid formulation, which possess pro-angiogenic, antioxidant, and anti-inflammatory properties that modulate mitochondrial homeostasis in cells within diabetic wounds. To enhance the penetration efficiency of EVs in the wound, ALDH2@Lipo/EV were loaded into methacrylated gelatin (GelMA) hydrogel to fabricate the ALDH2@Lipo/EV-MN patch system. The microneedles technology enabled precise and efficient delivery of ALDH2@Lipo/EV, ensuring an optimal depth of delivery for maximum therapeutic efficacy. Mechanistically, ALDH2@Lipo/EV promoted angiogenesis in vitro and alleviated oxidative damage and inflammation in macrophages by inhibiting the activation of dynamin-related protein 1 (Drp1) and activating the PINK1/Parkin signaling pathway. Furthermore, the ALDH2@Lipo/EV-MN patch was shown to enhance diabetic wound healing in a mouse model. This study explored the functions and mechanisms of the ALDH2@Lipo/EV-MNs system, providing a new strategy for the treatment of refractory diabetic wounds.