Hydrogel microneedles loaded with engineered extracellular vesicles accelerate diabetic wound healing by promoting...

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.