Controlled delivery of HIF-1α via extracellular vesicles with collagen-binding activity for enhanced wound healing

Chronic wounds are often characterized by prolonged inflammation, impaired angiogenesis, and dysregulated hypoxic response, partly caused by the insufficient activation of hypoxia-inducible factor-1 alpha (HIF-1α). This study investigated the potential of engineered extracellular vesicles (EVs) to deliver a stable, constitutively active form of HIF-1α (scHIF-1α) to promote wound healing. A collagen-binding domain (CBD) was integrated into EVs to enhance their retention at wound sites, and collagen sponges were employed as scaffolds to ensure sustained, localized release of scHIF-1α EVs. In vitro studies have demonstrated that scHIF-1α EVs significantly improved cell proliferation, migration, and angiogenesis in dermal fibroblasts, endothelial cells, and keratinocytes-key cells involved in the wound healing process. In vivo, scHIF-1α EVs accelerated wound closure, enhanced tissue regeneration, and promoted angiogenesis in various wound healing models, including excisional wounds, surgical skin flaps, and diabetic wounds. The integration of CBD further enhanced EV retention, amplifying therapeutic outcomes. These results propose that scHIF-1α delivery via EVs, particularly when combined with collagen-based sustained-release systems, offers a promising and patient-friendly therapeutic strategy for treating chronic wounds.