Hyaluronic Acid Hydrogel Incorporating Dexpanthenol-Engineered Extracellular Vesicles for Accelerated Wound Closure and Mitigated Secondary Infection Risk.

Background: Loss of epithelial integrity leaves the wound bed open to opportunistic bacterial colonization, and the risk of secondary infection persists for as long as the defect remains unclosed. Wound dressings must therefore provide an immediate external barrier while accelerating restoration of the skin's own barrier. This study aims to develop and evaluate a bioactive nanotechnological platform comprising dexpanthenol (Dxp)-engineered extracellular vesicles (EVs) embedded within cross-linked hyaluronic acid hydrogels (HA@Dxp-engineered EVs) for targeted wound treatment and protection against external contaminants. Methods: EVs were engineered via exogenous (extrusion; Exo EV) and endogenous (co-incubation; Endo EV) strategies to encapsulate Dxp. The physicochemical properties of the HA@Dxp-engineered EV systems were characterized, and their therapeutic efficacy was validated through in vitro assays, including fibroblast migration and endothelial tube formation, and in vivo using a full-thickness excisional wound model in mice. Results: Both engineering strategies successfully encapsulated Dxp while preserving the structural integrity of the EVs. The HA hydrogel enabled sustained EV release and provided a physical barrier. In vitro, HA@Endo EVs significantly promoted fibroblast proliferation, migration, and the formation of mature capillary-like networks in HUVECs compared to controls. In vivo, the HA@Endo EV group demonstrated accelerated wound closure, achieving 99.88% healing by day 10, and promoted tissue remodeling with upregulated expression of COL1A1, VEGF, and HIF-1α. Conclusions: The HA@Endo EV system provides a dual-action strategy against secondary infection risk. It supplies an immediate physical barrier over the wound bed and simultaneously accelerates re-epithelialization, thereby shortening the interval during which the tissue remains exposed.