Incorporating Stem Cell‐Derived Small Extracellular Vesicles into a Multifunctional OHAMA‐EPL Hydrogel Spray for Rapid Healing of Infected Skin Wounds

Abstract Wound healing is a significant clinical concern that can be hindered by excessive inflammation, infection, and insufficient regeneration. Small extracellular vesicles (sEVs) derived from stem cells have been extensively studied for wound healing, but their efficient delivery and controllable release in the targeted tissues remain a technical challenge. A stem cell‐derived sEVs incorporated dual‐network hydrogel spray system is prepared for the rapid healing of infected full‐thickness skin wounds for the first time. This multifunctional hydrogel spray, which is composed of methacrylate‐modified oxidative hyaluronic acid (OHAMA) and poly‐ε‐L‐lysine (EPL), possessed self‐healing, injectable, adhesive, antibacterial, and pH‐responsive degradation properties. These properties are crucial for facilitating the entire healing process. The efficacy of the sEVs‐loaded hydrogel spray is evaluated at cellular and animal levels. In vitro analyses demonstrated the sEVs’ specific functions in promoting cell proliferation, migration, and angiogenesis, working in concert with the hydrogels to augment these effects. In vivo, the spray exhibited rapid wound closure, with a 92.63% closure rate after 14 days of treatment. Furthermore, the spray also showed excellent angiogenesis and matrix deposition promotion, as well as inflammation amelioration in the treatment of infected full‐thickness wounds. This study provides new insights into the development of sEVs dosage forms for the rapid healing of acute infected wounds.