In-situ Sprayed platelet-derived small extracellular vesicles for the skin flap survival by reducing PANoptosis

Necrosis at the distal end of random skin flaps remains a significant challenge, limiting the clinical application of these flaps in plastic and reconstructive surgery. Inhibiting ischemia/reperfusion (I/R) injury and promoting the formation of neovascular networks are critical preventive strategies. Platelet-derived small extracellular vesicles (PL-sEV) are nanocarriers of growth factors that provide an alternative to clinically used platelet-rich plasma and platelet lysates, offering higher growth factor concentrations and lower immunogenicity. In this study, PANoptosis, a distinct form of inflammatory cell death, was fully characterized in a random skin flap model. Subcutaneous injection of PL-sEV improved ischemic skin flap survival by enhancing blood perfusion and reducing PANoptosis levels. In vitro, PL-sEV inhibited oxygen–glucose deprivation/reoxygenation-induced dysfunction in human umbilical vein endothelial cells. Furthermore, PL-sEV was incorporated into a thermosensitive triblock hydrogel, creating a sprayable delivery system (PLEL@PL-sEV). Mechanistic analysis through RNA sequencing indicated that the protective effects of PL-sEV against PANoptosis likely resulted from its anti-inflammatory properties, particularly via suppression of the NF-κB signaling pathway. This novel hydrogel system demonstrated controlled release of PL-sEV and proved effective in improving skin flap transplantation outcomes.