TNF-R1 Cellular Nanovesicles Loaded on the Thermosensitive F-127 Hydrogel Enhance the Repair of Scalded Skin

Excessive inflammatory response after severe scalding is an important cause of delayed wound healing and is even life-threatening. Tumor necrosis factor α (TNF-α) is a key pro-inflammatory factor of skin trauma. Interacting with tumor necrosis factor receptor 1 (TNF-R1), TNF-α causes excessive inflammation and poor prognosis by activating NF-κB pathway. Antagonizing high levels of TNF-α is one of the therapeutic approaches for diseases associated with the overactivation of inflammatory responses. However, the available monoclonal antibodies are limited in their application due to their complex preparation process, high price, and the lack of cell targeting ability leading to systemic toxicity and side effects. In this study, by using a genetic bioengineering technique, we modified TNF-R1 on the cell membrane surface-derived nanovesicles (NVs). We confirmed that TNF-R1 NVs stably expressed TNF-R1 on the membrane surface and interacted with its ligand TNF-α. Furthermore, TNF-R1 NVs competitively antagonized the effect of TNF-α in the wound healing assay in vitro. In the scalded mouse model, TNF-R1 NVs were released continuously from the thermosensitive hydrogel Pluronic F-127, resulting in less inflammation and better wound healing. Our results revealed TNF-R1 NVs as promising cell-free therapeutic agents in alleviating TNF-α-mediated pro-inflammatory signaling and promoting wound repair.