Camouflage Protein-Engineered Extracellular Vesicles Alleviate TMJ-OA by Hijacking Caspase-1 to Suppress Pyroptosis

Temporomandibular joint osteoarthritis (TMJ-OA) is highly prevalent with an insidious onset. Severe inflammation and significant degenerative changes are often associated with the condition, and current clinical treatments remain inadequate. In this study, we focus on pyroptosis and engineered the camouflage protein (GSDMD-C) attached to the membrane surface of small extracellular vesicles (sEVs)-sEV-p. sEV-p has two key effects: firstly, the inherent immunomodulatory and nutritional support properties of sEVs promote the recovery of cellular function under pathological conditions; secondly, camouflage protein bind to the activated caspase-1, reducing the cleavage of endogenous GSDMD. The therapeutic effects of sEV-p were evaluated through in vitro experiments and treatment of TMJ-OA models in mice and Bama pigs. We further elucidated the mechanisms by single-cell RNA sequencing analysis. Results show that sEV-p alleviates the abnormal activation of inflammatory factors induced by pyroptosis, accompanied by a reduction in the proportion of inflammatory cells and a mitigation of acute inflammatory responses.