Multimodal Mechano-adaptive Artificial Synovial Fluid Drives In-Situ Engineering of Anti-Pyroptotic Extracellular Vesicles to Arrest Preclinical Osteoarthritis

Abnormal mechanical loading initiates a dual pyroptotic loop between chondrocytes and macrophages, converting healthy cartilage to pathology. Herein, we engineered a multifunctional artificial synovial fluid, pPBA@MN UM6@Co (PMUC), to deliver graded protection and repair of early pathogenetic cartilage.

Intra articular PMUC builds a persistent hydration layer via water bonding, mimicking native synovial fluid, markedly enhancing lubrication and dissipating mechanical stress. When abnormal stress provokes ultra early cartilage lesions, the ensuing ROS (·OH) surge cleaves boronate esters and glycosidic bonds in PMUC, releasing mannose (Man) and UM6@Co (UC) nanocomplexes. Activation of the hexosamine biosynthetic pathway (HBP) suppresses Caspase-3–GSDME-mediated pyroptosis in chondrocytes while promoting in situ formation and engineering of extracellular vesicle (EV) derived from resident and synovial macrophages.