Abstract
Osteoarthritis (OA) is characterized by chondrocyte degeneration and associated intracellular organelle dysfunction. Restoring impaired mitophagy represents a critical strategy for ameliorating OA-induced chondrocyte dysfunction and promoting cartilage repair, yet a significant therapeutic gap persists due to the lack of highly potent agents that can effectively restore mitophagy in OA chondrocyte. In this work, we identified Salvianolic acid B (SaB), a novel small-molecule agent, which binds to PINK1/Parkin proteins to stabilize them, promote their expression, and activate mitophagy. SaB nano-assemblies (SaB NAs) were fabricated via hydrogen bonding and π-π stacking between SaB and triphenylphosphine, achieving exceptional drug loading (74.4%) and mitochondrial-targeted synergistic therapeutic effects. In vitro and in vivo assessments confirmed that SaB NAs significantly outperformed free SaB in restoring mitochondrial function, facilitating chondrocyte recovery, prolonging therapeutic residence time and alleviating OA progression. The intra-articular delivery of SaB NAs represents a promising approach for treating OA and other joint inflammatory diseases.