Catechol-based antioxidant nanoplatform alleviates chondrocyte senescence and osteoarthritis via ATM/ATR-PINK1-mediated mitophagy

Osteoarthritis (OA) is a degenerative joint disease associated with cellular senescence and mitochondrial dysfunction. Although epigallocatechin-3-gallate (EGCG) and D-methionine (D-Met) exhibit antioxidant and anti-senescent activities, poor bioavailability and rapid intra-articular clearance limit their therapeutic potential. Here, we developed an EGCG-based antioxidant nanoparticle, ED@F127 nanoparticles (NPs), by conjugating EGCG with D-Met through a green Mannich reaction, followed by encapsulation in Pluronic F127. The resulting NPs exhibited a uniform size of approximately 80 nm, high drug-loading efficiency, and favorable biocompatibility. Using basic calcium phosphate (BCP) crystals as an OA-relevant pathological stimulus, we showed that ED@F127 NPs attenuated BCP-induced chondrocyte senescence. ED@F127 NPs also increased ATM/ATR abundance and PINK1/PARKIN-associated mitophagy markers. These changes were accompanied by reduced reactive oxygen species accumulation and improved mitochondrial membrane potential and ATP-associated signals. In vivo , intra-articular administration of ED@F127 NPs alleviated cartilage degeneration, abnormal subchondral bone remodeling, and osteophyte formation in a BCP crystal-induced rat OA model. Together, these findings support ED@F127 NPs as a promising nanotherapeutic strategy for attenuating oxidative stress and cellular senescence in OA.