Mitochondrial respiratory chain dysfunction-induced chondrocyte senescence is a key contributor to the progression of osteoarthritis (OA), yet effective strategies for restoring mitochondrial respiratory homeostasis remain elusive. Herein, we develop a charge-guided micro/nano interpenetrating network hydrogel that targets cartilage and delivers a mitochondria-directed MnO2-based nanoparticles, in which the nanozyme catalyzes intracellular hydrogen peroxide to generate oxygen while releasing nicotinamide adenine dinucleotide (NAD+) precursor via particle degradation, thereby enabling synchronized electron donor and acceptor supply to fully reactivate the mitochondrial respiratory chain and alleviate chondrocyte senescence.
