Mitochondria-targeted NAD+/O2 co-delivery interpenetrating network hydrogel for respiratory chain restoration and osteoarthritis therapy.

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. Comprehensive evaluations reveal that this system enhances the activity of key antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase, elevates the intracellular nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen (NAD+/NADH) ratio, and suppresses the secretion of senescence-associated secretory phenotype factors, thereby preserving cartilage matrix integrity. Collectively, these findings underscore the therapeutic potential of this dual-delivery platform to achieve full-length mitochondrial respiratory chain activation, offering a compelling strategy to mitigate chondrocyte senescence and impede OA progression.