摘要
A lycopene-loaded CeO₂ nanozyme (Ly@Ce) is developed to combat chondrocyte senescence for osteoarthritis therapy • Ly@Ce efficiently scavenges mitochondrial ROS, restores mitochondrial dynamics, and elevates NAD + levels • Ly@Ce reverses H₂O₂-induced dysregulation of the p53-p21 signaling axis • Ly@Ce suppresses SASP expression and shifts ECM metabolism toward an anabolic program • The nanozyme integrates redox/NAD + reprogramming with senescence pathway inhibition, offering a disease-modifying strategy for OA Osteoarthritis (OA) is strongly associated with chondrocyte senescence, driven by oxidative stress, mitochondrial dysfunction, and the ensuing senescence-associated secretory phenotype (SASP). Herein, we report a lycopene-loaded ceria nanozyme (Ly@Ce) designed to simultaneously address these interconnected pathogenic cues. Ly@Ce markedly reduced intracellular and mitochondrial reactive oxygen species (ROS), mitigated excessive mitochondrial fragmentation, and restored mitochondrial membrane potential in senescent chondrocytes, indicating robust recovery of mitochondrial fitness. Notably, Ly@Ce also elevated intracellular nicotinamide adenine dinucleotide (NAD + ) levels, making it an active metabolic modulator rather than a passive ROS scavenger. Transcriptomic profiling revealed that Ly@Ce reversed H 2 O 2 -induced dysregulation of the p53-p21 signaling pathway, accompanied by suppression of SASP-related genes and a shift of extracellular matrix metabolism toward an anabolic program, thus delaying OA progression. Collectively, these findings establish Ly@Ce as a bioinspired, catalytic antioxidant nanoplatform that combines redox and NAD + reprogramming with p53-p21 inhibition, offering a disease-modifying strategy for senescence-associated OA and a potential framework for targeting other age-related pathologies characterized by mitochondrial decline and cellular senescence.
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