Mitochondria‐Targeted Supramolecular Nanoparticles Alleviate Cellular Senescence by Restoring Mitochondrial Homeostasis in Osteoarthritis

ABSTRACT Osteoarthritis (OA) is a common age‐related degenerative joint disorder with no effective disease‐modifying drugs. Cellular senescence and mitochondrial dysfunction that disrupt chondrocyte homeostasis are key drivers of OA initiation and progression. Here, we develop mitochondria‐targeted supramolecular nanoparticles (EG NPs) self‐assembled from Epigallocatechin‐3‐gallate (EGCG) and L‐Glutamic acid (L‐Glu), enabling efficient scavenging of mitochondrial reactive oxygen species (mtROS) through targeted delivery and ultimately restoring mitochondrial homeostasis. This leads to reduced DNA damage, inhibition of the NF‐κB inflammatory signaling pathway, and attenuation of cellular senescence along with its associated inflammatory senescence‐associated secretory phenotype (SASP). Simultaneously, mitochondria‐targeted EG NPs promote mitochondrial inner and outer membrane fusion and biogenesis by upregulating fusion markers and activating the AMPK pathway, enhancing energy supply, alleviating cellular senescence, and promoting matrix synthesis in chondrocytes. In vivo experiments in a mouse OA model prove that EG NPs markedly suppress synovial inflammation, alleviate articular cartilage damage and matrix degradation, and ameliorate abnormal subchondral bone remodeling, thereby preserving cartilage structural integrity and effectively slowing OA progression. This multifunctional mitochondria‐targeted nanoplatform, centered on restoring mitochondrial homeostasis, precisely modulates the function of senescent chondrocytes and alleviates their senescent phenotype, establishing a promising new paradigm for OA therapy and opening new avenues for nanotechnology‐based interventions in aging‐related diseases.