Metformin-Loaded Tannic Acid Nanoparticles AttenuateOsteoarthritis by Promoting Chondrocyte Mitochondria Homeostasis Basedon Mitocytosis

The oxidative stress microenvironment and mitochondrial dysfunction in chondrocytes are key mechanisms in the development of osteoarthritis (OA). Metformin (Met) has demonstrated multiple effects on mitochondria and is regarded as a potential therapeutic agent for OA. The low blood flow characteristics in the joint cavity make targeted local delivery of metformin crucial for its clinical application. In this study, tannic acid (TA), with its natural antioxidant and anti-inflammatory properties, was used to prepare self-assemble Met-loaded TA nanoparticles (NPs). The NPs exhibit excellent reactive oxygen scavenging capability, stability in various media, and an acid-responsive release of Met. In Vitro experiments showed that NPs possess excellent biocompatibility, effectively protecting chondrocyte viability in OA’s pathological environment and preventing the senescence phenotype. In addition, NPs promoted the expression of antioxidant elements in chondrocytes, restored mitochondrial membrane potential, and enhanced mitocytosis to improve mitochondrial quality. In vivo experiments further confirmed that intra-articular injection of NPs in rats with post-traumatic OA improves cartilage matrix degradation, osteophyte formation, and subchondral bone sclerosis over 8 weeks. Tissue staining further confirmed the protective effects of NPs on chondrocyte mitochondria. Importantly, both in vivo and in vitro experiments revealed that NPs provided superior cellular protection compared to TA or Met alone. Overall, this study demonstrates that NPs effectively against OA cartilage degeneration, with the advantages of easy preparation, high efficiency, and biosafety.