Nanoparticle-activated SIRT3/SOD2 axis involves amelioration of chondrocyte senescence to delay osteoarthritis progression

Osteoarthritis (OA) manifests as a joint condition marked by the gradual deterioration of articular cartilage and the neighboring subchondral bone. Treatment avenues focusing on the regulation of autophagy and targeting senescence pathways are gaining considerable attention as promising therapeutic approaches. The clinical application of intra-articular agents for knee OA treatment is common. However, their effectiveness is insufficient owing to the rapid clearance of the agents. To address this challenge, nanoparticles present a promising solution as delivery systems, offering significant potential for regulating the local pharmacokinetics of therapeutic agents. Herein, we have developed chitosan-based nanoparticles for the sustained delivery of berberine chloride (BBR). These BBR-encapsulated chitosan nanoparticles (BBR-CNPs) demonstrated potent efficacy, safety, and prolonged retention time (up to 20 days) within rat joints. When administered as a therapeutic regimen, intra-articular injection of BBR-CNPs effectively alleviated age-related cartilage tissue degradation in surgically induced OA, whereas CNPs and pure BBR exhibited very limited effects on cartilage aging resistance function. BBR-CNPs penetrated the cartilage matrix, induced autophagy, and prevented senescence in interleukin-1 beta-induced rat chondrocytes. Additionally, BBR-CNPs resisted rat chondrocyte senescence and regulated mitochondrial function by activating the sirtuin 3 (SIRT3)/superoxide dismutase 2 (SOD2) signaling pathway. Collectively, these findings demonstrate the feasibility of employing BBR-CNPs as a potentially translatable clinical therapy with anti-aging properties, which are capable of impeding the advancement of OA. These particulate systems show promise as a viable option for sustained intra-articular delivery in OA treatment.