Self-assembled polymeric nanoparticles for redox- and gene-regulated Osteoarthritis therapy.

Osteoarthritis (OA) is a progressive degenerative joint disease characterized by synovial inflammation and cartilage degradation, and its progression is closely related to excessive production of reactive oxygen species (ROS) and upregulation of catabolic enzymes such as matrix metalloproteinases. Here, we developed a self-assembled multifunctional polymeric nanoparticle (NP) system for the co-delivery the ROS scavenger 2,2,6,6-Tetramethylpiperidoxyl (TEMPO) and small interfering RNA (siRNA) against MMP-13 (siMMP-13). The nanoplatform is constructed from antioxidant TEMPO-PEG-PLGA and cationic PEG-PLGA-OA9 to enable efficient siRNA encapsulation and intra-articular delivery. TEMPO mimics superoxide dismutase to neutralize ROS, while siMMP-13 silences catabolic gene expression to suppress cartilage degradation. This redox- and gene-regulatory NP system demonstrated potent anti-inflammatory and cartilage-protective effects in vitro and in vivo, effectively attenuating cartilage damage and inflammation in Osteoarthritis. This work presents a promising and translational approach to Osteoarthritis treatment via integrated redox and gene regulation strategies. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) remains a major clinical challenge due to its complex and multifactorial pathogenesis, which current palliative therapies fail to adequately address. This study presents a novel, multifunctional therapeutic strategy that concurrently targets two critical pathological features of OA-oxidative stress and extracellular matrix degradation-through the co-delivery of a reactive oxygen species (ROS) scavenger (TEMPO) and MMP-13-targeting siRNA via a self-assembled polymeric nanoparticle system. By integrating redox modulation and gene silencing within a single nanoplatform, this approach enables precise regulation of inflammatory and catabolic pathways, thereby enhancing therapeutic efficacy and cartilage preservation. The findings offer a promising foundation for the development of next-generation disease-modifying OA therapies with strong potential for clinical translation.