Chondrocyte‐Targeted Nanoparticles Loaded with N ‐Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance

Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation. Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While N ‐acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte‐targeted, chondroitin sulfate (CS)‐modified PLGA nanoparticles (CS‐NAC‐NPs) is developed for sustained and localized delivery of NAC. These nanoparticles exhibit excellent physical and chemical properties, biocompatibility, and chondrocyte targeting capabilities. In vitro, CS‐NAC‐NPs attenuated mechanical stress‐induced ROS accumulation, preserved mitochondrial integrity, restored GSH levels, and suppressed ferroptosis, as evidenced by increased GPX4 expression and improved chondrocyte viability. In a murine model of OA, intraarticular injection of CS‐NAC‐NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC‐NPs. Notably, the therapeutic effect is abolished in GPX4‐deficient mice, confirming that CS‐NAC‐NPs act via GPX4‐mediated ferroptosis inhibition. Furthermore, in vivo tracking demonstrated excellent joint retention and no off‐target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox‐responsive delivery to modulate ferroptosis, offering a promising disease‐modifying approach for OA treatment.