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Abnormal mechanical loading exacerbates intracellular ROS accumulation and glutathione (GSH) depletion. While\n                    <jats:italic>N<\/jats:italic>\n                    \u2010acetylcysteine (NAC) has potent antioxidant properties, its therapeutic potential in OA is limited by rapid degradation and poor intraarticular retention. In this study, chondrocyte\u2010targeted, chondroitin sulfate (CS)\u2010modified PLGA nanoparticles (CS\u2010NAC\u2010NPs) 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\u2010NAC\u2010NPs attenuated mechanical stress\u2010induced 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\u2010NAC\u2010NPs significantly reduced cartilage degradation and osteophyte formation, improved histological scores, and maintained extracellular matrix homeostasis more effectively than free NAC or nontargeted NAC\u2010NPs. Notably, the therapeutic effect is abolished in GPX4\u2010deficient mice, confirming that CS\u2010NAC\u2010NPs act via GPX4\u2010mediated ferroptosis inhibition. Furthermore, in\u2009vivo tracking demonstrated excellent joint retention and no off\u2010target toxicity, underscoring their translational safety. This study introduces a novel nanotherapeutic platform that couples biomechanical targeting with redox\u2010responsive delivery to modulate ferroptosis, offering a promising disease\u2010modifying approach for OA treatment.\n                  <\/jats:p>","DOI":"10.1002\/smsc.202500440","type":"journal-article","created":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T07:40:22Z","timestamp":1764402022000},"source":"Crossref","is-referenced-by-count":5,"title":["Chondrocyte\u2010Targeted Nanoparticles Loaded with\n                    <i>N<\/i>\n                    \u2010Acetylcysteine Protect Articular Cartilage and Attenuate Osteoarthritis by Inhibiting Ferroptosis via Glutathione Maintenance"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-7981-9620","authenticated-orcid":false,"given":"Shaoyi","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery Qilu Hospital Cheeloo College of Medicine Shandong University  107 Wenhuaxi Road Jinan Shandong 250012 P. 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