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Recent studies highlight the role of ferroptosis in OA progression. Targeting ferroptosis regulation presents a promising therapeutic strategy for OA; however, current research primarily focuses on single targets associated with ferroptosis. In this study, a reactive oxygen species (ROS)\u2010responsive nanoparticle is developed by linking deferasirox (DEF) and pterostilbene (PTE) with thioketal and incorporating cerium ions (Ce), creating Ce@D&amp;P nanoparticles (NPs), which offer multitarget regulation of ferroptosis. The characteristics of Ce@D&amp;P NPs are evaluated and their therapeutic effects on IL\u20101\u03b2\u2010stimulated chondrocytes are verified. Results show that Ce@D&amp;P NPs reduce ROS levels, mitigate inflammation, chelate iron to inhibit ferroptosis, and balance extracellular matrix (ECM) metabolism in chondrocytes. Mechanistically, transcriptomics and metabolomics analyses suggest that Ce@D&amp;P NPs exerted their effects by regulating oxidative stress and lipid metabolism in chondrocytes. To better treat destabilization of the medial meniscus (DMM)\u2010induced OA in mice, Ce@D&amp;P NPs via intra\u2010articular injection are delivered. The results show that Ce@D&amp;P NPs alleviate cartilage matrix damage and slow OA progression. Overall, the findings indicate that Ce@D&amp;P NPs represent a promising multitarget drug delivery system, and Ce@D&amp;P NPs may be an effective strategy for OA treatment.<\/jats:p>","DOI":"10.1002\/advs.202412817","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T05:45:07Z","timestamp":1737524707000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Nanodrugs Targeting Key Factors of Ferroptosis Regulation for Enhanced Treatment of Osteoarthritis"],"prefix":"10.1002","volume":"12","author":[{"given":"Dong","family":"Wang","sequence":"first","affiliation":[{"name":"Institute of Orthopaedics and Traumatology The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine)  Hangzhou 310000 China"},{"name":"Department of Orthopaedics Hangzhou Hospital of Traditional Chinese Medicine Hangzhou TCM Hospital Affiliated to Zhejiang 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