Nanodrugs Targeting Key Factors of Ferroptosis Regulation for Enhanced Treatment of Osteoarthritis

Abstract Osteoarthritis (OA) is a globally prevalent degenerative joint disease. 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)‐responsive nanoparticle is developed by linking deferasirox (DEF) and pterostilbene (PTE) with thioketal and incorporating cerium ions (Ce), creating Ce@D&P nanoparticles (NPs), which offer multitarget regulation of ferroptosis. The characteristics of Ce@D&P NPs are evaluated and their therapeutic effects on IL‐1β‐stimulated chondrocytes are verified. Results show that Ce@D&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&P NPs exerted their effects by regulating oxidative stress and lipid metabolism in chondrocytes. To better treat destabilization of the medial meniscus (DMM)‐induced OA in mice, Ce@D&P NPs via intra‐articular injection are delivered. The results show that Ce@D&P NPs alleviate cartilage matrix damage and slow OA progression. Overall, the findings indicate that Ce@D&P NPs represent a promising multitarget drug delivery system, and Ce@D&P NPs may be an effective strategy for OA treatment.