Supramolecular self-assembly of EGCG–cysteine nanodrugs for ferroptosis and oxidative stress inhibition in chondrocytes to treat osteoarthritis

ABSTRACT: Osteoarthritis (OA) is a common chronic degenerative joint disease that is characterized mainly by the destruction of articular cartilage, synovial inflammation and the formation of bony encumbrances and severely affects the quality of life of middle-aged and elderly individuals. Recent studies have shown that ferroptosis plays an important role in the development of OA. The aim of this study was to utilize nanoparticles (EC NPs) formed by the self-assembly of epigallocatechin-3-gallate (EGCG) and cysteine to treat OA by inhibiting ferroptosis. The properties of the EC NPs were evaluated at the molecular level, and their therapeutic effects on H 2 O 2 -stimulated chondrocytes were verified. At the molecular level, EC NPs inhibited ROS levels, abnormal accumulation of Fe 2+ and lipid peroxidation, elevated the expression of glutathione peroxidase 4 (GPX4) to inhibit ferroptosis, repaired cartilage metabolism disorders, and alleviated the progression of OA. Transcriptomic analysis further revealed that EC NPs could exert therapeutic effects by inhibiting multiple inflammatory signaling pathways. To verify their efficacy in vivo, the present study used a mouse medial meniscus instability (DMM)-induced OA model, and EC NPs were administered via intra-articular injection. The results showed that EC NPs were able to significantly attenuate damage to the cartilage matrix and delay the pathological progression of OA. In conclusion, the use of EC NPs, as a green, simple and efficient biotherapeutic strategy, is expected to provide new ideas and methods for the clinical treatment of OA.