Targeting ferroptosis with a thiol-modified Fe3O4 nanozyme hydrogel to protect cartilage and attenuate osteoarthritis progression

Schematic illustration of the mechanism by which a Fe 3 O 4 @MPTS hydrogel achieves targeted delivery of Fer-1 and inhibits chondrocyte ferroptosis to delay the progression of OA by activating the Slc7a11/GPX4 axis. • Ferroptosis signatures in osteoarthritic cartilage were systematically identified. • A thiol-modified Fe 3 O 4 nanozyme hydrogel was engineered to inhibit ferroptosis. • The nanozyme hydrogel suppressed oxidative stress and restored chondrocyte function. • In vivo delivery of the hydrogel alleviated cartilage damage in a DMM OA model. Osteoarthritis (OA) is a degenerative disease closely associated with chondrocyte programmed cell death, in which ferroptosis plays a key role. The solute carrier family 7 member 11/glutathione peroxidase 4 (Slc7a11/GPX4) signaling axis is the central pathway regulating ferroptosis, but its role in OA has not been fully elucidated. In this study, we constructed a temperature-sensitive poly(lactic-co-glycolic acid)-polyethylene glycol-poly(lactic-co-glycolic acid) (PLGA-PEG-PLGA) hydrogel delivery system based on Fe 3 O 4 nanoparticles modified with 3-mercaptopropyltrimethoxysilane (Fe 3 O 4 @MPTS, thiol-modified Fe 3 O 4 nanoparticles) to achieve the targeted and controlled release of ferrostatin-1 (Fer-1), aiming to intervene in Slc7a11/GPX4-mediated ferroptosis. Key ferroptosis-related factors were screened via bioinformatics, and the nanocomposite was evaluated using an Erastin-induced chondrocyte model and a destabilization of the medial meniscus (DMM) mouse model. Results showed that the hydrogel effectively scavenged reactive oxygen species and accumulated ferrous iron, activated the Slc7a11/GPX4 pathway, and significantly inhibited ferroptosis. In vivo , the system markedly alleviated cartilage degeneration and remodeled subchondral bone. RNA sequencing revealed transcriptional reprogramming of ferroptosis, NF-κB, and glutathione metabolism pathways. This study clarifies the therapeutic value of the Slc7a11/GPX4 axis and presents a novel, targeted nanotherapeutic platform for retarding OA progression.