Supramolecular Self-assembled Polyphenol Nanoparticles Alleviate Osteoarthritis by Inhibiting Chondrocyte Ferroptosis

Osteoarthritis (OA) is a degenerative joint disease with no currently available curative treatments. Recent studies have implicated ferroptosis in the progression of cartilage degradation and inflammation in OA, highlighting it as a potential therapeutic target. Here, we report the synthesis of epigallocatechin gallate–proline polyphenolic nanodrugs (EP NDs), prepared via a Mannich condensation reaction between epigallocatechin gallate (EGCG) and proline (Pro), followed by self-assembly, aiming to attenuate disease progression through the suppression of ferroptosis. In vitro experiments demonstrated that EP NDs possess potent free radical scavenging activity, effectively scavenging free radicals (DPPH, ABTS, ·OH, O 2 - ·) and reducing intracellular reactive oxygen species (ROS) levels in chondrocytes. Furthermore, EP NDs significantly suppressed oxidative stress-induced downregulation of glutathione peroxidase 4 (GPX4), restored iron homeostasis, attenuated lipid peroxidation, and preserved mitochondrial function, thereby alleviating metabolic dysfunction in chondrocytes under ferroptotic conditions. Additionally, EP NDs exhibited excellent anti-inflammatory and immunomodulatory properties, promoting the polarization of macrophages from the M1 to the M2 phenotype. Transcriptomic analysis revealed that EP NDs upregulated the NRF2 signaling pathway while downregulating the MAPK pathway, contributing to ferroptosis inhibition and delayed OA progression. In a rat model of OA, EP NDs effectively mitigated ferroptosis, alleviated inflammation, and exerted significant chondroprotective effects. In general, these findings demonstrate that EP NDs enhance cartilage protection through synergistic anti-ferroptotic, antioxidant, anti-inflammatory, and immunomodulatory mechanisms, thereby presenting a simple, efficient, and promising therapeutic approach for OA.