Bai@Cu-MOF alleviates osteoarthritis by targeting ferroptosis and restoring chondrocyte redox balance.

Abstract

Cartilage degeneration in osteoarthritis (OA) is closely linked to ferroptosis-driven chondrocyte loss and extracellular matrix (ECM) degradation, yet effective therapeutic strategies targeting this process remain elusive. Herein, we engineered a novel baicalin-loaded copper-based metal-organic framework nanodelivery system (Bai@Cu-MOF) designed to activate endogenous antioxidant defenses to inhibit ferroptosis and restore ECM homeostasis. In both IL-1β-induced chondrocytes and OA model, Bai@Cu-MOF demonstrated superior efficacy compared to free baicalin. It potently activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/ heme oxygenase-1 (HO-1) signaling axis, leading to the upregulation of the anti-ferroptotic protein glutathione peroxidase 4 (GPX4) and downregulation of the pro-ferroptotic protein acyl-CoA synthetase long-chain family member 4 (ACSL4). This scavenged intracellular ROS and labile Fe2+, restored glutathione levels, and suppressed lipid peroxidation, thereby arresting the ferroptotic cascade in chondrocytes. Consequently, this molecular modulation promoted the synthesis of matrix components such as type II collagen (Col2), inhibited MMP13-mediated degradation, and significantly reduced glycosaminoglycan loss. Crucially, mechanistic validation using the specific Nrf2 inhibitor ML385 effectively abolished the protective effects of Bai@Cu-MOF against oxidative stress, ferroptosis markers, and ECM metabolic imbalance in vitro. Furthermore, ML385 abolished the therapeutic benefits in vivo, resulting in exacerbated cartilage degeneration characterized by elevated OARSI scores, loss of Safranin O staining, thinning of hyaline cartilage, and increased synovial CTX-II levels. Collectively, Bai@Cu-MOF employs inhibit the ferroptosis cascade via Nrf2/HO-1-GPX4 axis, effectively mitigating OA progression at the molecular, cellular, and tissue levels. These findings provide a novel theoretical basis for developing structure-preserving therapeutic strategies for OA based on ferroptosis regulation.