Ultra-small Iron-based Nanoparticles Mitigate Rheumatoid Arthritis Inflammation via Macrophage Repolarization and SLC7A11/GPX4-Mediated Ferroptosis Inhibition

The characteristic pathological manifestations of rheumatoid arthritis (RA) include inflammatory cell infiltration, abnormal synoviocyte proliferation, and progressive bone and cartilage destruction. An excessive buildup of reactive oxygen species (ROS) within the joints is a critical factor promoting RA pathological progression. In this study, we innovatively employed a hard template-restricted controlled sintering carbonization strategy to fabricate ultra-small Fe 3 O 4 @C nanoparticles with hierarchical structures. The ultra-small Fe 3 O 4 @C nanoparticles exhibit multiple natural enzyme-mimic catalytic activity, effectively diminishing intracellular ROS levels in macrophages, while also facilitating the polarization toward the M2 phenotype, and significantly suppresses the production of pro-inflammatory cytokines. Mechanistic investigations reveal that Fe 3 O 4 @C significantly suppresses ferroptosis in synoviocytes and chondrocytes through regulation of the SLC7A11/GPX4 signalling pathway, thereby alleviating synovial tissue erosion and promoting type II collagen synthesis. In the collagen-induced arthritis mouse model, Fe 3 O 4 @C exhibited remarkable anti-inflammatory and chondroprotective effects, providing an innovative nanozyme therapeutic approach for RA treatment.