Spatial Confinement‐Engineered Heteronuclear Diatomic Nanozymes for Modulation of Immune Homeostasis in Rheumatoid Arthritis

ABSTRACT The progression of rheumatoid arthritis (RA) is critically aggravated by synovial M1 macrophage‐mediated inflammatory infiltration and excessive reactive oxygen species (ROS) accumulation. While emerging heteronuclear diatomic catalysts show potential in inflammatory modulation, their therapeutic efficacy remains constrained by insufficient control over interatomic synergy and multi‐active sites regulatory precision. This work pioneers a spatial confinement strategy to engineer heteronuclear diatomic nanozymes (HDNs) with dual‐pathway therapeutic capabilities for RA. We investigate Fe and Co sites embedded in a nitrogen‐coordinated carbon matrix, where the heteronuclear pair adopts an asymmetric Fe and Co configuration with tunable interatomic distances, facilitated by N‐bridging ligands. This architecture enables spin‐state and d ‐band center alignment, lowering activation barriers for enzymatic ROS scavenging, which demonstrates multi‐enzyme mimetic activity, achieving 3.66‐fold higher SOD‐like enzyme reaction and 3.21‐fold enhanced CAT‐like catalytic efficiency versus monoatomic controls. HDNs reverse RA by enhancing M2 macrophage polarization to achieve an anti‐inflammatory environment. Transcriptome sequencing validates that HDNs modulate immune homeostasis and inhibits the IL‐17 and TNF pathways, promoting chondrocyte recovery. Our findings establish insights into the spatial confinement effect of HDNs, establishing a transformative platform for remodeling redox and immune homeostasis in RA‐related pathologies.