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While emerging heteronuclear diatomic catalysts show potential in inflammatory modulation, their therapeutic efficacy remains constrained by insufficient control over interatomic synergy and multi\u2010active sites regulatory precision. This work pioneers a spatial confinement strategy to engineer heteronuclear diatomic nanozymes (HDNs) with dual\u2010pathway therapeutic capabilities for RA. We investigate Fe and Co sites embedded in a nitrogen\u2010coordinated carbon matrix, where the heteronuclear pair adopts an asymmetric Fe and Co configuration with tunable interatomic distances, facilitated by N\u2010bridging ligands. This architecture enables spin\u2010state and\n                    <jats:italic>d<\/jats:italic>\n                    \u2010band center alignment, lowering activation barriers for enzymatic ROS scavenging, which demonstrates multi\u2010enzyme mimetic activity, achieving 3.66\u2010fold higher SOD\u2010like enzyme reaction and 3.21\u2010fold enhanced CAT\u2010like catalytic efficiency versus monoatomic controls. HDNs reverse RA by enhancing M2 macrophage polarization to achieve an anti\u2010inflammatory environment. Transcriptome sequencing validates that HDNs modulate immune homeostasis and inhibits the IL\u201017 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\u2010related pathologies.\n                  <\/jats:p>","DOI":"10.1002\/smll.73633","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T08:35:58Z","timestamp":1777624558000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Spatial Confinement\u2010Engineered Heteronuclear Diatomic Nanozymes for Modulation of Immune Homeostasis in Rheumatoid Arthritis"],"prefix":"10.1002","volume":"22","author":[{"given":"Minke","family":"Wu","sequence":"first","affiliation":[{"name":"Suzhou Key Laboratory of Nanotechnology and Biomedicine Institute of Functional Nano and Soft Materials (FUNSOM), Jiangsu Key Laboratory For Carbon\u2010Based Functional Materials and Devices Soochow University  Suzhou Jiangsu 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