Unlocking Catalytic Activity via Tuning Fe 3d Spin State in Fe Dual-Atom Nanozymes with Atomically Dispersed Fe2-N6 Configurations for Reprogramming Immuno-Redox Microenvironment in Rheumatoid Arthritis

Abstract Single-atom nanozymes hold great promise for treating reactive oxygen species (ROS)-driven inflammatory diseases, yet their catalytic activity remains limited by unfavorable spin configurations and strong adsorption of reaction intermediates. Here, we report a rational design of high-spin Fe dual-atom nanozymes (HS Fe 2 -N 6 /DANs) with atomically dispersed Fe 2 -N 6 configurations that unlocks superior ROS-scavenging catalytic performance by tuning the Fe 3d spin state, enabling effective reprogramming of the immuno-redox microenvironment in rheumatoid arthritis (RA). Density functional theory calculations verify that HS Fe 2 -N 6 /DAN exhibits superior hydroxyl radical scavenging, superoxide dismutase-like, and catalase-like activities. The enhanced performance originates from Fe-Fe dual-site coupling, optimized spin density, and reduced intermediate desorption energy relative to low-spin Fe-N 4 single-atom nanozymes (LS Fe-N 4 /SAN). To overcome RA acidic microenvironment-induced activity loss and chondrocyte pyroptosis, we further encapsulated Fe 2 -N 6 /DANs into a pH-responsive nMgO/Gel hydrogel (nMgO/Gel@Fe 2 -N 6 /DAN). In vitro and in vivo experiments in a collagen-induced arthritis model confirm that nMgO/Gel@Fe 2 -N 6 /DAN effectively eliminates ROS, repolarizes pro-inflammatory M1 macrophages into reparative M2 phenotypes, inhibits chondrocyte pyroptosis by suppressing the NF-κB pathway, alleviates synovial inflammation, and maintains cartilage integrity. This triadic design paradigm of ‘redox-regulated nanoarchitectures-electronic modulation-biological function’ establishes a versatile framework for engineering next-generation spin-dependent single-atom nanozymes for the therapy of ROS-driven degenerative diseases.