Spin-State Modulation by Atom–Cluster Synergy Steers H2O2 Conversion toward a Catalase-like Decomposition Pathway for Anti-Inflammatory Therapy

Abstract Nanozymes have emerged as promising enzyme mimics for anti-inflammatory therapy. However, their catalytic efficiency and substrate selectivity generally remain inferior to those of natural enzymes. Single-atom nanozymes (SAzymes), with isolated metal centers resembling enzymatic active sites, represent an important advance toward rational design of nanozyme, but achieving enzyme-like selectivity remains challenging. Herein, we reported a spin-state modulation strategy to prepare Fe–N–C nanozyme with coexisting single atoms and nanoclusters (Fe SA+NC ) via reductive-gas pyrolysis. Experimental analyses and density functional theory calculations revealed that Fe nanoclusters induced local symmetry breaking and charge redistribution around FeN 4 sites, shifting the Fe centers toward a higher spin configuration and thereby modulating the free energy changes of the H 2 O 2 conversion pathway. As a result, Fe SA+NC showed dramatically enhanced catalase (CAT)-like activity (333.79 U mg −1 ) and suppressed peroxidase (POD)-like activity (38.49 U mg −1 ), achieving superior selectivity compared to Fe SAzymes (Fe SA ), which showed comparable CAT- and POD-like activities (62.39 and 60.39 U mg −1 , respectively). Moreover, Fe SA+NC achieved a higher superoxide dismutase (SOD)-like activity (929.27 U mg −1 ) than Fe SA (249.68 U mg −1 ), enabling efficient SOD-CAT cascade. Fe SA+NC effectively scavenged excessive intracellular reactive oxygen species, suppressed M1 macrophage polarization, and enhanced the therapeutic efficacy of intra-articular stem cell injection in a rat model of rheumatoid arthritis, a representative chronic inflammatory disease. This work highlights an atom–cluster synergy strategy for steering H 2 O 2 conversion towards antioxidant pathway, offering a general design principle for safer, more controllable and more efficient nanozyme-based anti-inflammatory therapeutics.