Asymmetric Coordination of Iron Single‐Atom Nanozymes with Efficient Self‐Cascade Catalysis for Ferroptosis Therapy

Abstract

Single‐atom nanozymes (SAzymes) hold great promise in tumor therapy due to their maximized atomic utilization and well‐defined electronic structures. However, they still face challenges of activity, specificity, and targeting that impede therapeutic efficacy. Herein, a practical strategy is reported to construct asymmetric N, S‐coordinated Fe SAzymes (Fe‐S/N‐C). Benefiting from the regulatory influence of S atoms on the disruption of local charge symmetry of center Fe atoms, the Fe‐S/N‐C SAzymes exhibit significantly enhanced peroxidase (POD)‐ and glutathione oxidase (GSHOx)‐like activities, with catalytic efficiencies being 6.33 and 47.88 times higher than their symmetric Fe‐N₄ counterparts, respectively. Theoretical calculations demonstrate that the asymmetric atomic interface configuration increases electron localization around center Fe sites, thus facilitating the adsorption and activation of H₂O₂ and O₂. By camouflaging with macrophage membranes, the tumor‐targeting nanocatalytic agents (M@Fe‐S/N‐C) trigger enhanced self‐cascade catalysis in the tumor microenvironment for ferroptosis‐based tumor‐specific therapy. These results open up a promising avenue for addressing the limitations associated with current SAzymes‐based tumor therapies.