Chlorine-Coordinated Iron Single-Atom Nanozymes for Amplified Ferroptosis in Triple-Negative Breast Cancer Therapy

Triple-negative breast cancer (TNBC) represents an aggressive breast cancer subtype with limited therapeutic options and poor prognosis. Although single-atom nanozymes (SAzymes) show promise in cancer therapy, their ferroptosis-inducing capability remains limited. Herein, we present a rationally designed iron-based SAzyme with axial chlorine coordination (FeN₄Cl) that integrates catalytic and metabolic functions to enhance ferroptosis in TNBC. The engineered Fe-Cl coordination strategically modulates the d-band center relative to the Fermi level, resulting in significantly enhanced peroxidase-like activity (2.0-fold increase) and glutathione oxidase-like activity (3.2-fold increase) activities compared to conventional FeN₄ structures. Importantly, this electronic modulation triggers NCOA4-mediated ferritinophagy, establishing an autonomous iron supply mechanism that elevates intracellular labile Fe²⁺ levels. The synergistic disruption of redox homeostasis coupled with amplified Fenton reactions creates a potent feedback loop that induces cell death. By incorporating this SAzyme into a red blood cell membrane-based biomimetic delivery system (FeN₄Cl/RBC), we achieved enhanced biocompatibility and tumor targeting. In vivo studies demonstrated significant tumor suppression, presenting a promising approach for developing clinically relevant nanozyme-based therapeutics.