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 feedback loop that induces cell death. Encapsulation within red blood cell membranes (FeN4Cl/RBC) improves biocompatibility and tumor targeting. Both in vitro and in vivo studies demonstrate that FeN4Cl/RBC substantially suppresses tumor growth through effective ferroptosis, presenting a promising approach for developing clinically relevant nanozyme-based therapeutics.
Yin et al. (2026) studied this question.