塩素配位鉄単原子ナノザイムによるトリプルネガティブ乳がん治療における強迫性アポトーシスの増幅

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.