Biodegradable and Efficient Charge‐Migrated Z‐Scheme Heterojunction Amplifies Cancer Ferroptosis by Blocking Defensive Redox System

Abstract

Ferroptosis is an emerging non‐apoptotic death process, mainly involving lipid peroxidation (LPO) caused by iron accumulation, which is potentially lethal to the intrinsically apoptotic‐resistant malignant tumor. However, it is still restricted by the inherent antioxidant systems of tumor cells and the poor efficacy of traditional iron‐based ferroptosis initiators. Herein, the study develops a novel ferroptosis‐inducing agent based on PEGylated Cu⁺/Cu²⁺‐doped black phosphorus@polypyrrole heterojunction (BP@CPP), which is constructed by utilizing the phosphate on the surface of BP to chelate Cu ions and initiating subsequent in situ polymerization of pyrrole. As a novel Z‐scheme heterojunction, BP@CPP possesses an excellent photocatalytic activity in which the separated electron–hole pairs under laser irradiation endow it with powerful oxidizing and reducing capacities, which synergy with Cu⁺/Cu²⁺ self‐cycling catalyzing Fenton‐like reaction to further strengthen reactive oxygen species (ROS) accumulation, glutathione (GSH) depletion, and glutathione peroxidase 4 (GPX4) inactivation, ultimately leading to efficient ferroptosis. Systematic in vitro and in vivo evaluations demonstrate that BP@CPP effectively inhibit tumor growth by inducing desired ferroptosis while maintaining a favorable biosafety in the body. Therefore, the developed BP@CPP‐based ferroptosis initiator provides a promising strategy for ferroptosis‐like cancer therapy.