A Mitochondria‐Targeted Nanozyme Platform for Multi‐Pathway Tumor Therapy via Ferroptosis and Cuproptosis Regulation

Abstract Transition metal‐based nanotherapeutics, such as chemodynamic therapy and ferroptosis‐ or cuproptosis‐induced strategies, hold great potential for cancer treatment. Copper‐ and iron‐based nanozymes enhance reactive oxygen species (ROS) generation and regulate metal ion homeostasis, driving ferroptosis and cuproptosis. However, simultaneous delivery of copper and iron ions and the role of mitochondria‐targeted copper in inducing cuproptosis remain underexplored. Here, a dual‐functional nano‐heterojunction platform, MIL‐Cu 1.8 S‐TPP/FA, is reproted, integrating iron‐ and copper‐based components for synergistic ferroptosis and cuproptosis induction. Mitochondria‐targeted Cu 1.8 S nanodots demonstrated high biocompatibility and efficiently induced cuproptosis by disrupting mitochondrial iron‐sulfur proteins. Combined with MIL‐88B, the iron‐based metal‐organic framework, the MIL‐Cu 1.8 S heterojunction exhibited enhanced ROS catalytic activity, confirmed by density functional theory (DFT) analysis, with improved H 2 O 2 adsorption and lower energy barriers for peroxidase (POD)‐like reactions. The dual‐targeting MIL‐Cu 1.8 S‐TPP/FA nanoplatform effectively delivered copper ions to mitochondria and iron ions to tumor cells, modulating key ferroptosis‐ and cuproptosis‐related markers, such as GPX4, GSH, FDX‐1, and HSP70. The platform synergistically combined photothermal effects with multi‐pathway cell death mechanisms, achieving significant anti‐tumor efficacy in vitro and in vivo. This study underscores the therapeutic potential of synchronously delivering copper and iron ions and highlights mitochondria‐targeted strategies in advancing multi‐modal cancer therapies.