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_1.8S-TPP/FA, is reproted, integrating iron- and copper-based components for synergistic ferroptosis and cuproptosis induction. Mitochondria-targeted Cu_1.8S 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_1.8S heterojunction exhibited enhanced ROS catalytic activity, confirmed by density functional theory (DFT) analysis, with improved H₂O₂ adsorption and lower energy barriers for peroxidase (POD)-like reactions. The dual-targeting MIL-Cu_1.8S-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.