Mitochondrial‐Targeted Copper Delivery for Cuproptosis‐Based Synergistic Cancer Therapy

Abstract Cuproptosis is dependent on mitochondrial respiration modulation by targeting lipoylated tricarboxylic acid cycle (TCA) cycle proteins, showing great potential in cancer treatment. However, the specific release of copper ions at mitochondrial is highly needed and still a major challenge to trigger cellular cuproptosis. Herein, a metal‐organic framework‐based nanoplatform (ZCProP) is designed for mitochondrial‐targeted and ATP/pH‐responsive Cu 2+ and prodigiosin release. The released Cu 2+ promotes aggregation of lipoylated protein and loss of Fe‐S cluster protein, resulting in cell cuproptosis. In the meanwhile, Cu 2+ can concert with prodigiosin to induce mitochondrial dysfunction and DNA damage and enhance cell cuproptosis. Furthermore, this nanoplatform has an ability to deplete glutathione, which not only further promotes cuproptosis but also triggers cell ferroptosis by the suppression of glutathione peroxidase 4, an anti‐ferroptosis protein. Collectively, the designed ZCProP nanoplatform can responsively release cargos at mitochondrial and realize a conspicuous therapeutic efficacy through a cuproptosis‐mediated concerted effect. Along with its excellent biocompatibility, this nanoplatform may provide a novel therapeutic modality paradigm to boost cancer therapeutic strategies based on cuproptosis.