Design of a CuFe metal–organic framework nanozyme to enhance radiotherapy efficacy via mitochondrial oxidative stress amplification and induction of ferroptosis and cuproptosis

Despite advances in radiotherapy (RT), complete tumor eradication remains a clinical challenge, largely due to the insufficient activation of non-apoptotic cell death pathways such as ferroptosis and cuproptosis. To address this, we developed a bimetallic nanozyme, CuFe-MOF-TPP, comprising a CuFe-based metal–organic framework conjugated with triphenylphosphine to enhance RT sensitivity through provoking cuproptosis and ferroptosis. CuFe-MOF-TPP targeted to mitochondria, destroying redox balance by peroxidase-, oxidase-, and glutathione oxidase-like activities. These catalytic functions promoted excessive reactive oxygen species generation and glutathione depletion, leading to oxidative stress in mitochondria. This redox imbalance triggered the generation of ferrous ions, which accelerated lipid peroxidation and subsequently augmented ferroptosis. Concurrently, cuproptosis was promoted through copper ions-mediated aggregation of dihydrolipoamide S-acetyltransferase. Notably, the combination of CuFe-MOF-TPP and RT result in potent tumor suppression via the coordinated delivery of metal ions and spatiotemporally regulated catalytic activity. This strategy offers a promising approach for overcoming radioresistance by synergistically amplifying mitochondrial oxidative stress and activating ferroptosis and cuproptosis, with significant translational potential for clinical cancer therapy.