DNA-damage-targeting copper nanoparticles induce cuproptosis for enhanced cancer radiotherapy.

Radiotherapy is a cornerstone of cancer therapy but is often undermined by tumor radioresistance arising from insufficient generation of reactive oxygen species (ROS) and limited DNA damage. Cuproptosis-a newly identified form of copper-dependent cell death-offers an innovative, yet untapped, approach to enhance radiosensitivity. Here, we report a first-of-its-kind copper-doped metal-organic framework nanoplatform, based on a ZIF-8 framework and loaded with the copper ionophore elesclomol, to concurrently induce cuproptosis and amplify radiotherapy. This nanoplatform (Cu-MOF@ELS) efficiently shuttles copper into cancer cell mitochondria, triggering excessive reactive oxygen species (ROS) production and mitochondrial dysfunction that synergize with radiation to promote extensive DNA damage. We demonstrate that Cu-MOF@ELS strongly induces cuproptosis in tumor cells and significantly boosts radiotherapeutic efficacy in vitro and in vivo, with treated mice showing pronounced tumor regression and minimal systemic toxicity. Our work pioneers a novel therapeutic paradigm by integrating cuproptosis induction with radiotherapy, establishing Cu-MOF@ELS as a groundbreaking radiosensitizer that exploits metabolic cell-death mechanisms to overcome tumor radioresistance.