Hafnium oxide-based sensitizer with radiation-triggered cuproptosis for radiotherapy

Advanced sensitizers hold significant clinical importance in improving precise tumor radiotherapy while minimizing harm to normal tissues. In our work, the HfO₂-based radiosensitizer (ES@HM-HfO₂:Cu) is developed, in which Cu ions are doped in the shell of the HfO₂ nanocapsules, and elesclomol (ES), the Cu ionophore, is filled in the hollow mesoporous structure. Following the X-ray irradiation, ES@HM-HfO₂:Cu nanocapsules with high-energy deposition effect enable precise and controllable release of Cu ions within the tumor to trigger cuproptosis, exerting dual sensitization outcomes. Consequently, the ES@HM-HfO₂:Cu, leveraging the advantage of cuproptosis activation, achieves a tumor inhibition rate of 77.9 % with no apparent toxicity. Notably, the cuproptosis induced by the released Cu ions from ES@HM-HfO₂:Cu nanocapsules under X-ray irradiation reinforces the sensitization of HM-HfO₂ by promoting mitochondrial lipoylated protein aggregation and iron-sulfur cluster protein loss. Hence, the innovative HfO₂-based radioenhancer achieves intensified radiosensitization through X-ray-responsive cuproptosis, offering profound medical implications for advancing clinical radiotherapy.