Stimuli-responsive copper–iodide nanoparticles for low-dose X-ray-induced photodynamic therapy and enhanced cuproptosis

s High-dose radiotherapy is known to enhance cuproptosis, and when combined with copper–coordinated delivery to tumors, it shows promise as a synergistic treatment mechanism. In this study, we present a simple method for synthesizing stimuli-responsive copper-iodide nanoparticles using a commercial, insoluble copper-iodide powder that emitted a strong radioluminescence matching the absorbance of the clinical dye indocyanine green. The copper-iodide nanoparticles efficiently absorbed and transferred radiation energy to ICG activating an X-ray-induced photodynamic therapy (X-PDT) mechanism. After accumulating in tumors, the low-dose X-PDT process first generated reactive oxygen species to induce cell death. The tumor microenvironment then caused the copper-iodide nanoparticles to decompose and release copper and iodide ions, which promoted cuproptosis. X-PDT followed by ion-induced cell death achieved 87.7% tumor regression in CT26 tumor-bearing mice without systemic toxicity. This work establishes a therapeutic paradigm that exploits metal metabolism dysregulation to potentiate radiation-based therapies. Statement of significance Stimuli-responsive copper-iodide nanoparticles were synthesized and induced by X-ray-induced photodynamic therapy to decompose, releasing copper and iodide ions that caused tumor cell death. (1) Commercial copper–iodide powder exhibited strong radioluminescent properties and formed stable nanoparticles with the clinical dye indocyanine green, which realized X-ray-induced photodynamic therapy under X-ray irradiation. (2) After accumulating in tumors and following X-ray-induced photodynamic therapy, the decomposition of copper-iodide nanoparticles in the tumor tissue induced cell death.