A Multifaceted Nanodrug Disrupts the Copper–Iron Homeostasis to Enhance Cancer Radiotherapeutic Effect

Radiation therapy (RT) is a core modality in cancer treatment; however, its efficacy is often limited by tumor resistance. Studies have shown that RT induces abnormal copper ion accumulation and iron reduction, thereby inhibiting ferroptosis and exacerbating therapeutic resistance. In this study, multiomics database analysis revealed that various RT-resistant cancer cell lines and patient-derived tumor models exhibit characteristics of disrupted copper homeostasis and enhanced copper ion-binding capacity. Hence, we have created a pH-responsive nanomicelle system based on dynamic iron-coordinated polyurethane (PCEF@Fe), utilizing a “copper chelation-iron delivery” synergistic strategy to reverse tumor metal metabolism abnormalities. This platform exploits the differential coordination properties of oxime–urethane ligands for copper/ferrous ions, triggering competitive metal exchange in the acidic tumor microenvironment: on one hand, the ligand captures Cu 2+ to disrupt copper homeostasis; on the other hand, it releases Fe 2+ to promote ferroptosis. Experimental results confirm that PCEF@Fe significantly reduces intracellular copper while increasing iron, enhancing RT sensitivity. Furthermore, fluorescein isothiocyanate was incorporated into PCEF@Fe, leading to fluorescence properties for real-time monitoring of the distribution and metabolic process. In conclusion, this study presents an innovative therapeutic approach that integrates RT, copper chelation, ferroptosis induction, and fluorescence nanotechnology to improve cancer treatment outcomes.