A Dual‐Channel Ca2+ Nanomodulator Induces Intracellular Ca2+ Disorders via Endogenous Ca2+ Redistribution for Tumor Radiosensitization

Abstract Tumor cells harness Ca 2+ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, a dual‐channel Ca 2+ nanomodulator (CAP‐P‐NO) is constructed that can induce irreversible intracellular Ca 2+ disorders via the redistribution of tumor‐inherent Ca 2+ for disrupting cellular homeostasis and thus improving tumor radiosensitivity. Stimulated by tumor‐overexpressed acid and glutathione, capsaicin and nitric oxide are successively escaped from CAP‐P‐NO to activate the transient receptor potential cation channel subfamily V member 1 and the ryanodine receptor for the influx of extracellular Ca 2+ and the release of Ca 2+ in the endoplasmic reticulum, respectively. The overwhelming level of Ca 2+ in tumor cells not only impairs the function of organelles but also induces widespread changes in the gene transcriptome, including the downregulation of a set of radioresistance‐associated genes. Combining CAP‐P‐NO treatment with radiotherapy achieves a significant suppression against both pancreatic and patient‐derived hepatic tumors with negligible side effects. Together, the study provides a feasible approach for inducing tumor‐specific intracellular Ca 2+ overload via endogenous Ca 2+ redistribution and demonstrates the great potential of Ca 2+ disorder therapy in enhancing the sensitivity for tumor radiotherapy.