A Dual-Channel Ca 2+ Nanomodulator Induces Intracellular Ca 2+ Disorders via Endogenous Ca 2+ Redistribution for Tumor Radiosensitization.

Tumor cells harness Ca 2+ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, we construct a dual-channel Ca 2+ nanomodulator (CAP-P-NO) 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, our 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. This article is protected by copyright. All rights reserved.