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

AbstractTumor cells harness Ca2+ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, we construct a dual‐channel Ca2+ nanomodulator (CAP‐P‐NO) that can induce irreversible intracellular Ca2+ disorders via the redistribution of tumor‐inherent Ca2+ 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 Ca2+ and the release of Ca2+ in the endoplasmic reticulum, respectively. The overwhelming level of Ca2+ 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 Ca2+ overload via endogenous Ca2+ redistribution and demonstrates the great potential of Ca2+ disorder therapy in enhancing the sensitivity for tumor radiotherapy.This article is protected by copyright. All rights reserved