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

Abstract

Tumor cells harness Ca²⁺ to maintain cellular homeostasis and withstand external stresses from various treatments. Here, a dual-channel Ca²⁺ nanomodulator (CAP-P-NO) is constructed 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, the 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.