Hybrid calcium carbonate nanoparticles incorporated with capsaicin for tumor therapy via calcium overload mediated mitochondria damage and endoplasmic reticulum stress

Calcium ions (Ca 2+ ) play a critical role in a variety of cellular processes, with excessive intracellular Ca 2+ accumulation triggering cascades that can ultimately lead to cell death. This has prompted the development of calcium overload-based tumor therapies as a promising therapeutic strategy. In this study, we designed a pH-responsive nanoplatform where biocompatible calcium carbonate (CaCO 3 ) nanoparticles served as templates, co-doping with gallic acid (GA) and zinc ions (Zn 2+ ) to form a hollow structure. After PEGylation, the CaCO 3 hollow nanoparticles were utilized as an efficient drug delivery system for capsaicin (CAP), enabling a carrier-passenger synergy by providing Ca 2+ sources and enhancing TRPV1-agonized Ca 2+ influx in the tumor microenvironment, thereby promoting cancer cell apoptosis. The nanoparticles were further camouflaged with tumor-homologous cytomembranes, resulting in CAP/GA-Zn@CaCO 3 -PEG@M nanoparticles (CCaM NPs) with excellent stability and remarkable tumor-targeting ability. In TRPV1-overexpressing cancer cells, CCaM NPs effectively induce calcium overload, triggering three major cytotoxic mechanisms: i) mitochondria damage; ii) endoplasmic reticulum stress (ERS); and iii) cytoskeleton disruption. In both subcutaneous and orthotopic liver tumor models, intravenous administration of CCaM NPs demonstrated potent anti-tumor effects, enhanced tumor-specific accumulation, and favorable biosafety profiles. Overall, our work introduces a hybrid CAP delivery system based on CaCO 3 that modulates cellular calcium homeostasis, offering a synergetic and targeted approach to calcium-overload-directed tumor therapy. • A drug delivery system based on hollow calcium carbonate nanoparticles for capsaicin is proposed. • The CCaM NPs demonstrate effective tumor-targeting capability and calcium overload-mediated antitumor therapeutic effects. • The antitumor mechanisms of CCaM NPs involve Ca 2+ overload-triggered mitochondria damage, ERS, and cytoskeleton disruption.