Calcium carbonate-actuated ion homeostasis perturbator for oxidative damage-augmented Ca²⁺/Mg²⁺ interference therapy

Ion homeostasis distortion through exogenous overload or underload of intracellular ion species has become an arresting therapeutic approach against malignant tumor. Nevertheless, treatment outcomes of such ion interference are always compromised by the intrinsic ion homeostasis maintenance systems in cancer cells. Herein, an ion homeostasis perturbator (CTC) is facilely designed by co-encapsulation of carvacrol (CAR) and meso-tetra-(4-carboxyphenyl)porphine (TCPP) into pH-sensitive nano-CaCO₃, aiming to disrupt the self-defense mechanism during the process of ion imbalance. Upon the endocytosis of CTC into tumor cells, lysosomal acidity can render the decomposition of CaCO₃, resulting in the instant Ca²⁺ overload and CO₂ generation in cytoplasm. Simultaneously, CaCO₃ disintegration triggers the release of CAR and TCPP, which are devoted to TRPM7 inhibition and sonosensitization, respectively. The malfunction of TRPM7 can impede the influx of Mg²⁺ and allow unrestricted influx of Ca²⁺ based on the antagonism relationship between Mg²⁺ and Ca²⁺, leading to an aggravated Ca²⁺/Mg²⁺ dyshomeostasis through ion channel deactivation. In another aspect, US-triggered cavitation can be significantly enhanced by the presence of inert CO₂ microbubbles, further amplifying the generation of reactive oxygen species. Such oxidative damage-augmented Ca²⁺/Mg²⁺ interference therapy effectively impairs the mitochondrial function of tumor, which may provide useful insights in cancer therapy.