Ultrasound-actuated ion homeostasis perturbator for oxidative damage-augmented Ca2+ interference therapy and combined immunotherapy

Calcium ion therapy has shown promise for cancer treatment, but its efficacy is limited by the cellular calcium buffering mechanism. Herein, an ion homeostasis disruptor (PCCa) was synthesized using an in situ mineralization method. The surface of the porphyrin-metal-organic framework PCN was coated with calcium carbonate (CaCO₃), aimed at causing Ca²⁺ overload and disrupting the self-defense mechanism during ion imbalance. Upon internalization into tumor cells, PCCa undergoes lysosomal acidification-induced CaCO₃ decomposition, leading to instantaneous Ca²⁺ overload. Simultaneously, under ultrasonic irradiation, the meso-tetra-(4-carboxyphenyl)porphine (TCPP) within the ion homeostasis disruptor generates reactive oxygen species (ROS), which impairs cellular calcium buffering capacity and amplifies cell damage caused by calcium overload. In addition, PCCa could also induce immunogenic cell death, release tumor-associated antigens (TAA), and act as an adjuvant, thereby promoting dendritic cell maturation and enhancing the antitumor activity of CD8⁺ T cells. In mouse models, PCCa not only led to significant regression of subcutaneous mammary tumors but also demonstrated substantial anti-metastatic effects. In summary, the proposed ultrasound-actuated Ca²⁺ interference strategy is promising to deactivate the ion homeostasis maintenance system, contributing to the attainment of splendid tumor treatment outcome with reliable biosafety, which may provide useful insights in cancer therapy.