Tumor Microenvironment-Sensitive Ca²⁺ Nanomodulator Combined with the Sonodynamic Process for Enhanced Cancer Therapy

Tumor therapy presents significant challenges, and conventional treatments exhibit limited therapeutic effectiveness. Imbalance of calcium homeostasis as a key cause of tumor cell death has been extensively studied in tumor therapy. Calcium overload therapy has garnered significant interest as a new cancer treatment strategy. This study involves the synthesis of a transformable nanosonosensitizer with a shell of a calcium ion nanomodulator. The nanosystem is designed to induce mitochondrial dysfunction by combining the calcium ion nanomodulator, nanosonosensitizer, and chemotherapeutic drug. Under ultrasound-activated conditions, CaCO₃ dissolves in the tumor microenvironment, causing the nanosonosensitizer to switch from the "off" to the "on" state of ROS generation, exacerbating mitochondrial calcium overload. A two-dimensional Ti₃C₂/TiO₂ heterostructure generates reactive oxygen species (ROS) under ultrasound and exhibits an efficient sonodynamic effect, enhancing calcium overload. Under ultrasound irradiation, Ti₃C₂/TiO₂@CaCO₃/KAE causes multilevel damage to mitochondria by combining the effects of rapid Ca²⁺ release, inhibiting Ca²⁺ efflux, enhancing tumor inhibition, and converting a "cold" tumor into a "hot" tumor. Therefore, this study proposes a method to effectively combine mitochondrial Ca²⁺ homeostasis and sonodynamic therapy (SDT) by the preparing pH-sensitive, double-activated, and multifunctional Ti₃C₂/TiO₂-based nanosystems for cancer therapy.