An ultrasound-responsive smart nanoplatform leads to mitochondrial apoptosis of tumor cells from multiple levels

Mitochondria, the energy suppliers of cells, are crucial for cell survival and proliferation. Tumor therapy based on mitochondrial apoptosis holds good promise. Currently utilized strategies, such as the production of CO and ROS and Ca2+ overload, are not highly selective and have limited effectiveness. In this study, a smart nanoplatform (V-Mn@Ca) controlled by ultrasound (US) and with high therapeutic efficacy was designed, which can specifically target the tumor site and activate mitochondrial apoptosis at multiple levels. Specifically, VS4, featuring a narrow band gap, are utilized to generate a Fenton-like effect. Loading Mn(CO)5Br enables a US-induced release of CO and depletion of GSH, which would further enhance ROS-mediated mitochondrial apoptosis. Finally, an encapsulated CaCO3 shell layer disrupts Ca2+ homeostasis in tumor cells. Overall, our study shows that the V-Mn@Ca platform triggers CO, ROS, and Ca2+ production in a controlled manner. Thus, providing sonodynamic therapy and CO therapy on a timed-targeted basis for enhanced mitochondrial apoptosis and subsequent tumor cell death, which inhibits tumor growth.