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Mitochondria are the “power plant” of the cell, providing a constant source of energy, and are involved in a variety of intracellular signaling pathways. Among these pathways, Ca2+homeostasis is closely related to the normal function of mitochondria. By destroying the Ca2+steady state of mitochondria and disrupting their multiple cellular activities, tumor cell killing can be achieved. In addition, the presence of an intracellular oxidative stress state triggers the closure of cellular calcium channels, which leads to intracellular Ca2+retention and enrichment. We designed a targeted and tumor microenvironment (TME)-responsive CaO2-based nanosystem that can selectively target cancer cells for pH-controlled degradation and drug release, alter cellular physiological mechanisms by disrupting Ca2+homeostasis in an artificial manner, and introduce mitochondrial Ca2+excess-mediated apoptosis. Meanwhile, the production of Ca(OH)2will raise the pH of the microenvironment and subsequently promote the oxidation process of glutathione by H2O2released from CaO2degradation, achieving the goal of remodeling TME. Moreover, calcium overload of tumor cells and calcification of tissues can both inhibit tumor growth and act as a contrast agent for computed tomography imaging.