Mitochondrial Ca²⁺-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO₃ nanoplatform for tumor synergistic therapy

The Ca²⁺ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO₃-based tumor microenvironment (TME) responsive nanoplatform (CaNP_CAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca²⁺-overloading synergistic therapy. In acidic TME, CaCO₃ decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca²⁺). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated ¹O₂ during PDT process not only directly killed cancer cells but also destroyed the Ca²⁺ buffering capacity, leading to the mitochondrial Ca²⁺-overloading. The increased Ca²⁺ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca²⁺-overloading, the CaNP_CAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. Statement of significance: In the manuscript, a CaCO₃-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNP_CAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca²⁺ buffering capacity was destroyed which led to the mitochondrial Ca²⁺-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca²⁺-overloading made the CaNP_CAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.