CaCO3-based nanomedicine with multi-functions of ferroptosis-apoptosis and microenvironment regulation in cancer

Although chemotherapy combined with immunotherapy has become a widely accepted method of cancer treatment, their therapeutic outcomes are seriously hindered, including chemotherapy drugs resistance and the immunosuppression microenvironment. On one hand, overexpression of glutathione (GSH) leads to chemotherapy drugs resistance by reducing the oxidative stress caused by cytotoxic reactive oxygen species. On the other hand, hypoxia and lactic acid accumulation lead to poor efficacy of immunotherapy. In this study, we designed a pH-responsive CaCO3 nanoparticles coloading L-Buthionine-sulfoximine (BSO) and siPD-L1. Such system conferred oxidative stress augmentation through Ca2 +-overloading triggered mitochondrial dysfunction, BSO-mediated GSH exhaustion, and siPD-L1 induced gene knockdown, leading to remarkable apoptosis and ferroptosis. In vivo anti-tumor results revealed that CaCO3 could carry oxygen into cells, which can relieve tumor hypoxia, regulate the tumor microenvironment of immune suppression and enhance immunotherapy. This work highlighted that the construction of CaCO3-based nanomedicine to induce ferroptosis related to oxidative stress and reverse tumor immunosuppression, providing a new and promising strategy for cancer treatment.