“Trinity”\nComprehensively Regulates\nthe Tumor Microenvironment of Lipid-Coated CaCO<sub>3</sub>@CuO<sub>2</sub> Nanoparticles Induces “Cuproptosis” in HCC

Tumor\ncell death induced by “cuproptosis” is a novel\nform of tumor death that differs from apoptosis induced by chemotherapy.\nIt is expected to emerge as a new approach for cancer treatment. In\nthis study, our focus was on exploiting the characteristic of “cuproptosis”\nwhich necessitates increased aerobic respiration to induce tumor cell\ndeath. To achieve this, we developed a novel drug delivery system\nusing a CaCO<sub>3</sub>@CuO<sub>2</sub> lipid coating (CaCO<sub>3</sub>@CuO<sub>2</sub>@L). This system aimed to comprehensively modulate\nthe tumor microenvironment and trigger “cuproptosis”\nin hepatocellular carcinoma (HCC) through the interaction between\ncopper ions and peroxides. Experimental results revealed that the\nCaCO<sub>3</sub>@CuO<sub>2</sub>@L exhibited a distinct watermelon\nshape, with CuO<sub>2</sub> evenly distributed within the CaCO<sub>3</sub> nanoparticles. The nanoparticles had an average size of approximately\n191 nm. In vitro studies demonstrated that the nanoparticles released\nCuO<sub>2</sub> in a slightly acidic environment while simultaneously\nelevating pH levels, reducing glutathione (GSH), and increasing oxygen\nproduction. Within liver cancer cells, the CaCO<sub>3</sub>@CuO<sub>2</sub>@L effectively regulated the acidity, GSH levels, and oxygen-depleted\nmicroenvironment through the “trinity” mechanism, ultimately\ninducing “cuproptosis” in HCC. Furthermore, in mouse\nmodels with transplanted tumors and orthotopic liver cancer tumors,\nthe CaCO<sub>3</sub>@CuO<sub>2</sub>@L significantly suppressed tumor\ngrowth. By triggering “cuproptosis” in HCC, this study\noffers valuable insights for developing a comprehensive treatment\napproach for HCC. Ultimately, this research may pave the way for the\nclinical implementation of the drug delivery system based on “cuproptosis”\nin liver cancer treatment.