“Trinity” Comprehensively Regulates the Tumor Microenvironment of Lipid-Coated CaCO₃@CuO₂ Nanoparticles Induces “Cuproptosis” in HCC

Tumor cell death induced by “cuproptosis” is a novel form of tumor death that differs from apoptosis induced by chemotherapy. It is expected to emerge as a new approach for cancer treatment. In this study, our focus was on exploiting the characteristic of “cuproptosis” which necessitates increased aerobic respiration to induce tumor cell death. To achieve this, we developed a novel drug delivery system using a CaCO 3 @CuO 2 lipid coating (CaCO 3 @CuO 2 @L). This system aimed to comprehensively modulate the tumor microenvironment and trigger “cuproptosis” in hepatocellular carcinoma (HCC) through the interaction between copper ions and peroxides. Experimental results revealed that the CaCO 3 @CuO 2 @L exhibited a distinct watermelon shape, with CuO 2 evenly distributed within the CaCO 3 nanoparticles. The nanoparticles had an average size of approximately 191 nm. In vitro studies demonstrated that the nanoparticles released CuO 2 in a slightly acidic environment while simultaneously elevating pH levels, reducing glutathione (GSH), and increasing oxygen production. Within liver cancer cells, the CaCO 3 @CuO 2 @L effectively regulated the acidity, GSH levels, and oxygen-depleted microenvironment through the “trinity” mechanism, ultimately inducing “cuproptosis” in HCC. Furthermore, in mouse models with transplanted tumors and orthotopic liver cancer tumors, the CaCO 3 @CuO 2 @L significantly suppressed tumor growth. By triggering “cuproptosis” in HCC, this study offers valuable insights for developing a comprehensive treatment approach for HCC. Ultimately, this research may pave the way for the clinical implementation of the drug delivery system based on “cuproptosis” in liver cancer treatment.