Copper-based inorganic nanozymes enhance the electrical conductivity of tumors to synergistically induce the pyroptosis, ferroptosis, and apoptosis of tumors

Abstract

Electrotherapy (ET) effectively ablates solid tumors, inhibiting their growth. However, poor electrical conductivity limits ET efficacy for tumors. Herein, we have developed a novel copper-based inorganic nanozyme that enhances the electrical ablation of tumors. Our approach involves liposome-encapsulated copper oxide (CuO) embedded with potassium chloride nanoclusters (LCuPC). When LCuPCs enter cancer cells, they quickly dissolve due to the weakly acidic tumor microenvironment, releasing an abundance of salt ions, including Cu²⁺, K⁺, and Cl⁻. The release of salt ions significantly improves the tumor electroconductivity, thereby enhancing the ET efficiency for tumors. Furthermore, these salt ions also upregulate the expression of cleaved caspase-1 and GSDMD, activating the pyroptosis of cancer cells. Additionally, the released Cu²⁺ ions catalyze the conversion of cellular overexpressed H₂O₂ into highly toxic ˙OH through a Fenton-like reaction. This process causes damage to the mitochondria, leading to the induction of apoptosis and ferroptosis in cancer cells. Moreover, the electrical stimulation transforms chloride ions into hypochlorite radicals, further enhancing the oxidative stress levels in cancer cells and promoting ROS-mediated cancer cell death. In an in vivo experiment, we demonstrated that LCuPC dramatically inhibit tumor growth through the pathways of pyroptosis, ferroptosis, and apoptosis. This innovative strategy provides a promising approach for enhancing ET efficiency for tumors.