Dendritic Cu²⁺-Doped Ca₂SiO₄Nanosphere for Cancer Therapy via Double Ion Interference

Ion interference therapy (IIT) is a promising cancer treatment strategy that can reverse ion distribution via bioactive nanomaterials so as to interfere with or hinder the physiological processes such as metabolism and proliferation of tumor cells. In this study, a dendritic Cu²⁺-doped calcium silicate nanosphere (Ca₂SiO₄) loaded with ruthenium red (RuR) and disulfiram (DSF) (RD-CCP) was constructed for self-enhanced chemodynamic therapy and IIT of tumors through the combination of Cu and Ca. Under the slightly acidic environment of the tumor, dendritic RD-CCP nanospheres (NPs) rapidly collapsed, and a toxic dithiocarbamate-Cu complex was generated in situ through the chelation reaction between DSF and the co-released Cu²⁺ions. ROS accumulation was promoted by Fenton-like reaction between the Cu⁺ions and the high level of H₂O₂and glutathione. In addition, Ca²⁺-overload was promoted by the combination of the input of exogenous Ca²⁺and the participation of RuR, which can inhibit the Ca²⁺transport channel (MCU and SERCA), therefore promoting mitochondrial damage and enhancing oxidative stress in tumor cells. Furthermore, calcium transport channel imbalance caused by oxidative stress can promote tumor calcification and necrosis. In conclusion, dendritic RD-CCP NPs can simultaneously induce a Fenton-like response and a calcium-related signal imbalance at the tumor site through the double interference of Cu²⁺and Ca²⁺, eventually leading to rapid tumor apoptosis, which has great application potential in the clinical application of tumor therapy.