Nanoenhanced‐Cuproptosis Results From the Synergy of Calcium Overload and GSH Depletion with the Increasing of Intracellular Ca/Mn/Cu Ions

Abstract Cuproptosis is a newly discovered copper‐dependent form of cell death. Intracellular glutathione (GSH) acts as a copper chelator to inhibit cuproptosis, so the reduction of GSH concentration is conducive to enhancing the cuproptosis of cells. In order to reduce GSH content and interfere with mitochondrial metabolism, a strategy based on calcium overload and GSH depletion to enhance cuproptosis is proposed in this study. Containing manganese (Mn) and copper (Cu) elements, CaCO 3 nanoparticles (NPs) are modified with MCF‐7 cell aptamer (CaCO 3 /Mn/Cu@lip‐Apt). When entering the cell, CaCO 3 /Mn/Cu@lip‐Apt decomposed and released Mn* (Mn 2+ /Mn 3+ /Mn 4+ ), Cu 2+ and Ca 2+ . The high valence Mn ion in Mn* can effectively consume GSH to produce Mn 2+ which catalyzed H 2 O 2 to produce reactive oxygen species (ROS), while reducing the GSH concentration. The production of ROS promoted the influx of exogenous Ca 2+ . The large accumulation of Ca 2+ led to intracellular calcium overload, resulting in mitochondrial dysfunction and metabolism disorders. The depletion of GSH promoted the accumulation of Cu 2+ , which in turn triggered cuproptosis. This strategy showed excellent antitumor effects and provided a new way to study disease treatment.