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

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, CaCO₃ nanoparticles (NPs) are modified with MCF-7 cell aptamer (CaCO₃/Mn/Cu@lip-Apt). When entering the cell, CaCO₃/Mn/Cu@lip-Apt decomposed and released Mn* (Mn²⁺/Mn³⁺/Mn⁴⁺), Cu²⁺ and Ca²⁺. The high valence Mn ion in Mn* can effectively consume GSH to produce Mn²⁺ which catalyzed H₂O₂ to produce reactive oxygen species (ROS), while reducing the GSH concentration. The production of ROS promoted the influx of exogenous Ca²⁺. The large accumulation of Ca²⁺ led to intracellular calcium overload, resulting in mitochondrial dysfunction and metabolism disorders. The depletion of GSH promoted the accumulation of Cu²⁺, which in turn triggered cuproptosis. This strategy showed excellent antitumor effects and provided a new way to study disease treatment.