Engineering 2D Cu-composed metal-organic framework nanosheets for augmented nanocatalytic tumor therapy

The engineered nanoformulation that can be activated by intracellular tumor microenvironment, including acidic pH, overexpressed H₂O₂, and high concentration of glutathione (GSH), features high efficacy to eradicate tumor cells with the intrinsic specificity and therapeutic biosafety. However, the relatively slow reaction rate of traditional Fe²⁺-mediated Fenton reaction induces the low production amount of reactive oxygen species (ROS) and subsequently the limited therapeutic outcome against tumors. Here, we established Cu (II)-based two-dimensional (2D) metal-organic framework (MOF) nanosheets as a distinct chemoreactive nanocatalyst for GSH-triggered and H₂O₂-augmented chemodynamic therapy (CDT), depending on the "AND" logic gate, for significant tumor suppression. After internalization by tumor cells, the MOF catalytic nanosheets reacted with local GSH for inducing GSH consumption and reducing the Cu²⁺ into Cu⁺. Subsequently, abundant hydroxyl radicals (·OH) generation was achieved via Cu⁺-mediated Fenton-like catalytic reaction. The dual effects of ·OH production and GSH depletion thus enhanced ROS production and accumulation in tumor cells, leading to significant cellular apoptosis and tumor inhibition, which was systematically demonstrated in both 4T1 and MDA-MB-231 tumor models. Therefore, GSH and H₂O₂, serve as an "AND" logic gate to trigger the Cu⁺-mediated Fenton-like reaction and reduce GSH level for augmented CDT with high therapeutic specificity and efficacy, thus inducing cellular apoptosis primarily through ferroptosis at the RNA sequence level.