Inducing\nPyroptosis and Cuproptosis Using Copper Carriers\nfor ROS-Augmented Effective Cancer Therapy

Copper overload shows promise as a therapeutic strategy\nby disrupting\ncopper homeostasis and inducing cell death pathways. However, challenges\ninclude the expulsion of excess copper from cells. This study introduces\nZCCP NPs, three-metal MOF nanoparticles that amplify reactive oxygen\nspecies (ROS) to enhance cellular copper uptake and reduce copper\nefflux. In the tumor microenvironment, ZCCP NPs decompose in response\nto H<sup>+</sup> and glutathione (GSH), releasing Zn and Co ions that\nincrease intracellular ROS. Additionally, the TMPyP ligand converts\nto Phlorin under near-infrared (NIR) excitation, raising tumor site\ntemperature and increasing cancer cell susceptibility to cuproptosis.\nElevated ROS and temperature activate the NLRP3 inflammasome and Caspase-1,\nleading to gasdermin D cleavage and pyroptosis. Enhanced ROS generation\nimpairs mitochondrial function and reduces copper efflux protein ATP7A\nexpression, promoting cuproptosis. This strategy combines pyroptosis\nand cuproptosis for effective tumor treatment.