Multifunctional nanozyme-mediated synergistic activation of cuproptosis, ferroptosis, and pyroptosis for potent antitumor therapy.

Novel forms of programmed cell death are pivotal in regulating tumor progression and therapeutic response; however, single-mode cell death induction often fails to overcome apoptotic escape and drug resistance of tumor cells. This study designed and synthesized a multifunctional nanozyme, ZIF-8/Cu/Fe@GOx (ZCFG), to synergistically inhibit tumor cell growth via cuproptosis/ferroptosis/pyroptosis. Its compensatory mechanisms collectively overcome tumor cell characteristics such as apoptotic escape and drug resistance. Leveraging its multi-enzyme-like activity, ZCFG achieves self-sustained H₂O₂ production, massive glutathione (GSH) depletion, and hydroxyl radical (·OH) bursts to induce tumor cell death. Furthermore, copper and iron ions overload induce metabolic disruption and mitochondrial dysfunction, triggering abnormal aggregation of dihydrolipoamide S-acetyltransferase (DLAT), loss of Fe-S cluster proteins, and accumulation of lipid peroxides to induce cuproptosis and ferroptosis in tumor cells. Notably, the intracellular reactive oxygen species (ROS) bursts and zinc ion overload synergistically activate the caspase-1/GSDMD-dependent pyroptosis pathway, which further amplifies the antitumor effects of cuproptosis and ferroptosis, achieving mutually reinforcing therapeutic effects. This work provides a novel therapeutic strategy for tumor treatment by constructing a cascade-catalyzed nanozyme platform that mediates multimodal synergistic antitumor therapy via cuproptosis, ferroptosis, and pyroptosis.