PROTAC‐Armed Electron Pump Triggers Disulfidptosis and Cuproptosis for Lung Cancer Therapy

ABSTRACT As emerging tumor therapies, cuproptosis and disulfidptosis exhibit unique potentials. However, high‐level glutathione (GSH) in the tumor microenvironment neutralizes cuproptosis‐essential copper ions, while pentose phosphate pathway‐mediated nicotinamide adenine dinucleotide phosphate (NADPH) regeneration alleviates disulfidptosis‐required disulfide bonds accumulation, substantially restricting their efficacy. Synergistically inducing these two death mechanisms faces challenges, including antioxidant defense systems, compensatory effects between metabolic pathways, and precise regulation difficulties. Since NADPH deficiency inhibits GSH synthesis, targeting the “glucose metabolism‐NADPH‐GSH” axis may provide a key strategy for synergistically enhancing the cuproptosis and disulfidoptosis effects. Herein, a biomimetic nanosystem LCM@CM was constructed, consisting of a proteolysis‐targeting chimera (PROTAC)‐armed lanthanum single‐atom‐doped multivalent copper heterojunction encapsulated within A549 cell membranes. The heterojunction acts as an “electron pump,” catalyzing the consumption of glucose, GSH, and NADPH while generating O 2 and releasing copper ions, effectively triggering cuproptosis and disulfidptosis. Meanwhile, PROTAC MZ1 can precisely inhibit the BRD4‐c‐MYC‐G6PD signaling pathway, systematically depleting NADPH and GSH from their metabolic sources to directly induce disulfidptosis and enhance the cuproptosis. Additionally, the homologous membrane coating enhances tumor‐specific targeting, and improves nanosystem enrichment in the tumor. By ingeniously integrating chemical catalysis and biological targeting, a strategy using PROTAC and nanoheterojunction to synergistically trigger cuproptosis and disulfidptosis is innovatively proposed, offering novel insights for lung cancer therapy.