Bilayer self-assembly encapsulated by engineered vesicle disrupts glutathione to induce Disulfidptosis-enhanced cuproptosis for tumor immunotherapy

Cuproptosis, a copper-dependent programmed cell death, can effectively activate tumor immunogenicity and reverse the immunosuppressive tumor microenvironment (TME). Nevertheless, the overexpression of xCT-SLC7A11 in tumor cells is beneficial for maintaining the biosynthesis of glutathione (GSH) to counteract cuproptosis. Herein, copper-based bilayer self-assembly Cel-Cu/DHA (CCD) encapsulated by red blood cell vesicle engineered with folate (RF), CCD@RF nanoparticles (NPs), have been prepared to target synergistic therapeutic mechanisms and induce disulfidptosis-enhanced cuproptosis for augmented anti-tumor immunotherapy by disrupting intracellular GSH balance. In xCT-SLC7A11^high cancer cells, dihydroartemisinin (DHA) pre-released from CCD@RF NPs serves to impede glucose metabolism, thereby downregulating NADPH levels, causing the accumulation of cystine and the collapse of actin cytoskeleton proteins. This simultaneously induces disulfidptosis and blocks the source of cysteine which is essential for GSH synthesis, thereby amplifying cuproptosis with assistance of celastrol (Cel). Moreover, Cu²⁺ released from CCD@RF NPs, once reduced by GSH, could catalyze Fenton-like reactions to generate hydroxyl radicals (·OH), further disrupting intracellular redox homeostasis. Tumor cells undergoing immunogenic cell death (ICD) derived from disulfidptosis-enhanced cuproptosis, could release antigens, inducing robust immune responses, ultimately effectively inhibiting tumor growth and metastasis. This work proposes a novel dual-pronged therapeutic strategy by disrupting intracellular redox balance, offering a new direction for future anti-tumor immunotherapy.