GSH-responsive self-assembled nanoplatform synergistically enhances cuproptosis through metabolic reprogramming and oxidative stress amplification.

Cuproptosis, an emerging copper-dependent regulated cell death pathway, demonstrates significant potential for overcoming therapeutic resistance in oncology. However, its clinical translation remains constrained by the poor bioavailability of copper ionophores and intrinsic resistance mechanisms in tumor cells. Here, we developed a tumor microenvironment-responsive nanoparticle platform (PEMA) co-loading an MPC1 (mitochondrial pyruvate carrier 1) overexpression plasmid and the copper ionophore Elesclomol to establish a synergistic "metabolic reprogramming-oxidative stress amplification" strategy. The PEMA nanoparticle design incorporated disulfide bonds to deplete intracellular glutathione (GSH), while Elesclomol-mediated copper transport induced mitochondrial dysfunction and reactive oxygen species (ROS) generation. In vitro, PEMA achieved >99% tumor cell eradication in ACHN renal carcinoma models, accompanied by characteristic DLAT oligomerization, FDX1 downregulation, and disruption of mitochondrial ultrastructure. In vivo, PEMA treatment induced substantial tumor regression in xenograft models without detectable systemic toxicity. This study establishes a novel therapeutic paradigm that integrates metabolic targeting with oxidative stress potentiation to overcome therapeutic resistance in solid tumors.