A\nPeptide-Copper Self-Assembled Nanoparticle for Enhanced\nCuproptosis by Metabolic Reprogramming in Tumor Cells

Cuproptosis\nis a type of metabolic cell death and exhibits great\npotential for cancer treatment. However, currently, most cuproptosis-based\ntherapies are primarily effective in tumor cells reliant on mitochondrial\nrespiration, limiting their broader application. The Warburg effect\nhighlights that many tumors predominantly rely on glycolysis to meet\ntheir rapid metabolic demands, but glycolysis-dependent cells are\nless sensitive to copper ions than their mitochondrial-respiration-dependent\ncounterparts, making it difficult to induce cuproptosis in these cells.\nHerein, we designed a copper-loaded peptide-based nanoparticle (MHRC@Cu)\nto enhance cuproptosis by metabolic reprogramming in a wider range\nof glycolysis-dependent tumor cells. Specifically, triggered by the\nacidic environment and laser irradiation, MHRC@Cu effectively released\nCu<sup>2+</sup> inside the cells. Then the peptide-conjugated probe\n(MHRC) reprogrammed glycolysis-dependent tumor cells, making them\nmore dependent on mitochondrial respiration and increasing their sensitivity\nto copper ions. Additionally, the H<sub>2</sub>O<sub>2</sub> generated\nby the photodynamic effect underwent Fenton reaction with Cu<sup>2+</sup> <i>in situ</i>, producing highly toxic ·OH, which\ndepleted GSH and disrupted copper efflux protein, thereby exacerbating\ncopper deposition in cells. Through these synergistic mechanisms,\nMHRC@Cu significantly enhanced cuproptosis in glycolysis-dependent\ntumor cells, achieving up to 96% inhibition of tumor growth. This\ncopper-loaded peptide-based nanoparticle offers a versatile and potent\nstrategy for enhancing cuproptosis and may inspire the development\nof advanced self-assembled nanotherapeutic platforms.