A Peptide-Copper Self-Assembled Nanoparticle for Enhanced Cuproptosis by Metabolic Reprogramming in Tumor Cells

Cuproptosis is a type of metabolic cell death and exhibits great potential for cancer treatment. However, currently, most cuproptosis-based therapies are primarily effective in tumor cells reliant on mitochondrial respiration, limiting their broader application. The Warburg effect highlights that many tumors predominantly rely on glycolysis to meet their rapid metabolic demands, but glycolysis-dependent cells are less sensitive to copper ions than their mitochondrial-respiration-dependent counterparts, making it difficult to induce cuproptosis in these cells. Herein, we designed a copper-loaded peptide-based nanoparticle (MHRC@Cu) to enhance cuproptosis by metabolic reprogramming in a wider range of glycolysis-dependent tumor cells. Specifically, triggered by the acidic environment and laser irradiation, MHRC@Cu effectively released Cu²⁺ inside the cells. Then the peptide-conjugated probe (MHRC) reprogrammed glycolysis-dependent tumor cells, making them more dependent on mitochondrial respiration and increasing their sensitivity to copper ions. Additionally, the H₂O₂ generated by the photodynamic effect underwent Fenton reaction with Cu²⁺ <i>in situ</i>, producing highly toxic ·OH, which depleted GSH and disrupted copper efflux protein, thereby exacerbating copper deposition in cells. Through these synergistic mechanisms, MHRC@Cu significantly enhanced cuproptosis in glycolysis-dependent tumor cells, achieving up to 96% inhibition of tumor growth. This copper-loaded peptide-based nanoparticle offers a versatile and potent strategy for enhancing cuproptosis and may inspire the development of advanced self-assembled nanotherapeutic platforms.