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

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    A Peptide-Copper Self-Assembled Nanoparticle for Enhanced Cuproptosis by Metabolic Reprogramming in Tumor Cells
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    • Wei Zhang
      Wei Zhang
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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    • Ziling Chen
      Ziling Chen
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
      More by Ziling Chen
    • Chen Xiong
      Chen Xiong
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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    • Lizhen Yuan
      Lizhen Yuan
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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    • Jing-Jing Hu
      Jing-Jing Hu
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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      Orcidhttps://orcid.org/0000-0002-1449-6137
    • Jun Dai*
      Jun Dai
      Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China
      Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education) Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China
      *Email: [email protected]
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      Orcidhttps://orcid.org/0009-0003-8751-410X
    • Fan Xia
      Fan Xia
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
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      Orcidhttps://orcid.org/0000-0001-7705-4638
    • Xiaoding Lou*
      Xiaoding Lou
      State Key Laboratory of Biogeology and Environmental Geology, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan 430074, China
      *Email: [email protected]
      More by Xiaoding Lou
      Orcidhttps://orcid.org/0000-0002-6556-2034
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    ACS Nano

    Cite this: ACS Nano 2024, 18, 50, 34244–34256
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    https://doi.org/10.1021/acsnano.4c12123
    Published December 3, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    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+ in situ, 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.

    Copyright © 2024 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsnano.4c12123.

    • Synthesis pathways of fluorescent molecules and probes, characterization, in vitro and in vivo experiments, Figures S1–S37, Scheme S1, and Table S1 (PDF)

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    ACS Nano

    Cite this: ACS Nano 2024, 18, 50, 34244–34256
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.4c12123
    Published December 3, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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