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    Metabolic Nanoregulators Induce Ferroptosis and Change Metabolite Flow to Reverse Immunosuppressive Tumor Microenvironment
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    • Yu Wang
      Yu Wang
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Yu Wang
    • Qinjun Chen
      Qinjun Chen
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Qinjun Chen
    • Yifan Luo
      Yifan Luo
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Yifan Luo
    • Yangqi Qu
      Yangqi Qu
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Yangqi Qu
    • Xuwen Li
      Xuwen Li
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Xuwen Li
    • Haolin Song
      Haolin Song
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Haolin Song
    • Chufeng Li
      Chufeng Li
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Chufeng Li
    • Yiwen Zhang
      Yiwen Zhang
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Yiwen Zhang
    • Tao Sun
      Tao Sun
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      More by Tao Sun
    • Chen Jiang*
      Chen Jiang
      Department of Pharmaceutics, School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai 201203, China
      Department of Digestive Diseases, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0001-5223-2725
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    ACS Nano

    Cite this: ACS Nano 2024, 18, 51, 34996–35012
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    https://doi.org/10.1021/acsnano.4c13425
    Published December 12, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    Aberrant energy and substance metabolic pathways of tumor cells critically support tumor cell proliferation by hijacking the resources from nonmalignant cells, thereby establishing a metabolite flow favorable to tumor progression. This metabolic adaptation of tumor cells further modulates the immune landscape, ultimately creating a tumor microenvironment characterized by drug resistance and immunosuppression. The synergistic regulation of energy and substance metabolic pathways might be a good antitumor therapeutic paradigm. However, due to the metabolic convergence, it is crucial to selectively modulate the aberrant metabolism of tumor cells without compromising the functionality of other cells. Small-molecule drugs have the ability to target a wide range of biomolecules for antitumor therapy, but their application is limited by undesirable toxicities. Constructing nanodrug delivery systems can improve their properties and allow for the inclusion of multiple drugs, thereby exerting synergistic antitumor effects. In this study, we developed a two-drug codelivery system using drugs-conjugated multibranched polymers to modulate tumor cell metabolism by exploiting synthetic lethal pathways for safe and effective antitumor therapy. By delivery of adapalene and erastin simultaneously through nanoparticles, the material and energy metabolism of tumor cells can be regulated. This nanoparticle construction achieves tumor tissue targeting and responsive drug release, alters metabolite flow within tumor cells, and effectively kills tumor cells. Additionally, the nanoparticles can reverse the tumor immunosuppressive microenvironment, starting from single-cell regulation to whole-lesion control.

    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.4c13425.

    • 1H NMR spectrum results of A3, PA, PA2, and PA4 polymers; 1H NMR spectrum results of compounds and polymers; FT-IR and GPC results of A3, PA, PA2, and PA4 polymers; characteristics of A3, PA, PA2, and PA4 polymers; total energy, potential, and temperature temporal evolution of the three polymers; stability of three kinds of nanoparticles in vitro; in vivo, and ex vivo results of biodistribution of DiD-labeled nanoparticles; drug accumulation in the tumor tissues after administration of three kinds of nanoparticles; fluorescence results of tumor organoids; synergistic effects of two drugs on three cells; response mechanism of drug release; toxicity of nanoparticles on MIA PaCa-2 and KPC cells; Western blot results and its semiquantification results; relative metabolites changes on KPC cells after different treatments; EGFR expression and its semiquantification results on three types of cells; pharmacokinetic characteristic and accumulation of tissues of free drugs and nanoparticles; hemolysis test of nanoparticles; H&E staining of major organs after different treatments in MIA PaCa-2 tumor-bearing mice; Western blot analysis after treatments in MIA PaCa-2 tumor-bearing models; apoptosis and proliferation of tumor tissues after different treatments in MIA PaCa-2 tumor-bearing mice; changes in matrix abundance after different treatments in MIA PaCa-2 tumor-bearing mice; evaluation of biosafety after different treatments in KPC tumor-bearing mice; Western blot analysis after treatments in KPC tumor-bearing models; apoptosis and proliferation of tumor tissues after different treatments in KPC tumor-bearing mice; changes in matrix abundance after different treatments in KPC tumor-bearing mice; metabolites changes after G-PA4/E treatments in KPC tumor-bearing mice; changes in CTL, Th1, and Treg cells after different treatments in KPC tumor-bearing mice; and changes in MDSC, M1, and M2 cells after different treatments in KPC tumor-bearing mice (PDF)

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    ACS Nano

    Cite this: ACS Nano 2024, 18, 51, 34996–35012
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsnano.4c13425
    Published December 12, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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