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Download Hi-Res ImageDownload to MS-PowerPointCite This:J. Am. Chem. Soc. 2024, 146, 50, 34568-34582
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    Lysosome-Mitochondria Cascade Targeting Nanoparticle Drives Robust Pyroptosis for Cancer Immunotherapy
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    • Jianxiong Liu
      Jianxiong Liu
      State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Yue Yan
      Yue Yan
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Yimeng Zhang
      Yimeng Zhang
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Xingquan Pan
      Xingquan Pan
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Heming Xia
      Heming Xia
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Jiayi Zhou
      Jiayi Zhou
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Fangjie Wan
      Fangjie Wan
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Xinyu Huang
      Xinyu Huang
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Weiwei Zhang
      Weiwei Zhang
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
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    • Qiang Zhang
      Qiang Zhang
      State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      More by Qiang Zhang
      Orcidhttps://orcid.org/0000-0002-8862-3098
    • Binlong Chen*
      Binlong Chen
      State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-9529-2522
    • Yiguang Wang*
      Yiguang Wang
      State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China
      Chemical Biology Center, Peking University, Beijing 100191, China
      Ningbo Institute of Marine Medicine, Peking University, Ningbo 315832, China
      *Email: [email protected]
      More by Yiguang Wang
      Orcidhttps://orcid.org/0000-0002-1676-4211
    Other Access OptionsSupporting Information (3)

    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2024, 146, 50, 34568–34582
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.4c12264
    Published December 5, 2024
    Copyright © 2024 American Chemical Society
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    Abstract

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    The subcellular distribution of cargoes plays a crucial role in determining cell fate and therapeutic efficacy. However, achieving the precise delivery of therapeutics to specific intracellular targets remains a significant challenge. Here, we present a trimodular and acid/enzyme-gated nanoplatform (TAEN) that undergoes disassembly within acidic endosomes and then is cleaved by lysosomal cathepsin B to facilitate efficient and targeted transport of released cargoes into mitochondria compartments. By utilizing this nanovehicle, we successfully achieve selective sorting of photosensitizer molecules into mitochondria with a colocalization coefficient of up to 0.98, leading to the generation of reactive oxygen species stress specifically within the mitochondria for potent pyroptosis-based cancer therapy. The induction of mitochondrial stress triggers the intrinsic apoptotic pathway as well as caspase-3/gasdermin-E (GSDME) cascade, resulting in an enhanced cancer cell killing efficacy by nearly 2 orders of magnitude as compared to lysosomal stress. Furthermore, due to its superior capability to stimulate both innate and adaptive immune responses, our mitochondria-sorted nanophotosensitizer exhibits robust antitumor immune efficacy in multiple tumor-bearing mice models. This study not only provides insights into engineering nanomedicines for subcellular targeted delivery but also offers a valuable toolkit for advanced research in the field of nanobiology at subcellular resolution.

    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/jacs.4c12264.

    • Additional experimental details, materials, methods, and chemical characterizations (PDF).

    • MCF-7-GFP cells with TAENmi + IR treatment (AVI)

    • MCF-7-GFP cells with TAENly + IR treatment (AVI)

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    Journal of the American Chemical Society

    Cite this: J. Am. Chem. Soc. 2024, 146, 50, 34568–34582
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jacs.4c12264
    Published December 5, 2024
    Copyright © 2024 American Chemical Society
    Request reuse permissions

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