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Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction

Author

Listed:
  • Luwen Zhu

    (Zhejiang University
    Zhejiang University)

  • Jiahao Hu

    (Zhejiang University)

  • Xiaochuan Wu

    (Zhejiang University)

  • Jucong Zhang

    (Zhejiang University)

  • Xinyi Xu

    (Zhejiang University)

  • Xiajie Huang

    (Zhejiang University)

  • Bing Tian

    (Zhejiang University)

  • Chun-Xia Zhao

    (The University of Adelaide)

  • Yongzhong Du

    (Zhejiang University
    Zhejiang University)

  • Liming Wu

    (Zhejiang University)

Abstract

Ferroptosis and pyroptosis, as emerging regulated forms of cell death capable of overcoming apoptotic resistance, demonstrate promising potential in tumor therapy. Given that iron manipulation and reactive oxygen species elevation serve as common stimuli for both processes, inducing lysosomal membrane permeabilization (LMP) with ensuing release of lysosomal contents (including iron ions and cathepsins) is anticipated to realize dual induction of ferroptosis/pyroptosis. Herein, we report a folic acid and croconaine molecule-functionalized upconversion nanoparticle (UCNP-Cro/FA) that is able to mobilize intracellular stores of endogenous iron and spatiotemporally control the lysosome-intrinsic Fenton chemistry, thereby triggering LMP-associated cell death. The process of endogenous iron mobilization occurs through two key steps: Cro-mediated coordination of abundant Fe3+ ions within lysosomes, followed by UV-emitting upconversion core-mediated photoreduction, resulting in Fe2+ ions release. Both in vitro and in vivo experiments show that UCNP-Cro/FA + NIR treatment effectively boost LMP by endogenous iron-mediated •OH production, ultimately triggering irreversible tumor cell death via ferroptosis and Caspase-1/GSDMD-dependent pyroptosis pathways. Moreover, this process potentiates tumor immunogenicity, holding promise for tumor immunotherapy. Overall, this work proposes a feasible tumor therapy strategy that integrates ferroptosis and pyroptosis through the efficient application and activation of endogenous iron.

Suggested Citation

  • Luwen Zhu & Jiahao Hu & Xiaochuan Wu & Jucong Zhang & Xinyi Xu & Xiajie Huang & Bing Tian & Chun-Xia Zhao & Yongzhong Du & Liming Wu, 2025. "Programmed enhancement of endogenous iron-mediated lysosomal membrane permeabilization for tumor ferroptosis/pyroptosis dual-induction," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58124-7
    DOI: 10.1038/s41467-025-58124-7
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    References listed on IDEAS

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    1. Weier Bao & Ming Liu & Jiaqi Meng & Siyuan Liu & Shuang Wang & Rongrong Jia & Yugang Wang & Guanghui Ma & Wei Wei & Zhiyuan Tian, 2021. "MOFs-based nanoagent enables dual mitochondrial damage in synergistic antitumor therapy via oxidative stress and calcium overload," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
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