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

Luwen Zhu, Jiahao Hu, Xiaochuan Wu, Jucong Zhang, Xinyi Xu, Xiajie Huang, Bing Tian (), Chun-Xia Zhao (), Yongzhong Du () and Liming Wu ()
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Luwen Zhu: 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
Liming Wu: Zhejiang University

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58124-7

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