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Tandem-controlled lysosomal assembly of nanofibres induces pyroptosis for cancer immunotherapy

Nature Nanotechnology volume 20, pages 563–574 (2025)Cite this article

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Abstract

Pyroptosis has emerged as a promising approach for cancer immunotherapy. However, current pyroptosis inducers lack specificity for cancer cells and have a weak antitumour immune response. Here we report a tumour-specific nanoparticle (NP-NH-D5) that activates pyroptosis by disrupting lysosomes for cancer immunotherapy. NP-NH-D5 undergoes negative-to-positive charge reversal and nanoparticle-to-nanofibre transformation within tumour cell lysosomes through tandem response to extracellular matrix metallopeptidase-2 and intracellular reducing agents. The as-formed non-peptide nanofibres efficiently break the lysosomes and trigger gasdermin-D-mediated pyroptosis, leading to strong immunogenic cell death and alleviation of the immunosuppressive tumour microenvironment. In vivo, NP-NH-D5 inhibits orthotopic 4T1 breast tumours, prevents metastasis and recurrence, and prolongs survival without systemic side effects. Furthermore, it greatly enhances the effectiveness of PD-L1 antibody immunotherapy in the 4T1 late-stage lung metastasis and aggressive orthotopic Pan02 pancreatic tumour models. Our research may open pathways for developing stimuli-responsive pyroptosis inducers for precise cancer immunotherapy.

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Fig. 1: Schematic illustration of NP-NH-D5 to induce pyroptosis and an antitumour immune response.
Fig. 2: Characterization of F-C6-NH2 self-assembly into NFs.
Fig. 3: Characterization of NP-NH-D5 in vitro and in culture cells.
Fig. 4: NP-NH-D5 elicited robust antitumour immunity in orthotopic 4T1 tumour-bearing mice.
Fig. 5: NP-NH-D5 combined with anti-PD-L1 effectively eradicated late-stage 4T1 lung metastases.
Fig. 6: NP-NH-D5 synergized with anti-PD-L1 to effectively inhibit orthotopic Pan02 pancreatic tumours.

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Data availability

The main data that support the findings of this study are available within the paper and the Supplementary Information. Other raw and relevant data from the study are available for research purposes from the corresponding authors upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the National Key R&D Program of China (2021YFA0910003, 2020YFA0713801), the National Natural Science Foundation of China (22137003, 22274074), the Natural Science Foundation of Jiangsu Province (BK20232020), the State Key Laboratory of Analytical Chemistry for Life Science (5431ZZXM2408) and the Excellent Research Program of Nanjing University (ZYJH004).

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Authors and Affiliations

  1. State Key Laboratory of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Junya Zhang, Yuxuan Hu, Xidan Wen, Zhiyuan Feng, He Bai, Yinxing Miao, Jingjing Zhang, Jing-Juan Xu & Deju Ye

  2. State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China

    Zeyue Yang, Ziyi Wang, Qi Xue, Tian Tian, Peng Zheng & Jie Li

  3. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi, China

    Ling Qiu

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Contributions

D.Y. and Junya Zhang conceived the research plan. Junya Zhang and Y.H. synthesized the probes. X.W. established the tumour model. Z.Y. performed the AFM analysis. Z.W. and Z.Y. analysed the AFM data. H.B. and Junya Zhang performed the TEM analysis. Z.F. and Junya Zhang performed the CRISPR–Cas9-mediated knockout experiments. Junya Zhang, Q.X. and T.T. performed the flow cytometric analysis. Junya Zhang and Y.M. performed the in vivo experiments. L.Q. performed the molecular simulation. Junya Zhang, J.L., P.Z., Jingjing Zhang., J.-J.X. and D.Y. analysed the data. Junya Zhang. and D.Y. wrote the paper. All authors discussed the results and commented on the paper.

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Correspondence to Deju Ye.

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Nature Nanotechnology thanks Yuan Gao and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–147, Tables 1–7, Materials and Instruments, Methods and References.

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Zhang, J., Hu, Y., Wen, X. et al. Tandem-controlled lysosomal assembly of nanofibres induces pyroptosis for cancer immunotherapy. Nat. Nanotechnol. 20, 563–574 (2025). https://doi.org/10.1038/s41565-025-01857-9

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