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A pyroptosis nanotuner for cancer therapy

Nature Nanotechnology volume 17, pages 788–798 (2022)Cite this article

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Abstract

Pyroptosis is a gasdermin-mediated programmed necrosis that occurs via membrane perforation and that can be exploited for biomedical applications in cancer therapy. However, inducing specific pyroptotic cancer cell death while sparing normal cells is challenging. Here, we report an acid-activatable nanophotosensitizer library that can be used to spatiotemporally target distinct stages of endosomal maturation, enabling tunable cellular pyroptosis. Specific activation of phospholipase C signalling transduction in early endosomes triggers gasdermin-E-mediated pyroptosis, which is dramatically reduced when acid-activatable nanophotosensitizers are transported into late endosomes/lysosomes. This nanotuner platform induces pyroptotic cell death with up to 40-fold tunability in various gasdermin-E-positive human cancers, resulting in enhanced anti-tumour efficacy and minimized systemic side effects. This study offers new insights into how to engineer nanomedicines with tunable pyroptosis activity through specific targeting of distinct endocytic signalling for biomedical applications.

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Fig. 1: Schematic illustrations of ANPS and the tunable pyroptosis evoked by the ANPS library through temporal differentiation of endosome maturation.
Fig. 2: Tuning the organelle-specific cytotoxicity by engineering the ANPS library with pH differentiation capacity.
Fig. 3: EE-targeted PDT achieves excellent anti-tumour efficacy via pyroptotic cell death.
Fig. 4: PLC activation and caspase-3-mediated GSDME cleavage contribute to PDTee-induced pyroptosis.
Fig. 5: ANPS manipulates cellular distribution of photosensitizer for amplified photodynamic efficacy.
Fig. 6: ANPS minimizes phototoxicity by acid-activatable SOG and tunable pyroptosis.

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Data availability

Source data are provided with this paper. The main data that support the findings of this study are available within the paper, the source data and the Supplementary Information. The GEPIA database is accessible via http://gepia.cancer-pku.cn/. Other raw and relevant data from the study are available for research purposes from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFA0205600 and 2016YFA0201400 to Yiguang Wang), National Natural Science Foundation of China grants (81622046 and 81973260 to Yiguang Wang and 81903554 to B.C.) and the Beijing Natural Science Foundation (JQ19025 to Yiguang Wang).

Author information

Authors and Affiliations

  1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Binlong Chen, Bo Xu, Qiang Zhang & Yiguang Wang

  2. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery System, School of Pharmaceutical Sciences, Peking University, Beijing, China

    Binlong Chen, Yue Yan, Ye Yang, Guang Cao, Yaoqi Wang, Fangjie Wan, Qingqing Yin, Zenghui Wang, Letong Wang, Qiang Zhang & Yiguang Wang

  3. Institute of Systems Biomedicine, Department of Immunology, Beijing Key Laboratory of Tumour Systems Biology, Peking University Health Science Center, Beijing, China

    Xiao Wang, Yunfei Li & Fuping You

Authors
  1. Binlong Chen
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Contributions

B.C. and Yiguang Wang are responsible for all phases of the research. Y. Yan, Yaoqi Wang and F.W. helped with the characterization and efficacy evaluation of the nanophotosensitizer library. Z.W. helped with the synthesis and characterization of copolymers. X.W., Y.L. and L.W. performed the CRISPR-Cas9 knockout cell lines. Y. Yang and G.C. participated in the western blot. Q.Y. and B.X. performed the in vitro cell imaging and in vivo imaging. B.C. and Yiguang Wang wrote the manuscript. F.Y., Q.Z. and Yiguang Wang provided conceptual advice and supervised the study. All the authors discussed the results and assisted in the preparation of the manuscript.

Corresponding authors

Correspondence to Fuping You, Qiang Zhang or Yiguang Wang.

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The authors declare no competing interests.

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Nature Nanotechnology thanks Xiaoyuan Chen, Roger Gomis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary information

Supplementary Information

Supplementary Figs. 1–53, Tables 1–4, Discussion and Methods.

Reporting Summary.

Supplementary Video 1

PDTee can induce rapid membrane ballooning and pyroptotic cell death on A549 cells. A549 cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and immediately irradiated at 100 mW cm−2 for 1 min. Shown is the video of a representative field recorded immediately after irradiation. PI is used to indicate membrane rupture and dead cells. (The exact time duration is in hours:minutes:seconds:milliseconds).

Supplementary Video 2

PDTly switched off pyroptosis on A549 cells. A549 cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and then irradiated (100 mW cm−2 for 1 min) 2 h post micelle incubation. Shown is the video of a representative field recorded immediately after irradiation. PI is used to indicate membrane rupture and dead cells. (The exact time duration is in hours:minutes:seconds:milliseconds).

Supplementary Video 3

Knockout of GSDME switches PDTee-induced pyroptosis to apoptosis in A549 cells. GSDME–/– A549-GFP cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and immediately irradiated at 100 mW cm−2 for 1 min. Shown is the video of a representative field recorded immediately after irradiation. (The exact time duration is in hours:minutes:seconds:milliseconds).

Supplementary Video 4

Knockout of GSDMD cannot switch PDTee-induced pyroptosis to apoptosis in A549 cells. GSDMD–/– A549-GFP cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and immediately irradiated at 100 mW cm−2 for 1 min. Shown is the video of a representative field recorded immediately after irradiation. (The exact time duration is in hours:minutes:seconds:milliseconds).

Supplementary Video 5

PDTee can elevate the calcium ion signal in cytosol. A549 cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and immediately irradiated at 100 mW cm−2 for 1 min. Shown is the video of a representative field recorded immediately after irradiation. A fluo3 AM probe is used to indicate cellular calcium ion signal. (The exact time duration is in hours:minutes:seconds:milliseconds).

Supplementary Video 6

PDTly can slightly elevate the calcium ion signal in cytosol. A549 cells were incubated with ANPS6.5 (6 μg ml–1) for 15 min and then irradiated (100 mW cm−2 for 1 min) 2 h post micelle incubation. Shown is the video of a representative field recorded immediately after irradiation. A fluo3 AM probe is used to indicate cellular calcium ion signal. (The exact time duration is in hours:minutes:seconds:milliseconds).

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Chen, B., Yan, Y., Yang, Y. et al. A pyroptosis nanotuner for cancer therapy. Nat. Nanotechnol. 17, 788–798 (2022). https://doi.org/10.1038/s41565-022-01125-0

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