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Proton-driven transformable nanovaccine for cancer immunotherapy

Nature Nanotechnology volume 15, pages 1053–1064 (2020)Cite this article

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Abstract

Cancer vaccines hold great promise for improved cancer treatment. However, endosomal trapping and low immunogenicity of tumour antigens usually limit the efficiency of vaccination strategies. Here, we present a proton-driven nanotransformer-based vaccine, comprising a polymer–peptide conjugate-based nanotransformer and loaded antigenic peptide. The nanotransformer-based vaccine induces a strong immune response without substantial systemic toxicity. In the acidic endosomal environment, the nanotransformer-based vaccine undergoes a dramatic morphological change from nanospheres (about 100 nanometres in diameter) into nanosheets (several micrometres in length or width), which mechanically disrupts the endosomal membrane and directly delivers the antigenic peptide into the cytoplasm. The re-assembled nanosheets also boost tumour immunity via activation of specific inflammation pathways. The nanotransformer-based vaccine effectively inhibits tumour growth in the B16F10-OVA and human papilloma virus-E6/E7 tumour models in mice. Moreover, combining the nanotransformer-based vaccine with anti-PD-L1 antibodies results in over 83 days of survival and in about half of the mice produces complete tumour regression in the B16F10 model. This proton-driven transformable nanovaccine offers a robust and safe strategy for cancer immunotherapy.

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Fig. 1: Schematic illustration of a proton-driven NTV for cancer immunotherapy.
Fig. 2: Design and characterization of the NTV.
Fig. 3: NTV2 induces strong and sustained cross-presentation to CD8+ T-cells.
Fig. 4: NTV2 promotes AP delivery to lymph nodes and elicits cytotoxic lymphocyte responses.
Fig. 5: NTV2 inhibits tumour growth and prolongs survival in tumour-bearing mice.
Fig. 6: Neoantigen peptide-loaded NTV2 in combination with anti-PD-L1 for efficient cancer immunotherapy in the B16F10 model.

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Data availability

All relevant data during the study are available from the corresponding authors upon request. Source data are provided with this paper.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (grant numbers 31630027, 31430031, 21327806, 21621003 and 21235004) and NSFC-German Research Foundation (DFG) project (grant number 31761133013). We are grateful for support from the Strategic Priority Research Program of the Chinese Academy of Sciences (grant numbers XDA09030301 and XDB36000000), the National Key Research and Development Program of China (grant numbers 2018YFE0117800 and 2016YFA0203101). We also acknowledge support from the NIH/NIMHHD (grant number U54MD007597). We thank Z. Ao for help with the AFM measurements and X. Hu and H. Guo for help with the TEM analysis.

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Authors and Affiliations

  1. Department of Chemistry, Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing, China

    Ningqiang Gong, Xucong Teng, Qiankun Ni, Yongji Wang & Jinghong Li

  2. Laboratory of Controllable Nanopharmaceuticals, Chinese Academy of Sciences (CAS) Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology, Beijing, China

    Ningqiang Gong, Yuxuan Zhang, Yongchao Wang, Shuaidong Huo, Guangchao Qing, Qiankun Ni, Xianlei Li, Jinjin Wang, Xiaoxia Ye, Tingbin Zhang, Shizhu Chen, Paul C. Wang, Yaling Gan & Xing-Jie Liang

  3. Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA

    Ningqiang Gong & Michael J. Mitchell

  4. University of Chinese Academy of Sciences, Beijing, China

    Ningqiang Gong, Yuxuan Zhang, Qiankun Ni, Xianlei Li, Jinjin Wang & Xing-Jie Liang

  5. Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Science, Xiamen University, Xiamen, China

    Shuaidong Huo

  6. Key Laboratory of Medicinal Chemistry and Molecular Diagnosis of the Ministry of Education, College of Chemistry and Environmental Science, Hebei University, Baoding, China

    Shizhu Chen, Jinchao Zhang & Xing-Jie Liang

  7. Department of Interventional Ultrasound, Chinese PLA General Hospital, Beijing, China

    Jie Yu

  8. Laboratory of Molecular Imaging, Department of Radiology, Howard University, Washington DC, USA

    Paul C. Wang

  9. Department of Electrical Engineering, Fu Jen Catholic University, Taipei, Taiwan

    Paul C. Wang

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  1. Ningqiang Gong
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Contributions

N.G., J.L. and X.-J.L. conceived and designed the experiments. N.G., Y.Z., X.T., Yongchao Wang, S.H., G.Q., Q.N., X.L., J.W., X.Y., T.Z., S.C. and Yongji Wang performed the experiments. N.G., X.Y., T.Z., J.L. and X.-J.L. analysed the results. J.Y., Y.G., J.Z., P.C.W and M.J.M. developed the discussion. N.G., J.L. and X.-J.L. wrote the manuscript. J.L. and X.-J.L. supervised the entire project. All authors discussed the results and commented on the manuscript.

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Correspondence to Jinghong Li or Xing-Jie Liang.

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Peer review information Nature Nanotechnology thanks Rona Chandrawati, Bartosz Grzybowski, Jeffrey Hubbell and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Gong, N., Zhang, Y., Teng, X. et al. Proton-driven transformable nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 15, 1053–1064 (2020). https://doi.org/10.1038/s41565-020-00782-3

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