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A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo

Nature Biotechnology volume 36, pages 258–264 (2018)Cite this article

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Abstract

Nanoscale robots have potential as intelligent drug delivery systems that respond to molecular triggers1,2,3,4. Using DNA origami we constructed an autonomous DNA robot programmed to transport payloads and present them specifically in tumors. Our nanorobot is functionalized on the outside with a DNA aptamer that binds nucleolin, a protein specifically expressed on tumor-associated endothelial cells5, and the blood coagulation protease thrombin within its inner cavity. The nucleolin-targeting aptamer serves both as a targeting domain and as a molecular trigger for the mechanical opening of the DNA nanorobot. The thrombin inside is thus exposed and activates coagulation at the tumor site. Using tumor-bearing mouse models, we demonstrate that intravenously injected DNA nanorobots deliver thrombin specifically to tumor-associated blood vessels and induce intravascular thrombosis, resulting in tumor necrosis and inhibition of tumor growth. The nanorobot proved safe and immunologically inert in mice and Bama miniature pigs. Our data show that DNA nanorobots represent a promising strategy for precise drug delivery in cancer therapy.

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Figure 1: Design and characterization of thrombin-functionalized DNA nanorobot.
Figure 2: Analysis of DNA nanorobot-triggered activation and endothelial cell targeting.
Figure 3: DNA nanorobots target tumors, induce thrombosis in tumor vessels and inhibit tumor growth in vivo.
Figure 4: Treatment with nanorobot-Th inhibits the growth of melanoma and poorly vascularized SK-OV3 ovarian cancer.

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Acknowledgements

The authors thank L.Z. Xu (Medical and Health Analysis Center of Peking University) for animal imaging and G. Z. Shi (Laboratory Animal Center of Institute of Biophysics, Chinese Academy of Sciences) for histological examination of minipigs. We also thank A. Sheftel from High Impact Editing for improving the English of the manuscript. This work was supported by grants from National Basic Research Plan of China (MoST Program 2016YFA0201601 to G.N. and B.D.), the National Natural Science Foundation of China (31730032 to G.N., 21222311, 21573051, 91127021 to B.D., the National Distinguished Young Scientists program 31325010 to G.N.), Innovation Research Group of National Natural Science Foundation (11621505 to G.N. and Yuliang Z., 21721002 to B.D.), Beijing Municipal Science & Technology Commission (Z161100000116035 to G.N., Z161100000116036 to B.D.), CAS Interdisciplinary Innovation Team to B.D., G.N. & Yuliang Z., Key Research Program of Frontier Sciences, CAS, Grant No. QYZDB-SSW-SLH029 to B.D. and US National Institute of Health Director's Transformative Research Award (R01GM104960-01 to H.Y.).

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Author notes

  1. Suping Li, Qiao Jiang, Shaoli Liu and Yinlong Zhang: These authors contributed equally to this work.

Authors and Affiliations

  1. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, China, Beijing, China.,

    Suping Li, Qiao Jiang, Shaoli Liu, Yinlong Zhang, Yanhua Tian, Chen Song, Jing Wang, Yiguo Zou, Guangjun Nie, Baoquan Ding & Yuliang Zhao

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

    Suping Li, Shaoli Liu, Guangjun Nie, Baoquan Ding & Yuliang Zhao

  3. College of Pharmaceutical Science, Jilin University, Changchun, China

    Yinlong Zhang

  4. Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China

    Yanhua Tian

  5. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    Gregory J Anderson

  6. Department of Integration of Chinese and Western Medicine, School of Basic Medical Sciences, Peking University, Beijing, China

    Jing-Yan Han

  7. School of Molecular Sciences, Center for Molecular Design and Biomimetics,

    Yung Chang, Yan Liu & Hao Yan

  8. School of Life Sciences, Center for Immunotherapy, Vaccines, and Virotherapy at the Biodesign Institute, Arizona State University, Tempe, Arizona, USA

    Yung Chang, Yan Liu & Hao Yan

  9. Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Chen Zhang & Guangbiao Zhou

  10. Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China

    Liang Chen

Authors
  1. Suping Li
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Contributions

Suping L., Q.J., Shaoli L., Yinlong Z., Y.T., C.S., B.D., Yuliang Z. and G.N. conceived and designed the experiments. Suping L., Q.J., Shaoli L., Yinlong Z., C.S., Y.T. and C.Z. performed the experiments. Y.T., C.S., H.Y., B.D., Yinlong Z. and G.N. collected and analyzed the data. J.W., G.A., J.H., Yiguo Z., Y.C., Y.L., L.C., G.-B.Z., G.Z. and C.Z. provided suggestions and technical support on the project. H.Y., B.D., Yuliang Z., and G.N. supervised the project. Suping L., Q.J., H.Y., B.D. and G.N. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Guangjun Nie, Hao Yan, Baoquan Ding or Yuliang Zhao.

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An international provisional patent has been filed based on this work.

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Li, S., Jiang, Q., Liu, S. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat Biotechnol 36, 258–264 (2018). https://doi.org/10.1038/nbt.4071

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