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

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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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.

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Correspondence to Guangjun Nie or Hao Yan or 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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