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An intelligent DNA nanodevice for precision thrombolysis

Nature Materials volume 23, pages 854–862 (2024)Cite this article

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Abstract

Thrombosis is a leading global cause of death, in part due to the low efficacy of thrombolytic therapy. Here, we describe a method for precise delivery and accurate dosing of tissue plasminogen activator (tPA) using an intelligent DNA nanodevice. We use DNA origami to integrate DNA nanosheets with predesigned tPA binding sites and thrombin-responsive DNA fasteners. The fastener is an interlocking DNA triplex structure that acts as a thrombin recognizer, threshold controller and opening switch. When loaded with tPA and intravenously administrated in vivo, these DNA nanodevices rapidly target the site of thrombosis, track the circulating microemboli and expose the active tPA only when the concentration of thrombin exceeds a threshold. We demonstrate their improved therapeutic efficacy in ischaemic stroke and pulmonary embolism models, supporting the potential of these nanodevices to provide accurate tPA dosing for the treatment of different thromboses.

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Fig. 1: Design and characterization of the tPA–DNA nanodevices.
Fig. 2: Assessment of drug loading and tPA activity.
Fig. 3: Thrombin-responsive opening of DNA nanodevice by threshold controller.
Fig. 4: The DNA nanodevice improves therapeutic efficacy in the transient MCAO model.
Fig. 5: The DNA nanodevice improves therapeutic efficacy in the PE model.

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Data availability

All the data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request. Source data are provided with this paper.

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Acknowledgements

This work was supported by the Natural Science Foundation of Jiangsu Province, major project (BK20212012 (L.W.)), the NSFC (62288102 (L.W.), 21922408 (J.C.), 22274081 (J.C.), 22277058 (Y.G.), 21991134 (C.F.), T2188102 (C.F.)), the Natural Science Foundation of Jiangsu Province (BE2023839 (J.C.)), and the New Cornerstone Science Foundation (C.F.).

Author information

Author notes

  1. These authors contributed equally: Jue Yin, Siyu Wang, Jiahui Wang.

Authors and Affiliations

  1. State Key Laboratory for Organic Electronics and Information Displays & Jiangsu Key Laboratory for Biosensors, Institute of Advanced Materials (IAM), Jiangsu National Synergistic Innovation Center for Advanced Materials (SICAM), Nanjing University of Posts and Telecommunications, Nanjing, China

    Jue Yin, Siyu Wang, Jiahui Wang, Jie Chao, Yu Gao & Lianhui Wang

  2. Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China

    Yewei Zhang

  3. School of Chemistry and Chemical Engineering, New Cornerstone Science Laboratory, Frontiers Science Center for Transformative Molecules, Zhangjiang Institute for Advanced Study and National Center for Translational Medicine, Shanghai Jiao Tong University, Shanghai, China

    Chunhai Fan

  4. Institute of Molecular Medicine, Shanghai Key Laboratory for Nucleic Acids Chemistry and Nanomedicine, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Chunhai Fan

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Contributions

J.C., Y.G. and L.W. conceived the project. J.C., Y.G., J.Y., S.W., and J.W. designed the experiments. J.Y., S.W. and J.W. carried out the experiments. S.W., J.W. and Y.Z. performed the in vivo experiments. J.Y., S.W., J.W., J.C. and Y.G. collected and analysed the data. Y.G., J.C., J.Y., S.W., C.F. and L.W. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Jie Chao, Yu Gao or Lianhui Wang.

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Nature Materials thanks Guangjun Nie, Hao Yan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Supplementary Figs. 1–52, Tables 1 and 2, Note and unprocessed gels.

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Yin, J., Wang, S., Wang, J. et al. An intelligent DNA nanodevice for precision thrombolysis. Nat. Mater. 23, 854–862 (2024). https://doi.org/10.1038/s41563-024-01826-y

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