Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An intelligent DNA nanodevice for precision thrombolysis

Nature Materials (2024)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

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.

References

  1. Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  2. Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Emberson, J. et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 384, 1929–1935 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Derex, L. & Nighoghossian, N. Thrombolysis, stroke-unit admission and early rehabilitation in elderly patients. Nat. Rev. Neurol. 5, 506–511 (2009).

    Article  PubMed  Google Scholar 

  5. Betts, K. A. et al. Real-world outcomes of acute ischemic stroke treatment with intravenous recombinant tissue plasminogen activator. J. Stroke Cerebrovasc. 26, 1996–2003 (2017).

    Article  Google Scholar 

  6. Hassanpour, S. et al. Thrombolytic agents: nanocarriers in controlled release. Small 16, e2001647 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Xu, J. C., Zhang, Y. L. & Nie, G. J. Intelligent antithrombotic nanomedicines: progress, opportunities, and challenges. View 2, 20200145 (2021).

    Article  Google Scholar 

  8. Marder, V. J. & Novokhatny, V. Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential. J. Thromb. Haemost. 8, 433–444 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Zenych, A., Fournier, L. & Chauvierre, C. Nanomedicine progress in thrombolytic therapy. Biomaterials 258, 120297 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Xu, J. C. et al. Engineered nanoplatelets for targeted delivery of plasminogen activators to reverse thrombus in multiple mouse thrombosis models. Adv. Mater. 32, e1905145 (2020).

    Article  PubMed  Google Scholar 

  11. Hu, J. N. et al. Tissue plasminogen activator-porous magnetic microrods for targeted thrombolytic therapy after ischemic stroke. ACS Appl. Mater. Interfaces 10, 32988–32997 (2018).

    Article  CAS  PubMed  ADS  Google Scholar 

  12. Wang, S. Y. et al. Accelerating thrombolysis using a precision and clot-penetrating drug delivery strategy by nanoparticle-shelled microbubbles. Sci. Adv. 6, eaaz8204 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  13. Korin, N. et al. Shear-activated nanotherapeutics for drug targeting to obstructed blood vessels. Science 337, 738–742 (2008).

    Article  ADS  Google Scholar 

  14. Zhao, Y. et al. Biomimetic fibrin-targeted and H2O2-responsive nanocarriers for thrombus therapy. Nano Today 35, 100986 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mei, T. et al. Encapsulation of tissue plasminogen activator in pH-sensitive self-assembled antioxidant nanoparticles for ischemic stroke treatment—synergistic effect of thrombolysis and antioxidant. Biomaterials 215, 119209 (2019).

    Article  CAS  PubMed  Google Scholar 

  16. Rabanel, J. M. et al. Nanoparticle heterogeneity: an emerging structural parameter influencing particle fate in biological media? Nanoscale 11, 383–406 (2019).

    Article  CAS  PubMed  Google Scholar 

  17. Li, S. P. et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nat. Biotechnol. 36, 258–264 (2018).

    Article  CAS  PubMed  Google Scholar 

  18. Li, J., Fan, C. H., Pei, H., Shi, J. Y. & Huang, Q. Smart drug delivery nanocarriers with self-assembled DNA nanostructures. Adv. Mater. 25, 4386–4396 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. He, L. C., Mu, J., Gang, O. & Chen, X. Y. Rationally programming nanomaterials with DNA for biomedical applications. Adv. Sci. 8, 2003775 (2021).

    Article  CAS  Google Scholar 

  20. Hu, Q. Q., Li, H., Wang, L. H., Gu, H. Z. & Fan, C. H. DNA nanotechnology-enabled drug delivery systems. Chem. Rev. 119, 6459–6506 (2019).

    Article  CAS  PubMed  Google Scholar 

  21. Liu, S. L. et al. A DNA nanodevice-based vaccine for cancer immunotherapy. Nat. Mater. 20, 421–430 (2020).

    Article  PubMed  ADS  Google Scholar 

  22. Nakatsuka, M. A., Mattrey, R. F., Esener, S. C., Cha, J. N. & Goodwin, A. P. Aptamer-crosslinked microbubbles: smart contrast agents for thrombin-activated ultrasound imaging. Adv. Mater. 24, 6010–6016 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rothemund, P. W. K. Folding DNA to create nanoscale shapes and patterns. Nature 440, 297–302 (2006).

    Article  CAS  PubMed  ADS  Google Scholar 

  24. Mutch, N. J., Thomas, L., Moore, N. R., Lisiak, K. M. & Booth, N. A. TAFIa, PAI-1 and α2-antiplasmin: complementary roles in regulating lysis of thrombi and plasma clots. J. Thromb. Haemost. 5, 812–817 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Hu, Q. Y. et al. Engineered nanoplatelets for enhanced treatment of multiple myeloma and thrombus. Adv. Mater. 28, 9573–9580 (2016).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  26. Chapin, J. C. & Hajjar, K. A. Fibrinolysis and the control of blood coagulation. Blood Rev. 29, 17–24 (2015).

    Article  CAS  PubMed  Google Scholar 

  27. Mann, K. G. Thrombin generation in hemorrhage control and vascular occlusion. Circulation 124, 225–235 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Brummel-Ziedins, K. E., Vossen, C. Y., Butenas, S., Mann, K. G. & Rosendaal, F. R. Thrombin generation profiles in deep venous thrombosis. J. Thromb. Haemost. 3, 2497–2505 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wolberg, A. S. & Campbell, R. A. Thrombin generation, fibrin clot formation and hemostasis. Transfus. Apher. Sci. 38, 15–23 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Tanaka, K. A., Key, N. S. & Levy, J. H. Blood coagulation: hemostasis and thrombin regulation. Anesth. Analg. 108, 1433–1446 (2009).

    Article  CAS  PubMed  Google Scholar 

  31. Del Zoppo, G. J., Saver, J. L., Jauch, E. C. & Adams, H. P. Jr. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 40, 2945–2948 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Schwartz, R. S. et al. Microemboli and microvascular obstruction in acute coronary thrombosis and sudden coronary death: relation to epicardial plaque histopathology. J. Am. Coll. Cardiol. 54, 2167–2173 (2009).

    Article  PubMed  Google Scholar 

  33. Brown, W. R., Moody, D. M., Challa, V. R., Stump, D. A. & Hammon, J. W. Longer duration of cardiopulmonary bypass is associated with greater numbers of cerebral microemboli. Stroke 31, 707–713 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Pongmoragot, J. et al. Pulmonary embolism in ischemic stroke: clinical presentation, risk factors, and outcome. J. Am. Heart Assoc. 2, e000372 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Xu, X. et al. Self-regulated hirudin delivery for anticoagulant therapy. Sci. Adv. 6, eabc0382 (2020).

    Article  CAS  PubMed  PubMed Central  ADS  Google Scholar 

  36. Mutch, N. J., Robbie, L. A. & Booth, N. A. Human thrombi contain an abundance of active thrombin. Thromb. Haemost. 86, 1028–1034 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Xu, J. P. et al. Sequentially site-specific delivery of thrombolytics and neuroprotectant for enhanced treatment of ischemic stroke. ACS Nano 13, 8577–8588 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

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

Authors
  1. Jue Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Siyu Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiahui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yewei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chunhai Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jie Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lianhui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

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

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Information

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

Reporting Summary

Supplementary Data

Source Data for Supplementary Figure.

Source data

Source Data Fig. 1

Statistical source data and unprocessed gels.

Source Data Fig. 1

Unprocessed gels.

Source Data Fig. 2

Statistical source data.

Source Data Fig. 3

Statistical source data.

Source Data Fig. 4

Statistical source data.

Source Data Fig. 5

Statistical source data.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41563-024-01826-y

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing