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:

Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound

Nature Biomedical Engineering volume 7, pages 149–163 (2023)Cite this article

Subjects

Abstract

Deep brain stimulation via implanted electrodes can alleviate neuronal disorders. However, its applicability is constrained by side effects resulting from the insertion of electrodes into the brain. Here, we show that systemically administered piezoelectric nanoparticles producing nitric oxide and generating direct current under high-intensity focused ultrasound can be used to stimulate deep tissue in the brain. The release of nitric oxide temporarily disrupted tight junctions in the blood–brain barrier, allowing for the accumulation of the nanoparticles into brain parenchyma, and the piezoelectrically induced output current stimulated the release of dopamine by dopaminergic neuron-like cells. In a mouse model of Parkinson’s disease, the ultrasound-responsive nanoparticles alleviated the symptoms of the disease without causing overt toxicity. The strategy may inspire the development of other minimally invasive therapies for neurodegenerative diseases.

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: Ultrasound-responsive piezoelectric nanoparticle for neural stimulation.
Fig. 2: Characterization of the nanoparticle.
Fig. 3: Piezoelectric neural stimulation in vitro.
Fig. 4: Nanoparticle accumulation in brain tissue.
Fig. 5: NO-activated BBB opening via disrupting of tight junctions.
Fig. 6: In vivo DBS.
Fig. 7: In vivo DBS for neuroprotection.
Fig. 8: In vivo safety of the nanoparticle.

Similar content being viewed by others

Data availability

The main data supporting the results in this study are available within the paper and its Supplementary Information. Source data for the figures are provided with this paper.

References

  1. Wyss-Coray, T. Ageing, neurodegeneration and brain rejuvenation. Nature 539, 180–186 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kringelbach, M. L., Jenkinson, N., Owen, S. L. & Aziz, T. Z. Translational principles of deep brain stimulation. Nat. Rev. Neurosci. 8, 623–635 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Chen, R., Canales, A. & Anikeeva, P. Neural recording and modulation technologies. Nat. Rev. Mater. 2, 16093 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Chen, R., Romero, G., Christiansen, M. G., Mohr, A. & Anikeeva, P. Wireless magnetothermal deep brain stimulation. Science 347, 1477–1480 (2015).

    Article  CAS  PubMed  Google Scholar 

  5. Guduru, R. et al. Magnetoelectric ‘spin’ on stimulating the brain. Nanomedicine 10, 2051–2061 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Chen, S. et al. Near-infrared deep brain stimulation via upconversion nanoparticle-mediated optogenetics. Science 359, 679–684 (2018).

    Article  CAS  PubMed  Google Scholar 

  7. Rivnay, J., Wang, H., Fenno, L., Deisseroth, K. & Malliaras, G. G. Next-generation probes, particles, and proteins for neural interfacing. Sci. Adv. 3, e1601649 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Tu, J. et al. Controllable in vivo hyperthermia effect induced by pulsed high intensity focused ultrasound with low duty cycles. Appl. Phys. Lett. 101, 124102 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Hinchet, R. et al. Transcutaneous ultrasound energy harvesting using capacitive triboelectric technology. Science 365, 491–494 (2019).

    Article  CAS  PubMed  Google Scholar 

  10. Mace, E. et al. Functional ultrasound imaging of the brain. Nat. Methods 8, 662–664 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Kang, Y. et al. Tumor vasodilation by N-heterocyclic carbene-based nitric oxide delivery triggered by high-intensity focused ultrasound and enhanced drug homing to tumor sites for anti-cancer therapy. Biomaterials 217, 119297 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Marino, A. et al. Piezoelectric nanoparticle-assisted wireless neuronal stimulation. ACS Nano 9, 7678–7689 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rojas, C. et al. Acoustic stimulation can induce a selective neural network response mediated by piezoelectric nanoparticles. J. Neural Eng. 15, 036016 (2018).

    Article  PubMed  Google Scholar 

  14. Hendricks, B. K., Cohen-Gadol, A. A. & Miller, J. C. Novel delivery methods bypassing the blood–brain and blood–tumor barriers. Neurosurg. Focus 38, E10 (2015).

    Article  PubMed  Google Scholar 

  15. Wiley, D. T., Webster, P., Gale, A. & Davis, M. E. Transcytosis and brain uptake of transferrin-containing nanoparticles by tuning avidity to transferrin receptor. Proc. Natl Acad. Sci. USA 110, 8662–8667 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ting, C. Y. et al. Concurrent blood–brain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment. Biomaterials 33, 704–712 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Martinez, H. R. et al. Stem-cell transplantation into the frontal motor cortex in amyotrophic lateral sclerosis patients. Cytotherapy 11, 26–34 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Lipsman, N. et al. Blood–brain barrier opening in Alzheimer’s disease using MR-guided focused ultrasound. Nat. Commun. 9, 2336 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Wong, K. H. et al. Review of current strategies for delivering Alzheimer’s disease drugs across the blood–brain barrier. Int. J. Mol. Sci. 20, 381 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kim, T., Suh, J. & Kim, W. J. Polymeric aggregate-embodied hybrid nitric-oxide-scavenging and sequential drug-releasing hydrogel for combinatorial treatment of rheumatoid arthritis. Adv. Mater. 33, 2008793 (2021).

    Article  CAS  Google Scholar 

  21. Parathath, S. R., Parathath, S. & Tsirka, S. E. Nitric oxide mediates neurodegeneration and breakdown of the blood–brain barrier in tPA-dependent excitotoxic injury in mice. J. Cell Sci. 119, 339–349 (2006).

    Article  CAS  PubMed  Google Scholar 

  22. Jin, Z. K. et al. MRI-guided and ultrasound-triggered release of NO by advanced nanomedicine. Nanoscale 9, 3637–3645 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Hong, S. et al. Attenuation of the in vivo toxicity of biomaterials by polydopamine surface modification. Nanomedicine 6, 793–801 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Xie, C. M. et al. Electroresponsive and cell-affinitive polydopamine/polypyrrole composite microcapsules with a dual-function of on-demand drug delivery and cell stimulation for electrical therapy. NPG Asia Mater. 9, e358 (2017).

    Article  CAS  Google Scholar 

  25. Wei, G., Yang, G., Wei, B., Wang, Y. & Zhou, S. Near-infrared light switching nitric oxide nanoemitter for triple-combination therapy of multidrug resistant cancer. Acta Biomater. 100, 365–377 (2019).

    Article  CAS  PubMed  Google Scholar 

  26. Li, Y. et al. Antifouling, high-flux nanofiltration membranes enabled by dual functional polydopamine. ACS Appl. Mater. Interfaces 6, 5548–5557 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Herrington, T. M., Cheng, J. J. & Eskandar, E. N. Mechanisms of deep brain stimulation. J. Neurophysiol. 115, 19–38 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Neher, E. & Sakaba, T. Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 59, 861–872 (2008).

    Article  CAS  PubMed  Google Scholar 

  29. Xicoy, H., Wieringa, B. & Martens, G. J. The SH-SY5Y cell line in Parkinson’s disease research: a systematic review. Mol. Neurodegener. 12, 10 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lonart, G., Cassels, K. L. & Johnson, K. M. Nitric oxide induces calcium-dependent [3H]dopamine release from striatal slices. J. Neurosci. Res. 35, 192–198 (1993).

    Article  CAS  PubMed  Google Scholar 

  31. Rodriguez, A., Tatter, S. B. & Debinski, W. Neurosurgical techniques for disruption of the blood–brain barrier for glioblastoma treatment. Pharmaceutics 7, 175–187 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ridnour, L. A. et al. Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 104, 16898–16903 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. O’Sullivan, S., Medina, C., Ledwidge, M., Radomski, M. W. & Gilmer, J. F. Nitric oxide–matrix metaloproteinase-9 interactions: biological and pharmacological significance—NO and MMP-9 interactions. Biochim. Piophys. Acta 1843, 603–617 (2014).

    Article  Google Scholar 

  34. Rempe, R. G. et al. Matrix metalloproteinase-mediated blood–brain barrier dysfunction in epilepsy. J. Neurosci. 38, 4301–4315 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gu, Z. et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297, 1186–1190 (2002).

    Article  CAS  PubMed  Google Scholar 

  36. Obermeier, B., Daneman, R. & Ransohoff, R. M. Development, maintenance and disruption of the blood–brain barrier. Nat. Med. 19, 1584–1596 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Surmeier, D. J. Determinants of dopaminergic neuron loss in Parkinson’s disease. FEBS J. 285, 3657–3668 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kwon, O. B. et al. Dopamine regulation of amygdala inhibitory circuits for expression of learned fear. Neuron 88, 378–389 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Lippert, R. N. et al. Time-dependent assessment of stimulus-evoked regional dopamine release. Nat. Commun. 10, 336 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Williams, N. R. & Okun, M. S. Deep brain stimulation (DBS) at the interface of neurology and psychiatry. J. Clin. Invest. 123, 4546–4556 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jackson-Lewis, V. & Przedborski, S. Protocol for the MPTP mouse model of Parkinson’s disease. Nat. Protoc. 2, 141–151 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. McKinnon, C. et al. Deep brain stimulation: potential for neuroprotection. Ann. Clin. Transl. Neurol. 6, 174–185 (2019).

    Article  PubMed  Google Scholar 

  43. Fadok, J. P., Dickerson, T. M. K. & Palmiter, R. D. Dopamine Is necessary for cue-dependent fear conditioning. J. Neurosci. 29, 11089–11097 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Ehlerding, E. B., Chen, F. & Cai, W. Biodegradable and renal clearable inorganic nanoparticles. Adv. Sci. 3, 1500223 (2016).

    Article  Google Scholar 

  45. Liu, J. B., Yu, M. X., Zhou, C. & Zheng, J. Renal clearable inorganic nanoparticles: a new frontier of bionanotechnology. Mater. Today 16, 477–486 (2013).

    Article  CAS  Google Scholar 

  46. Hao, Y. N. et al. Glutathione triggered degradation of polydopamine to facilitate controlled drug release for synergic combinational cancer treatment. J. Mater. Chem. B 7, 6742–6750 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Neubrand, A., Lindner, R. & Hoffmann, P. Room-temperature solubility behavior of barium titanate in aqueous media. J. Am. Ceram. Soc. 83, 860–864 (2000).

    Article  CAS  Google Scholar 

  48. Morishita, T. et al. Postoperative lead migration in deep brain stimulation surgery: incidence, risk factors, and clinical impact. PLoS ONE 12, e0183711 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Ahn, J. H. et al. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature 572, 62–66 (2019).

    Article  CAS  PubMed  Google Scholar 

  50. Fan, J. et al. A novel self-assembled sandwich nanomedicine for NIR-responsive release of NO. Nanoscale 7, 20055–20062 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This research was supported by the National Research Foundation of Korea (NRF) grants (NRF-2019R1A2C2006269 and NRF-2020R1A6A1A03047902 to C.K. and NRF-2020R1A4A1019456 and NRF-2022R1A3B1077354 to W.J.K.), by the Creative Materials Discovery Program (NRF-2018M3D1A1058813 to W.J.K.), by the Korean government (Ministry of Science and ICT) and by OmniaMed Co., Ltd.

Author information

Authors and Affiliations

  1. Department of Chemistry, Postech-Catholic Biomedical Engineering Institute, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea

    Taejeong Kim, Yeong Mi Lee, Junseok Lee & Won Jong Kim

  2. Department of Life Sciences, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea

    Hyun Jin Kim, Jung Hyun Pyo & Joung-Hun Kim

  3. Department of Electrical Engineering and Creative IT Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea

    Wonseok Choi, Jeesu Kim & Chulhong Kim

  4. Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA

    Jihoon Kim

  5. School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology (POSTECH), Pohang, Republic of Korea

    Chulhong Kim & Won Jong Kim

  6. OmniaMed Co., Ltd., Pohang, Republic of Korea

    Won Jong Kim

Authors
  1. Taejeong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyun Jin Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Wonseok Choi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yeong Mi Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jung Hyun Pyo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junseok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jeesu Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jihoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Joung-Hun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chulhong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Won Jong Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K. and W.J.K. conceived the idea, designed the study and directed the project. T.K. performed all the experiments and analysed the data. H.J.K. assisted with the patch-clamp set-up and with mouse-behaviour monitoring. W.C. and Jeesu Kim helped with HIFU treatment in vivo. Y.M.L. and J.H.P. assisted with the in vivo and ex vivo experiments. J.L. helped with the in vitro fluorescence imaging. C.K., J.-H.K. and Jihoon Kim provided insightful advice. T.K., Jihoon Kim and W.J.K. wrote the manuscript.

Corresponding author

Correspondence to Won Jong Kim.

Ethics declarations

Competing interests

W.J.K. is the Chief Executive Officer at OmniaMed. The other authors declare no competing interests.

Peer review

Peer review information

Nature Biomedical Engineering thanks Thomas McHugh and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available.

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 figures, tables, methods and references.

Reporting Summary

Peer Review File

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

Kim, T., Kim, H.J., Choi, W. et al. Deep brain stimulation by blood–brain-barrier-crossing piezoelectric nanoparticles generating current and nitric oxide under focused ultrasound. Nat. Biomed. Eng 7, 149–163 (2023). https://doi.org/10.1038/s41551-022-00965-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41551-022-00965-4

This article is cited by

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