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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

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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.

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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.

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.

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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

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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.

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

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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

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