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Cited by 57Ultrasound and Hyperthermia ApplicationsRNA Interference and Gene DeliveryMicrobial Inactivation Methods

Sonoselective transfection of cerebral vasculature without blood–brain barrier disruption

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Gorick, Catherine M., Mathew, Alexander S., Garrison, William J., Thim, E. Andrew, Fisher, Delaney G., Copeland, Caitleen A., Song, Ji, Klibanov, Alexander L. +2 more·2020·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1914595117PMC PMC7084076
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Abstract

Treatment of many pathologies of the brain could be improved markedly by the development of noninvasive therapeutic approaches that elicit robust, endothelial cell-selective gene expression in specific brain regions that are targeted under MR image guidance. While focused ultrasound (FUS) in conjunction with gas-filled microbubbles (MBs) has emerged as a noninvasive modality for MR image-guided gene delivery to the brain, it has been used exclusively to transiently disrupt the blood–brain barrier (BBB), which may induce a sterile inflammation response. Here, we introduce an MR image-guided FUS method that elicits endothelial-selective transfection of the cerebral vasculature (i.e., “sonoselective” transfection), without opening the BBB. We first determined that activating circulating, cationic plasmid-bearing MBs with pulsed low-pressure (0.1 MPa) 1.1-MHz FUS facilitates sonoselective gene delivery to the endothelium without MRI-detectable disruption of the BBB. The degree of endothelial selectivity varied inversely with the FUS pressure, with higher pressures (i.e., 0.3-MPa and 0.4-MPa FUS) consistently inducing BBB opening and extravascular transfection. Bulk RNA sequencing analyses revealed that the sonoselective low-pressure regimen does not up-regulate inflammatory or immune responses. Single-cell RNA sequencing indicated that the transcriptome of sonoselectively transfected brain endothelium was unaffected by the treatment. The approach developed here permits targeted gene delivery to blood vessels and could be used to promote angiogenesis, release endothelial cell-secreted factors to stimulate nerve regrowth, or recruit neural stem cells.

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  • Oscillating microbubbles under ultrasound implement transport of gene product beyond blood vessels without breaking tight junctions and disrupting BBB.

    “Their method through the oscillating of microbubbles under the ultrasound field could implement the transport of the gene product beyond the blood vessels without breaking the tight junctions and disrupting the BBB.”

    From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [225]

    The Abstract says the method uses low-pressure ultrasound and oscillating microbubbles to transfect cerebral endothelial cells without opening the BBB. Contrary to the claim of transport beyond blood vessels, the Discussion section “In Vivo Endothelial Cell Sonoporation without Tight Junction Disruption or Transcellular Transport” says transfection is nearly all confined to the endothelium and does not promote additional transcellular transport. (LLM, conf=0.90)

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  • Price's group strategy achieved around 90% cell specificity of selective transfection with no extra cell-specific promoter.

    “demonstrating their strategy achieved around 90% cell specificity of selective transfection with no extra use of a cell-specific promoter.”

    From The blood–brain barrier: Structure, regulation and drug delivery (2023) · cites this paper as [225]

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Authors
Gorick, C. M., Mathew, A. S., Garrison, W. J., Thim, E. A., Fisher, D. G., Copeland, C. A., Song, J., Klibanov, A. L., Miller, G. W., & Price, R. J.
Affiliations
University of Virginia (US)
Corresponding author
Price, Richard J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2020-03-02
Volume
117
Issue
11
Pages
5644-5654
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1914595117
PMC
PMC7084076
OpenAlex
W3009105183
Cited by
57
References
3
Citations by year
2026: 3 · 2025: 6 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 18 · 2020: 7
FWCI
3.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of Biomedical Imaging and Bioengineering (R01EB020147, R21EB024323)
  • American Heart Association (18PRE34030022)
Topics
  • Physical Sciences › Engineering › Biomedical Engineering › Ultrasound and Hyperthermia Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Inactivation Methods
Keywords
focused ultrasound, microbubbles, blood-brain barrier, cerebral vasculature, sterile inflammation, single-cell RNA sequencing, angiogenesis, nerve regeneration
MeSH terms
Ultrasonic Waves, Animals, Blood-Brain Barrier, Magnetic Resonance Imaging, Male, Mice, Inbred C57BL, Transfection, Microbubbles, Mice, Transcriptome

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