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Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection

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Download Hi-Res ImageDownload to MS-PowerPointCite This:Biochemistry 2023, 62, 24, 3533-3547
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    Lipid Nanoparticles Deliver mRNA to the Brain after an Intracerebral Injection
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    • Jan Tuma
      Jan Tuma
      The Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
      Department of Pathophysiology, Faculty of Medicine in Pilsen, Charles University, alej Svobody 75, 323 00 Plzen, Czech Republic
      More by Jan Tuma
      Orcidhttps://orcid.org/0000-0002-7197-8482
    • Yu-Ju Chen
      Yu-Ju Chen
      The Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
      More by Yu-Ju Chen
      Orcidhttps://orcid.org/0000-0002-1197-1086
    • Michael G. Collins
      Michael G. Collins
      The Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
      More by Michael G. Collins
      Orcidhttps://orcid.org/0000-0002-3161-0595
    • Abhik Paul
      Abhik Paul
      The Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
      More by Abhik Paul
      Orcidhttps://orcid.org/0000-0003-3797-2439
    • Jie Li
      Jie Li
      Department of Bioengineering, University of California, Berkeley, California 94720, United States
      The Innovative Genomics Institute, 2151 Berkeley Way, Berkeley, California 94704, United States
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      Orcidhttps://orcid.org/0000-0003-0189-2787
    • Hesong Han
      Hesong Han
      Department of Bioengineering, University of California, Berkeley, California 94720, United States
      The Innovative Genomics Institute, 2151 Berkeley Way, Berkeley, California 94704, United States
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      Orcidhttps://orcid.org/0000-0001-5545-5238
    • Rohit Sharma
      Rohit Sharma
      Department of Bioengineering, University of California, Berkeley, California 94720, United States
      The Innovative Genomics Institute, 2151 Berkeley Way, Berkeley, California 94704, United States
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      Orcidhttps://orcid.org/0000-0003-1428-5521
    • Niren Murthy
      Niren Murthy
      Department of Bioengineering, University of California, Berkeley, California 94720, United States
      The Innovative Genomics Institute, 2151 Berkeley Way, Berkeley, California 94704, United States
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      Orcidhttps://orcid.org/0000-0002-7815-7337
    • Hye Young Lee*
      Hye Young Lee
      The Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States
      *Email: [email protected]
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      Orcidhttps://orcid.org/0000-0002-3150-6886
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    Biochemistry

    Cite this: Biochemistry 2023, 62, 24, 3533–3547
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    https://doi.org/10.1021/acs.biochem.3c00371
    Published September 20, 2023
    Copyright © 2023 American Chemical Society
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    Abstract

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    Neurological disorders are often debilitating conditions with no cure. The majority of current therapies are palliative rather than disease-modifying; therefore, new strategies for treating neurological disorders are greatly needed. mRNA-based therapeutics have great potential for treating such neurological disorders; however, challenges with delivery have limited their clinical potential. Lipid nanoparticles (LNPs) are a promising delivery vector for the brain, given their safer toxicity profile and higher efficacy. Despite this, very little is known about LNP-mediated delivery of mRNA into the brain. Here, we employ MC3-based LNPs and successfully deliver Cre mRNA and Cas9 mRNA/Ai9 sgRNA to the adult Ai9 mouse brain; greater than half of the entire striatum and hippocampus was found to be penetrated along the rostro-caudal axis by direct intracerebral injections of MC3 LNP mRNAs. MC3 LNP Cre mRNA successfully transfected cells in the striatum (∼52% efficiency) and hippocampus (∼49% efficiency). In addition, we demonstrate that MC3 LNP Cas9 mRNA/Ai9 sgRNA edited cells in the striatum (∼7% efficiency) and hippocampus (∼3% efficiency). Further analysis demonstrates that MC3 LNPs mediate mRNA delivery to multiple cell types including neurons, astrocytes, and microglia in the brain. Overall, LNP-based mRNA delivery is effective in brain tissue and shows great promise for treating complex neurological disorders.

    Copyright © 2023 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.biochem.3c00371.

    • Size distribution and polydispersity index of MC3 LNP mRNA complexes (Figure S1); quantification of total number of DAPI+, tdTomato+, NeuN+, Iba1+, and GFAP+ cells as well as total number of NeuN+; tdTomato+, GFAP+; tdTomato+, and Iba1+; tdTomato+ cells in the striatum and hippocampus of Ai9 mice after the injection with MC3 LNP Cre mRNA or with MC3 LNP Cas9 mRNA/Ai9 sgRNA (Figures S2–S6); quantification of tdTomato+; DAPI+ cells normalized by injection concentration of MC3 LNP mRNA (Figure S7) (PDF)

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    Cited By

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    This article is cited by 1 publications.

    1. Yu-Ju Chen, Abhik Paul, Michael Gregory Collins, Hye Young Lee. The changing landscape of gene editing tool delivery in neurological disorders. Current Opinion in Biomedical Engineering 2023, 28 , 100509. https://doi.org/10.1016/j.cobme.2023.100509
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    Biochemistry

    Cite this: Biochemistry 2023, 62, 24, 3533–3547
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acs.biochem.3c00371
    Published September 20, 2023
    Copyright © 2023 American Chemical Society
    Request reuse permissions

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