IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31993-y.html
   My bibliography  Save this article

Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression

Author

Listed:
  • Yining Zhu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Ruochen Shen

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Ivan Vuong

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Rebekah A. Reynolds

    (University of Washington
    University of Washington)

  • Melanie J. Shears

    (University of Washington
    University of Washington)

  • Zhi-Cheng Yao

    (Johns Hopkins University
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

  • Yizong Hu

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Won June Cho

    (Johns Hopkins University
    Johns Hopkins University)

  • Jiayuan Kong

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Sashank K. Reddy

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Sean C. Murphy

    (University of Washington
    University of Washington
    University of Washington
    Fred Hutch Cancer Research Center)

  • Hai-Quan Mao

    (Johns Hopkins University School of Medicine
    Johns Hopkins University
    Johns Hopkins University School of Medicine
    Johns Hopkins University)

Abstract

Lipid nanoparticles hold great potential as an effective non-viral vector for nucleic acid-based gene therapy. Plasmid DNA delivery can result in extended transgene expression compared to mRNA-based technologies, yet there is a lack of systematic investigation into lipid nanoparticle compositions for plasmid DNA delivery. Here, we report a multi-step screening platform to identify optimized plasmid DNA lipid nanoparticles for liver-targeted transgene expression. To achieve this, we analyze the role of different helper lipids and component ratios in plasmid DNA lipid nanoparticle-mediated gene delivery in vitro and in vivo. Compared to mRNA LNPs and in vivo-jetPEI/DNA nanoparticles, the identified plasmid DNA lipid nanoparticles successfully deliver transgenes and mediate prolonged expression in the liver following intravenous administration in mice. By addressing different physiological barriers in a stepwise manner, this screening platform can efficiently down select effective lipid nanoparticle candidates from a lipid nanoparticle library of over 1000 formulations. In addition, we substantially extend the duration of plasmid DNA nanoparticle-mediated transgene expression using a DNA/siRNA co-delivery approach that targets transcription factors regulating inflammatory response pathways. This lipid nanoparticle-based co-delivery strategy further highlights the unique advantages of an extended transgene expression profile using plasmid DNA delivery and offers new opportunities for DNA-based gene medicine applications.

Suggested Citation

  • Yining Zhu & Ruochen Shen & Ivan Vuong & Rebekah A. Reynolds & Melanie J. Shears & Zhi-Cheng Yao & Yizong Hu & Won June Cho & Jiayuan Kong & Sashank K. Reddy & Sean C. Murphy & Hai-Quan Mao, 2022. "Multi-step screening of DNA/lipid nanoparticles and co-delivery with siRNA to enhance and prolong gene expression," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31993-y
    DOI: 10.1038/s41467-022-31993-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31993-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-31993-y?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Tuo Wei & Qiang Cheng & Yi-Li Min & Eric N. Olson & Daniel J. Siegwart, 2020. "Systemic nanoparticle delivery of CRISPR-Cas9 ribonucleoproteins for effective tissue specific genome editing," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Milan Gautam & Antony Jozic & Grace Li-Na Su & Marco Herrera-Barrera & Allison Curtis & Sebastian Arrizabalaga & Wayne Tschetter & Renee C. Ryals & Gaurav Sahay, 2023. "Lipid nanoparticles with PEG-variant surface modifications mediate genome editing in the mouse retina," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Tuo Wei & Yehui Sun & Qiang Cheng & Sumanta Chatterjee & Zachary Traylor & Lindsay T. Johnson & Melissa L. Coquelin & Jialu Wang & Michael J. Torres & Xizhen Lian & Xu Wang & Yufen Xiao & Craig A. Hod, 2023. "Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Mohamed Fareh & Wei Zhao & Wenxin Hu & Joshua M. L. Casan & Amit Kumar & Jori Symons & Jennifer M. Zerbato & Danielle Fong & Ilia Voskoboinik & Paul G. Ekert & Rajeev Rudraraju & Damian F. J. Purcell , 2021. "Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31993-y. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.