IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v11y2020i1d10.1038_s41467-020-14527-2.html
   My bibliography  Save this article

Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA

Author

Listed:
  • Siddharth Patel

    (Oregon State University, Robertson Life Sciences Building)

  • N. Ashwanikumar

    (Oregon State University, Robertson Life Sciences Building)

  • Ema Robinson

    (Oregon State University, Robertson Life Sciences Building)

  • Yan Xia

    (Moderna Therapeutics)

  • Cosmin Mihai

    (Moderna Therapeutics)

  • Joseph P. Griffith

    (Duke University)

  • Shangguo Hou

    (Duke University)

  • Adam A. Esposito

    (Moderna Therapeutics)

  • Tatiana Ketova

    (Moderna Therapeutics)

  • Kevin Welsher

    (Duke University)

  • John L. Joyal

    (Moderna Therapeutics)

  • Örn Almarsson

    (Moderna Therapeutics)

  • Gaurav Sahay

    (Oregon State University, Robertson Life Sciences Building
    Oregon Health and Science University, Robertson Life Science Building)

Abstract

Endosomal sequestration of lipid-based nanoparticles (LNPs) remains a formidable barrier to delivery. Herein, structure-activity analysis of cholesterol analogues reveals that incorporation of C-24 alkyl phytosterols into LNPs (eLNPs) enhances gene transfection and the length of alkyl tail, flexibility of sterol ring and polarity due to -OH group is required to maintain high transfection. Cryo-TEM displays a polyhedral shape for eLNPs compared to spherical LNPs, while x-ray scattering shows little disparity in internal structure. eLNPs exhibit higher cellular uptake and retention, potentially leading to a steady release from the endosomes over time. 3D single-particle tracking shows enhanced intracellular diffusivity of eLNPs relative to LNPs, suggesting eLNP traffic to productive pathways for escape. Our findings show the importance of cholesterol in subcellular transport of LNPs carrying mRNA and emphasize the need for greater insights into surface composition and structural properties of nanoparticles, and their subcellular interactions which enable designs to improve endosomal escape.

Suggested Citation

  • Siddharth Patel & N. Ashwanikumar & Ema Robinson & Yan Xia & Cosmin Mihai & Joseph P. Griffith & Shangguo Hou & Adam A. Esposito & Tatiana Ketova & Kevin Welsher & John L. Joyal & Örn Almarsson & Gaur, 2020. "Naturally-occurring cholesterol analogues in lipid nanoparticles induce polymorphic shape and enhance intracellular delivery of mRNA," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14527-2
    DOI: 10.1038/s41467-020-14527-2
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-020-14527-2
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-020-14527-2?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
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Man Wu & Pok Man Hau & Linxian Li & Chi Man Tsang & Yike Yang & Aziz Taghbalout & Grace Tin-Yun Chung & Shin Yee Hui & Wing Chung Tang & Nathaniel Jillette & Jacqueline Jufen Zhu & Horace Hok Yeung Le, 2024. "Synthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Xinzhu Shan & Zhiqiang Zhao & Pingping Lai & Yuxiu Liu & Buyao Li & Yubin Ke & Hanqiu Jiang & Yilong Zhou & Wenzhe Li & Qian Wang & Pengxia Qin & Yizhe Xue & Zihan Zhang & Chenlong Wei & Bin Ma & Wei , 2024. "RNA nanotherapeutics with fibrosis overexpression and retention for MASH treatment," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Roy Pattipeiluhu & Ye Zeng & Marco M.R.M. Hendrix & Ilja K. Voets & Alexander Kros & Thomas H. Sharp, 2024. "Liquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    4. Kexin Su & Lu Shi & Tao Sheng & Xinxin Yan & Lixin Lin & Chaoyang Meng & Shiqi Wu & Yuxuan Chen & Yao Zhang & Chaorong Wang & Zichuan Wang & Junjie Qiu & Jiahui Zhao & Tengfei Xu & Yuan Ping & Zhen Gu, 2024. "Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Kai Liu & Ralf Nilsson & Elisa Lázaro-Ibáñez & Hanna Duàn & Tasso Miliotis & Marie Strimfors & Michael Lerche & Ana Rita Salgado Ribeiro & Johan Ulander & Daniel Lindén & Anna Salvati & Alan Sabirsh, 2023. "Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function," Nature Communications, Nature, vol. 14(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:11:y:2020:i:1:d:10.1038_s41467-020-14527-2. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.