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

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 and Gaurav Sahay ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-14527-2

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