Deconvoluting Lipid Nanoparticle Structure for Messenger RNA Delivery

Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure...

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Bibliographic Details
Published inNano Letters Vol. 20; no. 6; pp. 4543 - 4549
Main Authors Eygeris, Yulia, Patel, Siddharth, Jozic, Antony, Sahay, Gaurav
Format Journal Article Web Resource
LanguageEnglish
Published United States American Chemical Society 10.06.2020
Subjects
Betacoronavirus - isolation & purification
Cholesterol - analogs & derivatives
Coronavirus Infections - genetics
Coronavirus Infections - prevention & control
COVID-19
COVID-19 Vaccines
Drug Carriers - chemistry
Gene Transfer Techniques
HeLa Cells
Humans
Letter
Lipids - chemistry
Nanoparticles - chemistry
Nanoparticles - ultrastructure
Pandemics - prevention & control
Phase Transition
Phytosterols - chemistry
Pneumonia, Viral - prevention & control
RNA, Messenger - administration & dosage
RNA, Messenger - genetics
SARS-CoV-2
Transfection
Viral Vaccines - administration & dosage
Viral Vaccines - genetics
gene therapy
lipid nanoparticles
cryo-TEM
mRNA delivery
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Summary:Lipid nanoparticle (LNP) packaged mRNA vaccines have been deployed against infectious diseases such as COVID-19, yet their structural features remain unclear. Cholesterol, a major constituent within LNPs, contributes to their morphology that influences gene delivery. Herein, we examine the structure of LNPs containing cholesterol derivatives using electron microscopy, differential scanning calorimetry, and membrane fluidity assays. LNPs formulated with C24 alkyl derivatives of cholesterol show a polymorphic shape and various degrees of multilamellarity and lipid partitioning, likely due to phase separation. The addition of methyl and ethyl groups to the C24 alkyl tail of the cholesterol backbone induces multilamellarity (>50% increase compared to cholesterol), while the addition of a double bond induces lipid partitioning (>90% increase compared to cholesterol). LNPs with multilamellar and faceted structures, as well as a lamellar lipid phase, showed higher gene transfection. Unraveling the structure of mRNA-LNPs can enable their rational design toward enhanced gene delivery.
ISSN:1530-6984
1530-6992
DOI:10.1021/acs.nanolett.0c01386