Payload distribution and capacity of mRNA lipid nanoparticles

Sixuan Li, Yizong Hu (), Andrew Li, Jinghan Lin, Kuangwen Hsieh, Zachary Schneiderman, Pengfei Zhang, Yining Zhu, Chenhu Qiu, Efrosini Kokkoli, Tza-Huei Wang () and Hai-Quan Mao ()
Additional contact information
Sixuan Li: Johns Hopkins University
Yizong Hu: Johns Hopkins University
Andrew Li: Johns Hopkins University School of Medicine
Jinghan Lin: Johns Hopkins University
Kuangwen Hsieh: Johns Hopkins University
Zachary Schneiderman: Johns Hopkins University
Pengfei Zhang: Johns Hopkins University School of Medicine
Yining Zhu: Johns Hopkins University
Chenhu Qiu: Johns Hopkins University
Efrosini Kokkoli: Johns Hopkins University
Tza-Huei Wang: Johns Hopkins University
Hai-Quan Mao: Johns Hopkins University

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Lipid nanoparticles (LNPs) are effective vehicles to deliver mRNA vaccines and therapeutics. It has been challenging to assess mRNA packaging characteristics in LNPs, including payload distribution and capacity, which are critical to understanding structure-property-function relationships for further carrier development. Here, we report a method based on the multi-laser cylindrical illumination confocal spectroscopy (CICS) technique to examine mRNA and lipid contents in LNP formulations at the single-nanoparticle level. By differentiating unencapsulated mRNAs, empty LNPs and mRNA-loaded LNPs via coincidence analysis of fluorescent tags on different LNP components, and quantitatively resolving single-mRNA fluorescence, we reveal that a commonly referenced benchmark formulation using DLin-MC3 as the ionizable lipid contains mostly 2 mRNAs per loaded LNP with a presence of 40%–80% empty LNPs depending on the assembly conditions. Systematic analysis of different formulations with control variables reveals a kinetically controlled assembly mechanism that governs the payload distribution and capacity in LNPs. These results form the foundation for a holistic understanding of the molecular assembly of mRNA LNPs.

Date: 2022
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DOI: 10.1038/s41467-022-33157-4

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