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Payload distribution and capacity of mRNA lipid nanoparticles

Author

Listed:
  • Sixuan Li

    (Johns Hopkins University)

  • Yizong Hu

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

  • Andrew Li

    (Johns Hopkins University School of Medicine)

  • Jinghan Lin

    (Johns Hopkins University
    Johns Hopkins University School of Medicine)

  • Kuangwen Hsieh

    (Johns Hopkins University)

  • Zachary Schneiderman

    (Johns Hopkins University
    Johns Hopkins University)

  • Pengfei Zhang

    (Johns Hopkins University School of Medicine)

  • Yining Zhu

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

  • Chenhu Qiu

    (Johns Hopkins University
    Johns Hopkins University)

  • Efrosini Kokkoli

    (Johns Hopkins University
    Johns Hopkins University)

  • Tza-Huei Wang

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

  • Hai-Quan Mao

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

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.

Suggested Citation

  • Sixuan Li & Yizong Hu & Andrew Li & Jinghan Lin & Kuangwen Hsieh & Zachary Schneiderman & Pengfei Zhang & Yining Zhu & Chenhu Qiu & Efrosini Kokkoli & Tza-Huei Wang & Hai-Quan Mao, 2022. "Payload distribution and capacity of mRNA lipid nanoparticles," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33157-4
    DOI: 10.1038/s41467-022-33157-4
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    Cited by:

    1. Yu Zhao & Zhongfeng Ye & Donghui Song & Douglas Wich & Shuliang Gao & Jennifer Khirallah & Qiaobing Xu, 2023. "Nanomechanical action opens endo-lysosomal compartments," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    2. 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.

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