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Issue 18, 2019
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Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads

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Abstract

The success of Onpattro™ (patisiran) clearly demonstrates the utility of lipid nanoparticle (LNP) systems for enabling gene therapies. These systems are composed of ionizable cationic lipids, phospholipid, cholesterol, and polyethylene glycol (PEG)-lipids, and are produced through rapid-mixing of an ethanolic-lipid solution with an acidic aqueous solution followed by dialysis into neutralizing buffer. A detailed understanding of the mechanism of LNP formation is crucial to improving LNP design. Here we use cryogenic transmission electron microscopy and fluorescence techniques to further demonstrate that LNP are formed through the fusion of precursor, pH-sensitive liposomes into large electron-dense core structures as the pH is neutralized. Next, we show that the fusion process is limited by the accumulation of PEG-lipid on the emerging particle. Finally, we show that the fusion-dependent mechanism of formation also applies to LNP containing macromolecular payloads including mRNA, DNA vectors, and gold nanoparticles.

Graphical abstract: Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads

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Publication details

The article was received on 06 Mar 2019, accepted on 20 Apr 2019 and first published on 22 Apr 2019


Article type: Paper
DOI: 10.1039/C9NR02004G
Nanoscale, 2019,11, 9023-9031

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    Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads

    J. A. Kulkarni, D. Witzigmann, J. Leung, R. van der Meel, J. Zaifman, M. M. Darjuan, H. M. Grisch-Chan, B. Thöny, Y. Y. C. Tam and P. R. Cullis, Nanoscale, 2019, 11, 9023
    DOI: 10.1039/C9NR02004G

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