Uittreksel
| Taal | Engels |
|---|---|
| Pagina's | 9023-9031 |
| Aantal pagina's | 9 |
| Tijdschrift | Nanoscale |
| Volume | 11 |
| Nummer van het tijdschrift | 18 |
| Vroegere onlinedatum | 22 apr 2019 |
| DOI's | |
| Status | Gepubliceerd - 14 mei 2019 |
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Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads. / Kulkarni, Jayesh A. (Corresponding author); Witzigmann, Dominik; Leung, Jerry; van der Meel, Roy; Zaifman, Josh; Darjuan, Maria M.; Grisch-Chan, Hiu Man; Thöny, Beat; Tam, Yuen Yi C.; Cullis, Pieter R. (Corresponding author).
In: Nanoscale, Vol. 11, Nr. 18, 14.05.2019, blz. 9023-9031.Onderzoeksoutput: Bijdrage aan tijdschrift › Tijdschriftartikel › Academic › peer review
TY - JOUR
T1 - Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads
AU - Kulkarni,Jayesh A.
AU - Witzigmann,Dominik
AU - Leung,Jerry
AU - van der Meel,Roy
AU - Zaifman,Josh
AU - Darjuan,Maria M.
AU - Grisch-Chan,Hiu Man
AU - Thöny,Beat
AU - Tam,Yuen Yi C.
AU - Cullis,Pieter R.
PY - 2019/5/14
Y1 - 2019/5/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065574154&partnerID=8YFLogxK
U2 - 10.1039/C9NR02004G
DO - 10.1039/C9NR02004G
M3 - Article
VL - 11
SP - 9023
EP - 9031
JO - Nanoscale
T2 - Nanoscale
JF - Nanoscale
SN - 2040-3364
IS - 18
ER -