Liposomal lipid nanoparticles for extrahepatic delivery of mRNA

Miffy Hok Yan Cheng (), Yao Zhang, Kevin Fox, Jerry Leung, Colton Strong, Emma Kang, Yihang Chen, Michelle Tong, Hemashree Bommadevara, Eric Jan, Owen Yuk Long Ip, Cristina Rodríguez-Rodríguez, Katayoun Saatchi, Urs O. Häfeli, Amir Abdolahzadeh, Dominik Witzigmann and Pieter R. Cullis ()
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Miffy Hok Yan Cheng: University of British Columbia
Yao Zhang: University of British Columbia
Kevin Fox: University of British Columbia
Jerry Leung: University of British Columbia
Colton Strong: University of British Columbia
Emma Kang: University of British Columbia
Yihang Chen: University of British Columbia
Michelle Tong: University of British Columbia
Hemashree Bommadevara: University of British Columbia
Eric Jan: University of British Columbia
Owen Yuk Long Ip: Polymorphic BioSciences
Cristina Rodríguez-Rodríguez: Faculty of Pharmaceutical Sciences
Katayoun Saatchi: Faculty of Pharmaceutical Sciences
Urs O. Häfeli: Faculty of Pharmaceutical Sciences
Amir Abdolahzadeh: NanoVation Therapeutics Inc.
Dominik Witzigmann: University of British Columbia
Pieter R. Cullis: University of British Columbia

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: Abstract Long-circulating, transfection-competent lipid nanoparticle (LNP)-mRNA delivery systems are critical for achieving efficient transfection in extrahepatic tissues. Here we investigate the properties of LNP mRNA systems containing high proportions of bilayer forming lipids, using equimolar egg sphingomyelin and cholesterol as the bilayer-forming components. We show that LNP mRNA systems prepared at bilayer lipid to ionizable lipid molar ratios of 4-0.67 exhibit high mRNA encapsulation efficiencies (90–100%) and excellent transfection potencies in vitro. Systems with bilayer lipid to ionizable lipid molar ratios equating to 4 exhibit a liposomal morphology with a solid core suspended in an aqueous interior surrounded by a lipid bilayer. These liposomal LNPs exhibit longer circulation lifetimes than LNP systems with Onpattro-like lipid compositions and have enhanced extrahepatic transfection properties. The prolonged blood circulation lifetime is attributed to reduced plasma protein adsorption. The transfection competency of liposomal LNP systems is attributed to export of the solid core containing mRNA from the LNP as the endosomal pH is lowered.

Date: 2025
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58523-w

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DOI: 10.1038/s41467-025-58523-w

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