Liposomal lipid nanoparticles for extrahepatic delivery of mRNA
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.
Authors
- Urs O. Häfeli (ORCID: https://orcid.org/0000-0003-0671-4509)
- Cristina Rodríguez‐Rodríguez (ORCID: https://orcid.org/0000-0002-3313-4422)
- Katayoun Saatchi (ORCID: https://orcid.org/0000-0002-5372-6791)
- Amir Abdolahzadeh (ORCID: https://orcid.org/0000-0003-3964-7867)
- Michelle Tong (ORCID: https://orcid.org/0009-0005-0832-5242)
- Pieter R. Cullis (ORCID: https://orcid.org/0000-0001-9586-2508)
- Hemashree Bommadevara
- Dominik Witzigmann (ORCID: https://orcid.org/0000-0002-8197-8558)
- Kevin Fox (ORCID: https://orcid.org/0009-0008-8316-5674)
- Jerry Leung (ORCID: https://orcid.org/0000-0002-8714-8440)
- Colton Strong (ORCID: https://orcid.org/0000-0003-4031-9932)
- Eric Jan (ORCID: https://orcid.org/0000-0003-0523-8467)
- Miffy H. Y. Cheng (ORCID: https://orcid.org/0000-0002-0261-4642)
- Yao Zhang (ORCID: https://orcid.org/0000-0003-2783-1317)
- Yihang Chen
- Emma Kang (ORCID: https://orcid.org/0009-0009-2485-1735)
- Owen Yuk Long Ip
Institutions
- University of British Columbia Hospital (CA)
- University of British Columbia (CA)
- FPInnovations (CA)
- Spinal Cord Injury BC (CA)
- Canada's Michael Smith Genome Sciences Centre (CA)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-03
- DOI
- https://doi.org/10.1038/s41467-025-58523-w
- Citations
- 33
- Primary Topic
- RNA Interference and Gene Delivery
- Type
- article
- Field-Weighted Citation Impact
- 26.60
Funders
- Canadian Institutes of Health Research
- British Columbia Knowledge Development Fund