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Liposomal lipid nanoparticles for extrahepatic delivery of mRNA

Author

Listed:
  • Miffy Hok Yan Cheng

    (University of British Columbia)

  • Yao Zhang

    (University of British Columbia
    University of British Columbia
    University of British Columbia)

  • Kevin Fox

    (University of British Columbia)

  • Jerry Leung

    (University of British Columbia
    University of British Columbia)

  • Colton Strong

    (University of British Columbia
    University of British Columbia)

  • Emma Kang

    (University of British Columbia
    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
    University of British Columbia)

  • 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)

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.

Suggested Citation

  • 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, 2025. "Liposomal lipid nanoparticles for extrahepatic delivery of mRNA," Nature Communications, Nature, vol. 16(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-58523-w
    DOI: 10.1038/s41467-025-58523-w
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