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Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells

Author

Listed:
  • Marco Maugeri

    (University of Gothenburg)

  • Muhammad Nawaz

    (University of Gothenburg)

  • Alexandros Papadimitriou

    (University of Gothenburg)

  • Annelie Angerfors

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Alessandro Camponeschi

    (University of Gothenburg)

  • Manli Na

    (University of Gothenburg)

  • Mikko Hölttä

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Pia Skantze

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Svante Johansson

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Martina Sundqvist

    (University of Gothenburg)

  • Johnny Lindquist

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Tomas Kjellman

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Inga-Lill Mårtensson

    (University of Gothenburg)

  • Tao Jin

    (University of Gothenburg)

  • Per Sunnerhagen

    (University of Gothenburg)

  • Sofia Östman

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Lennart Lindfors

    (BioPharmaceuticals R&D, AstraZeneca, Gothenburg)

  • Hadi Valadi

    (University of Gothenburg)

Abstract

RNA-based therapeutics hold great promise for treating diseases and lipid nanoparticles (LNPs) represent the most advanced platform for RNA delivery. However, the fate of the LNP-mRNA after endosome-engulfing and escape from the autophagy-lysosomal pathway remains unclear. To investigate this, mRNA (encoding human erythropoietin) was delivered to cells using LNPs, which shows, for the first time, a link between LNP-mRNA endocytosis and its packaging into extracellular vesicles (endo-EVs: secreted after the endocytosis of LNP-mRNA). Endosomal escape of LNP-mRNA is dependent on the molar ratio between ionizable lipids and mRNA nucleotides. Our results show that fractions of ionizable lipids and mRNA (1:1 molar ratio of hEPO mRNA nucleotides:ionizable lipids) of endocytosed LNPs were detected in endo-EVs. Importantly, these EVs can protect the exogenous mRNA during in vivo delivery to produce human protein in mice, detected in plasma and organs. Compared to LNPs, endo-EVs cause lower expression of inflammatory cytokines.

Suggested Citation

  • Marco Maugeri & Muhammad Nawaz & Alexandros Papadimitriou & Annelie Angerfors & Alessandro Camponeschi & Manli Na & Mikko Hölttä & Pia Skantze & Svante Johansson & Martina Sundqvist & Johnny Lindquist, 2019. "Linkage between endosomal escape of LNP-mRNA and loading into EVs for transport to other cells," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12275-6
    DOI: 10.1038/s41467-019-12275-6
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    Cited by:

    1. Kexin Su & Lu Shi & Tao Sheng & Xinxin Yan & Lixin Lin & Chaoyang Meng & Shiqi Wu & Yuxuan Chen & Yao Zhang & Chaorong Wang & Zichuan Wang & Junjie Qiu & Jiahui Zhao & Tengfei Xu & Yuan Ping & Zhen Gu, 2024. "Reformulating lipid nanoparticles for organ-targeted mRNA accumulation and translation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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