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

Marco Maugeri, Muhammad Nawaz, Alexandros Papadimitriou, Annelie Angerfors, Alessandro Camponeschi, Manli Na, Mikko Hölttä, Pia Skantze, Svante Johansson, Martina Sundqvist, Johnny Lindquist, Tomas Kjellman, Inga-Lill Mårtensson, Tao Jin, Per Sunnerhagen, Sofia Östman, Lennart Lindfors and Hadi Valadi ()
Additional contact information
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

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12275-6

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