• Open Access

Maximizing the Potency of siRNA Lipid Nanoparticles for Hepatic Gene Silencing In Vivo


  • This work was supported in part by the Canadian Institutes for Health Research (CIHR) through U/I grant FRN 59836. We would like to thank John Maraganore for helpful comments.


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Special (lipid) delivery: The role of the ionizable lipid pKa in the in vivo delivery of siRNA by lipid nanoparticles has been studied with a large number of head group modifications to the lipids. A tight correlation between the lipid pKa value and silencing of the mouse FVII gene (FVII ED50) was found, with an optimal pKa range of 6.2–6.5 (see graph). The most potent cationic lipid from this study has ED50 levels around 0.005 mg kg−1 in mice and less than 0.03 mg kg−1 in non-human primates.