Structure, activity and uptake mechanism of siRNA-lipid nanoparticles with an asymmetric ionizable lipid

Jul 5, 2016International journal of pharmaceutics

Structure, function, and cell entry of siRNA lipid nanoparticles with uneven ionizable lipids

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Abstract

Lipid nanoparticles (LNPs) with an asymmetric ionizable lipid enhance cellular uptake and biodistribution influenced by Apolipoprotein E (apoE).

LNPs are neutral in the blood but become increasingly charged in acidic environments.
The mobility of siRNA within LNPs is reduced due to electrostatic interactions with the ionizable lipid.
Apolipoprotein E significantly affects the in vivo distribution of LNPs and promotes cellular uptake.
Gene-silencing efficacy of LNPs is compromised when low-density lipoprotein receptor (LDLR) is targeted prior to siRNA treatment.
Understanding these mechanisms may facilitate the development of advanced LNP-based RNA interference therapeutics.

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Lipid nanoparticles (LNPs) represent the most advanced platform for the systemic delivery of siRNA. We have previously reported the discovery of novel ionizable lipids with asymmetric lipid tails, enabling potent gene-silencing activity in hepatocytes in vivo; however, the structure and delivery mechanism had not been elucidated. Here, we report the structure, activity and uptake mechanism of LNPs with an asymmetric ionizable lipid. Zeta potential and hemolytic activity of LNPs showed that LNPs were neutral at the pH of the blood compartment but become increasingly charged and fusogenic in the acidic endosomal compartment. (31)P NMR experiments indicated that the siRNA was less mobile inside particles, presumably because of an electrostatic interaction with an ionizable lipid. The role of Apolipoprotein E (apoE) was studied using recombinant human apoE both in vitro and in vivo. A comparative study in wild-type and apoE-deficient mice revealed that apoE significantly influenced the in vivo biodistribution of LNPs and enhanced the cellular uptake. Pretreatment of mice with siRNA targeting low-density lipoprotein receptor (LDLR) impaired gene-silencing of the following siRNA treatment, demonstrating that in vivo activity of LNPs is dependent on LDLR. Our studies on the detailed mechanism should lead to the creation of more sophisticated LNP-based RNAi therapeutics.

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Structure, activity and uptake mechanism of siRNA-lipid nanoparticles with an asymmetric ionizable lipid

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