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

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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