Apolipoprotein E Binding Drives Structural and Compositional Rearrangement of mRNA-Containing Lipid Nanoparticles.

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery

Background:

• Messenger RNA (mRNA) therapeutics are emerging, utilizing lipid nanoparticles (LNPs) for delivery.
• Understanding LNP structure and behavior is crucial for effective mRNA delivery.
• Apolipoprotein E (ApoE) influences LNP fate in circulation, affecting biodistribution and cellular uptake.

Purpose of the Study:

• To elucidate the structural changes in mRNA-LNPs upon interaction with ApoE.
• To investigate the distribution of lipid components within LNPs with and without ApoE.
• To explore the implications of ApoE-induced structural rearrangements on mRNA release and endosomal escape.

Main Methods:

• Small-angle neutron scattering (SANS) was employed for structural analysis.
• Selective deuteration of lipids, cholesterol, and solvent was used to differentiate components.
• In vitro incubation of mRNA-LNPs with ApoE was performed.

Main Results:

• DSPC and cholesterol are surface-enriched in LNPs in buffer.
• ApoE binding induces lipid redistribution between the LNP shell and core.
• This rearrangement impacts internal LNP structure and leads to mRNA release.

Conclusions:

• ApoE binding significantly alters mRNA-LNP structure and composition.
• The observed lipid redistribution and mRNA release are relevant to LNP endosomal escape mechanisms.
• Further research into ApoE interactions can optimize mRNA-LNP delivery systems.