Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver

Jan 6, 2021Biomaterials science

Helper lipid structure affects protein binding and delivery of lipid nanoparticles to the spleen and liver

AI simplified

mRNA Technology on OpenScience ↗PubMed ↗DOI ↗

Abstract

High-throughput in vivo screening identified several lipid nanoparticle (LNP) formulations that preferentially accumulated in the liver or spleen.

LNPs containing the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) were found to preferentially target the liver.
LNPs that used the helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) showed a preference for accumulation in the spleen.
One LNP formulation with DOPE (LNP 42) exhibited stronger interactions with apolipoprotein E (ApoE) compared to its DSPC counterpart (LNP 90).
LNP 90 increased delivery of siRNA and mRNA to the spleen by two-fold and five-fold, respectively.
LNP 42 enhanced mRNA delivery to the liver by two-fold and improved liver transfection by three-fold.
The findings suggest that the choice of helper lipid in LNP formulations may significantly influence the biodistribution of nucleic acid therapeutics.

AI simplified

Nucleic acids, such as messenger RNAs, antisense oligonucleotides, and short interfering RNAs, hold great promise for treating previously 'undruggable' diseases. However, there are numerous biological barriers that hinder nucleic acid delivery to target cells and tissues. While lipid nanoparticles (LNPs) have been developed to protect nucleic acids from degradation and mediate their intracellular delivery, it is challenging to predict how alterations in LNP formulation parameters influence delivery to different organs. In this study, we utilized high-throughput in vivo screening to probe for structure-function relationships of intravenously administered LNPs along with quartz crystal microbalance with dissipation monitoring (QCM-D) to measure the binding affinity of LNPs to apolipoprotein E (ApoE), a protein implicated in the clearance and uptake of lipoproteins by the liver. High-throughput in vivo screening of a library consisting of 96 LNPs identified several formulations containing the helper lipid 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) that preferentially accumulated in the liver, while identical LNPs that substituted DOPE with the helper lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) preferentially accumulated in the spleen. Using QCM-D, it was found that one DOPE-containing LNP formulation (LNP 42) had stronger interactions with ApoE than an identical LNP formulation that substituted DOPE with DSPC (LNP 90). In order to further validate our findings, we formulated LNP 42 and LNP 90 to encapsulate Cy3-siRNA or mRNA encoding for firefly luciferase. The DSPC-containing LNP (LNP 90) was found to increase delivery to the spleen for both siRNA (two-fold) and mRNA (five-fold). In terms of liver delivery, the DOPE-containing LNP (LNP 42) enhanced mRNA delivery to the liver by two-fold and improved liver transfection by three-fold. Understanding the role of the helper lipid in LNP biodistribution and ApoE adsorption may aid in the future design of LNPs for nucleic acid therapeutics.

Full Text

Full text is available at the source.

View full text (PDF) ↗View full text ↗

Helper lipid structure influences protein adsorption and delivery of lipid nanoparticles to spleen and liver

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the mrna technology brief