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

作者：Rui Zhang, Rakan El‐Mayta, Timothy J. Murdoch, Claude C. Warzecha, Margaret M. Billingsley, Sarah J. Shepherd, Ningqiang Gong, Lili Wang, James M. Wilson, Daeyeon Lee, Michael J. Mitchell · 发表于：Biomaterials Science · 年份：2020 · DOI：10.1039/d0bm01609h · 被引用次数：256 · 研究领域：RNA Interference and Gene Delivery、Lipid Membrane Structure and Behavior、Advanced biosensing and bioanalysis techniques

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 findi...