Contact
    Start Publications Helper lipid structure influences protein adsorption and ...
    ←  Publication Finder
    QSense

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

    Year: 2021

    Journal: Biomater. Sci., Volume 9, FEB 21, page 1449–1463

    Authors: Zhang, Rui; El-Mayta, Rakan; Murdoch, Timothy J.; Warzecha, Claude C.; Billingsley, Margaret M.; Shepherd, Sarah J.; Gong, Ningqiang; Wang, Lili; Wilson, James M.; Lee, Daeyeon; Mitchell, Michael J.

    Organizations: Tau Beta Pi Graduate Research Fellowship; NIH Training in HIV Pathogenesis T32 Program [T32 AI007632]; National Science Foundation (NSF) Graduate Research Fellowship [DGE 1845298]; Burroughs Wellcome Fund Career Award at the Scientific Interface (CASI), a US National Institutes of Health (NIH) Director's New Innovator Award [DP2 TR002776]; American Cancer Society [129784-IRG-16-188-38-IRG]; National Institutes of Health [NCI R01 CA241661, NCI R37 CA244911, NIDDK R01 DK123049]; Abramson Cancer Center (ACC)-School of Engineering and Applied Sciences (SEAS) [P30 CA016520]; 2018 AACR-Bayer Innovation and Discovery Grant [18-80-44-MITC]

    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.
    View publication