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Proc Natl Acad Sci U S A. 2018 Oct 16;115(42):E9944-E9952. doi: 10.1073/pnas.1811276115. Epub 2018 Oct 1.

High-throughput in vivo screen of functional mRNA delivery identifies nanoparticles for endothelial cell gene editing.

Author information

1
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332.
2
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332.
3
Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332.
4
Department of Orthopaedics, Emory University, Atlanta, GA 30322.
5
Atlanta Veterans Affairs Medical Center, Decatur, GA 30033.
6
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA 30332; james.dahlman@bme.gatech.edu.

Abstract

Dysfunctional endothelium causes more disease than any other cell type. Systemically administered RNA delivery to nonliver tissues remains challenging, in large part because there is no high-throughput method to identify nanoparticles that deliver functional mRNA to cells in vivo. Here we report a system capable of simultaneously quantifying how >100 lipid nanoparticles (LNPs) deliver mRNA that is translated into functional protein. Using this system (named FIND), we measured how >250 LNPs delivered mRNA to multiple cell types in vivo and identified 7C2 and 7C3, two LNPs that efficiently deliver siRNA, single-guide RNA (sgRNA), and mRNA to endothelial cells. The 7C3 delivered Cas9 mRNA and sgRNA to splenic endothelial cells as efficiently as hepatocytes, distinguishing it from LNPs that deliver Cas9 mRNA and sgRNA to hepatocytes more than other cell types. These data demonstrate that FIND can identify nanoparticles with novel tropisms in vivo.

KEYWORDS:

CRISPR; RNAi; barcoded nanoparticle; mRNA; nanoparticle

PMID:
30275336
PMCID:
PMC6196543
DOI:
10.1073/pnas.1811276115
[Indexed for MEDLINE]
Free PMC Article

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