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

被引：230

作者：

Sago, Cory D. ^{[1
,2
]}

Lokugamage, Melissa P. ^{[1
,2
]}

Paunovska, Kalina ^{[1
,2
]}

Vanover, Daryll A. ^{[1
,2
]}

Monaco, Christopher M. ^{[3
]}

Shah, Nirav N. ^{[3
]}

Castro, Marielena Gamboa ^{[1
,2
]}

Anderson, Shannon E. ^{[1
,2
]}

Rudoltz, Tobi G. ^{[1
,2
]}

Lando, Gwyneth N. ^{[1
,2
]}

Tiwari, Pooja Mummilal ^{[1
,2
]}

Kirschman, Jonathan L. ^{[1
,2
]}

Willett, Nick ^{[1
,2
,4
,5
,6
]}

Jang, Young C. ^{[3
]}

Santangelo, Philip J. ^{[1
,2
]}

Bryksin, Anton V. ^{[4
]}

Dahlman, James E. ^{[1
,2
]}

机构：

[1] Georgia Inst Technol, Wallace H Coulter Dept Biomed Engn, Atlanta, GA 30332 USA

[2] Emory Univ, Sch Med, Atlanta, GA 30332 USA

[3] Georgia Inst Technol, Sch Biol Sci, Atlanta, GA 30332 USA

[4] Georgia Inst Technol, Parker H Petit Inst Bioengn & Biosci, Atlanta, GA 30332 USA

[5] Emory Univ, Dept Orthopaed, Atlanta, GA 30322 USA

[6] Atlanta Vet Affairs Med Ctr, Decatur, GA 30033 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2018年 / 115卷 / 42期

基金：

美国国家卫生研究院;

关键词：

nanoparticle; CRISPR; RNAi; barcoded nanoparticle; mRNA; LIPID NANOPARTICLES; SIRNA DELIVERY; TRANSTHYRETIN AMYLOIDOSIS; DISCOVERY; CRISPR; TRAFFICKING; PATISIRAN; SYSTEM; MOUSE; MICE;

D O I：

10.1073/pnas.1811276115

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：E9944 / E9952

页数：9

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