In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight

James E. Dahlman, Carmen Barnes, Omar F. Khan, Aude Thiriot, Siddharth Jhunjunwala, Taylor E. Shaw, Yiping Xing, Hendrik B. Sager, Gaurav Sahay, Lauren Speciner, Andrew Bader, Roman L. Bogorad, Hao Yin, Tim Racie, Yizhou Dong, Shan Jiang, Danielle Seedorf, Apeksha Dave, Kamaljeet Singh Sandhu, Matthew J. WebberTatiana Novobrantseva, Vera M. Ruda, Abigail K.R. Lytton-Jean, Christopher G. Levins, Brian Kalish, Dayna K. Mudge, Mario Perez, Ludmila Abezgauz, Partha Dutta, Lynelle Smith, Klaus Charisse, Mark W. Kieran, Kevin Fitzgerald, Matthias Nahrendorf, Dganit Danino, Rubin M. Tuder, Ulrich H. Von Andrian, Akin Akinc, Dipak Panigrahy, Avi Schroeder, Victor Koteliansky, Robert Langer, Daniel G. Anderson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

315 Scopus citations

Abstract

Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo. Unlike lipid or lipid-like nanoparticles, this formulation does not significantly reduce gene expression in hepatocytes or immune cells even at the dosage necessary for endothelial gene silencing. These nanoparticles mediate the most durable non-liver silencing reported so far and facilitate the delivery of siRNAs that modify endothelial function in mouse models of vascular permeability, emphysema, primary tumour growth and metastasis.

Original languageEnglish
Pages (from-to)648-655
Number of pages8
JournalNature Nanotechnology
Volume9
Issue number8
DOIs
StatePublished - Aug 2014
Externally publishedYes

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