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Nat Nanotechnol. 2014 Aug;9(8):648-655. doi: 10.1038/nnano.2014.84. Epub 2014 May 11.

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

Author information

1
Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
2
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
3
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
4
Alnylam Pharmaceuticals, Cambridge, Massachusetts 02139, USA.
5
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
6
Department of Microbiology and Immunology, Harvard Medical School, Boston 02115, USA.
7
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston 02114, USA.
8
Vascular Biology Program, Children's Hospital Boston, and Division of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston 02115, USA.
9
Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Program, Department of Medicine, University of Colorado School of Medicine, Aurora, USA.
10
Deparment of Biotechnology and Food Engineering, and The Russell Berrie Nanotechnology Institute, Technion Israel Institute of Technology, Haifa 3200, Israel.
11
Department of Chemical Engineering, Technion Israel Institute of Technology, Haifa 32000, Israel.
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Contributed equally

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.

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PMID:
24813696
PMCID:
PMC4207430
DOI:
10.1038/nnano.2014.84
[Indexed for MEDLINE]
Free PMC Article

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