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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Change history
20 June 2014
In the version of this Article originally published online, the following authors' names were written incorrectly: Victor Koteliansky, Omar F. Khan and Kamaljeet Singh Sandhu. These have now been corrected in all versions of the Article.
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Acknowledgements
The authors thank J. Cattie, T. O'Shea and T. Tammela. J.E.D. was supported by National Defense Science and Engineering (NDSEG), the National Science Foundation (NSF) and MIT Presidential Fellowships. D.P. was supported by R01 CA148663. M.W.K. was supported by the Stop and Shop Pediatric Brain Tumour Fund, as well as the Pediatric Brain Tumour Fund. H.S. was supported by the Deutsche Forschungsgemeinschaft (SA1668/2-1). Research was also supported by Alnylam and the Center for RNA Therapeutics and Biology.
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J.E.D., C.B., V.K., R.L. and D.G.A. conceived the experiments. J.E.D., C.B., O.F.K., A.T., S.J., T.E.S., Y.X., H.B.S., G.S., L.S., A.B., R.L.B., H.Y., T.R., Y.D., S.J., D.S., A.D., K.S.S., M.J.W., T.N., V.M.R., A.K.R.L.J., C.G.L., B.K., D.K.M., M.P., L.A., P.D., L.S., K.C., M.W.K., K.F., M.N., D.D., R.M.T., U.H.V.A., A.A., A.S. and D.P. performed experiments. J.E.D., C.B., V.K., R.L. and D.G.A. co-wrote the paper. All authors discussed the results and commented on the manuscript.
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R.L. is a shareholder and member of the Scientific Advisory Board of Alnylam. R.L and D.G.A have sponsored research grants from Alnylam. Alnylam also has a licence to certain intellectual property that was invented at the Massachusetts Institute of Technology by D.G.A. and R.L.
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Dahlman, J., Barnes, C., Khan, O. et al. In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight. Nature Nanotech 9, 648–655 (2014). https://doi.org/10.1038/nnano.2014.84
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DOI: https://doi.org/10.1038/nnano.2014.84
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