Article abstract

Nature Biotechnology 25, 1149 - 1157 (2007)
Published online: 16 September 2007 | doi:10.1038/nbt1339

Mechanisms and optimization of in vivo delivery of lipophilic siRNAs

Christian Wolfrum1,2,3, Shuanping Shi3, K Narayanannair Jayaprakash4, Muthusamy Jayaraman4, Gang Wang4, Rajendra K Pandey4, Kallanthottathil G Rajeev4, Tomoko Nakayama4, Klaus Charrise4, Esther M Ndungo3, Tracy Zimmermann4, Victor Koteliansky4, Muthiah Manoharan4 & Markus Stoffel1,2,3

Cholesterol-conjugated siRNAs can silence gene expression in vivo. Here we synthesize a variety of lipophilic siRNAs and use them to elucidate the requirements for siRNA delivery in vivo. We show that conjugation to bile acids and long-chain fatty acids, in addition to cholesterol, mediates siRNA uptake into cells and gene silencing in vivo. Efficient and selective uptake of these siRNA conjugates depends on interactions with lipoprotein particles, lipoprotein receptors and transmembrane proteins. High-density lipoprotein (HDL) directs siRNA delivery into liver, gut, kidney and steroidogenic organs, whereas low-density lipoprotein (LDL) targets siRNA primarily to the liver. LDL-receptor expression is essential for siRNA delivery by LDL particles, and SR-BI receptor expression is required for uptake of HDL-bound siRNAs. Cellular uptake also requires the mammalian homolog of the Caenorhabditis elegans transmembrane protein Sid1. Our results demonstrate that conjugation to lipophilic molecules enables effective siRNA uptake through a common mechanism that can be exploited to optimize therapeutic siRNA delivery.

  1. Institute of Molecular Systems Biology, Swiss Federal Institute of Technology, ETH Zürich, HPT E73.
  2. Competence Center of Systems Biology and Metabolic Diseases, ETH Zürich, CH-8093 Zürich, Switzerland.
  3. The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
  4. Alnylam Pharmaceuticals Inc., 300 3rd Street, Cambridge, Massachusetts 02142, USA.

Correspondence to: Markus Stoffel1,2,3 e-mail:


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