RNA Therapeutics Institute; Program in Molecular Medicine
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Nucleic Acids, Nucleotides, and Nucleosides
Efficient delivery of therapeutic RNA beyond the liver is the fundamental obstacle preventing its clinical utility. Lipid conjugation increases plasma half-life and enhances tissue accumulation and cellular uptake of small interfering RNAs (siRNAs). However, the mechanism relating lipid hydrophobicity, structure, and siRNA pharmacokinetics is unclear. Here, using a diverse panel of biologically occurring lipids, we show that lipid conjugation directly modulates siRNA hydrophobicity. When administered in vivo, highly hydrophobic lipid-siRNAs preferentially and spontaneously associate with circulating low-density lipoprotein (LDL), while less lipophilic lipid-siRNAs bind to high-density lipoprotein (HDL). Lipid-siRNAs are targeted to lipoprotein receptor-enriched tissues, eliciting significant mRNA silencing in liver (65%), adrenal gland (37%), ovary (35%), and kidney (78%). Interestingly, siRNA internalization may not be completely driven by lipoprotein endocytosis, but the extent of siRNA phosphorothioate modifications may also be a factor. Although biomimetic lipoprotein nanoparticles have been explored for the enhancement of siRNA delivery, our findings suggest that hydrophobic modifications can be leveraged to incorporate therapeutic siRNA into endogenous lipid transport pathways without the requirement for synthetic formulation.
small interfering RNAs, siRNAs, lipid transport, delivery, hydrophobicity
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Copyright The Author(s) 2018. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
DOI of Published Version
Nucleic Acids Res. 2019 Feb 20;47(3):1070-1081. doi: 10.1093/nar/gky1232. Link to article on publisher's site
Nucleic acids research
Osborn, Maire F.; Coles, Andrew H.; Biscans, Annabelle; Haraszti, Reka A.; Roux, Loic; Davis, Sarah M.; Ly, Socheata; Echeverria, Dimas; Hassler, Matthew R.; Godinho, Bruno M. D. C.; Nikan, Mehran; and Khvorova, Anastasia, "Hydrophobicity drives the systemic distribution of lipid-conjugated siRNAs via lipid transport pathways" (2019). RNA Therapeutics Institute Publications. 55.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
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