RNA Therapeutics Institute Publications
UMMS Affiliation
RNA Therapeutics Institute; Program in Molecular Medicine
Publication Date
2019-02-20
Document Type
Article
Disciplines
Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Biochemistry, Biophysics, and Structural Biology | Genetics and Genomics | Nucleic Acids, Nucleotides, and Nucleosides
Abstract
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.
Keywords
small interfering RNAs, siRNAs, lipid transport, delivery, hydrophobicity
Rights and Permissions
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
10.1093/nar/gky1232
Source
Nucleic Acids Res. 2019 Feb 20;47(3):1070-1081. doi: 10.1093/nar/gky1232. Link to article on publisher's site
Journal/Book/Conference Title
Nucleic acids research
Related Resources
PubMed ID
30535404
Repository Citation
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.
https://escholarship.umassmed.edu/rti_pubs/55
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Amino Acids, Peptides, and Proteins Commons, Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, Genetics and Genomics Commons, Nucleic Acids, Nucleotides, and Nucleosides Commons