Reduction of the therapeutic dose of silencing RNA via its integration into the backbone of a pre-microRNA highly enriched in exosome-like vesicles
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AIP_Gibbings_edited.pdf
Description
Accepted version
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324.09 KB
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Author(s)
Reshke, Ryan
Taylor, James A.
Savard, Alexandre
Guo, Huishan
Rhym, Luke Hyunsik
Kowalski, Piotr S
Trung, My Tran
Campbell, Charles
Little, Wheaton
Anderson, Daniel Griffith
Alternative Title
Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone
Date Issued
January 2020
Journal
Nature Biomedical Engineering
Publisher
Springer Science and Business Media LLC
Citation
Reshke, Ryan et al. "Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone." Nature Biomedical Engineering 4, 1 (January 2020): 52–68. © 2020 The Author(s)
Version
Original manuscript
Abstract
A small percentage of the short interfering RNA (siRNA) delivered via passive lipid nanoparticles and other delivery vehicles reaches the cytoplasm of cells. The high doses of siRNA and delivery vehicle that are thus required to achieve therapeutic outcomes can lead to toxicity. Here, we show that the integration of siRNA sequences into a Dicer-independent RNA stem–loop based on pre-miR-451 microRNA—which is highly enriched in small extracellular vesicles secreted by many cell types—reduces the expression of the genes targeted by the siRNA in the liver, intestine and kidney glomeruli of mice at siRNA doses that are at least tenfold lower than the siRNA doses typically delivered via lipid nanoparticles. Small extracellular vesicles that efficiently package siRNA can significantly reduce its therapeutic dose.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/s41551-019-0502-4
