Reduction of the therapeutic dose of silencing RNA via its integration into the backbone of a pre-microRNA highly enriched in exosome-like vesicles

Reduction of the therapeutic dose of silencing RNA via its integration into the backbone of a pre-microRNA highly enriched in exosome-like vesicles

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 t...

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Bibliographic Details
Main Authors: 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, Gibbings, Derrick
Other Authors: Koch Institute for Integrative Cancer Research at MIT
Format: Article
Language:English
Published: Springer Science and Business Media LLC 2021
Online Access:https://hdl.handle.net/1721.1/132611
Description
Summary: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.

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