Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone
- 14 January 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Biomedical Engineering
- Vol. 4 (1), 52-68
- https://doi.org/10.1038/s41551-019-0502-4
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.Keywords
Funding Information
- Juvenile Diabetes Research Foundation (3-PDF-2017-383-A-N)
- Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada (436104-2013)
- Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (141720)
- Ontario Centres of Excellence (23931)
- ALS Society of Canada (Discovery 2017)
This publication has 50 references indexed in Scilit:
- Alternative miRNA Biogenesis Pathways and the Interpretation of Core miRNA Pathway MutantsMolecular Cell, 2011
- Analysis of microRNA turnover in mammalian cells following Dicer1 ablationNucleic Acids Research, 2011
- Conserved vertebrate mir-451 provides a platform for Dicer-independent, Ago2-mediated microRNA biogenesisProceedings of the National Academy of Sciences of the United States of America, 2010
- A dicer-independent miRNA biogenesis pathway that requires Ago catalysisNature, 2010
- Functional delivery of viral miRNAs via exosomesProceedings of the National Academy of Sciences of the United States of America, 2010
- Lipid-like materials for low-dose, in vivo gene silencingProceedings of the National Academy of Sciences of the United States of America, 2010
- Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkersNature, 2008
- Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cellsNature, 2007
- Cellular delivery of small interfering RNA by a non-covalently attached cell-penetrating peptide: quantitative analysis of uptake and biological effectNucleic Acids Research, 2006
- Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein deliveryLeukemia, 2006