Reduction of the therapeutic dose of silencing RNA by packaging it in extracellular vesicles via a pre-microRNA backbone
| Autor: | Wheaton Little, Charles Campbell, Daniel G. Anderson, Ryan Reshke, Piotr S. Kowalski, Luke H. Rhym, My Tran Trung, James A. Taylor, Derrick Gibbings, Alexandre Savard, Huishan Guo |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Small interfering RNA Cell Biomedical Engineering Gene Expression Medicine (miscellaneous) Bioengineering Extracellular Vesicles Mice 03 medical and health sciences Drug Delivery Systems 0302 clinical medicine Therapeutic index RNA interference Cell Line Tumor microRNA medicine Animals Humans RNA Small Interfering Motor Neurons Chemistry RNA Computer Science Applications Cell biology MicroRNAs RNA silencing 030104 developmental biology medicine.anatomical_structure Cell culture Nanoparticles RNA Interference 030217 neurology & neurosurgery Biotechnology |
| Zdroj: | Nature Biomedical Engineering. 4:52-68 |
| ISSN: | 2157-846X |
| DOI: | 10.1038/s41551-019-0502-4 |
| Popis: | 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. Integrating silencing RNA into the backbone of a microRNA that is highly enriched in small extracellular vesicles reduces the therapeutic dose of the silencing RNA. |
| Databáze: | OpenAIRE |
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