RNA Therapeutics Institute; Department of Medicine; Mass Spectrometry Facility; Department of Biochemistry and Molecular Pharmacology; MassBiologics; Program in Molecular Medicine; Graduate School of Biomedical Sciences, Interdisciplinary Graduate Program
Amino Acids, Peptides, and Proteins | Biochemistry | Cell Biology | Cells | Enzymes and Coenzymes | Lipids | Molecular Biology | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics
Exosomes can serve as delivery vehicles for advanced therapeutics. The components necessary and sufficient to support exosomal delivery have not been established. Here we connect biochemical composition and activity of exosomes to optimize exosome-mediated delivery of small interfering RNAs (siRNAs). This information is used to create effective artificial exosomes. We show that serum-deprived mesenchymal stem cells produce exosomes up to 22-fold more effective at delivering siRNAs to neurons than exosomes derived from control cells. Proteinase treatment of exosomes stops siRNA transfer, indicating that surface proteins on exosomes are involved in trafficking. Proteomic and lipidomic analyses show that exosomes derived in serum-deprived conditions are enriched in six protein pathways and one lipid class, dilysocardiolipin. Inspired by these findings, we engineer an "artificial exosome," in which the incorporation of one lipid (dilysocardiolipin) and three proteins (Rab7, Desmoplakin, and AHSG) into conventional neutral liposomes produces vesicles that mimic cargo delivering activity of natural exosomes.
Biochemistry, Biological Sciences, Lipidomics, Molecular Biology, Proteomics, UMCCTS funding
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Copyright 2019 The Author(s). This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
DOI of Published Version
iScience. 2019 May 27;16:230-241. doi: 10.1016/j.isci.2019.05.029. [Epub ahead of print] Link to article on publisher's site
Haraszti, Reka A.; Miller, Rachael; Dubuke, Michelle L.; Coles, Andrew H.; Didiot, Marie C.; Echeverria, Dimas; Stoppato, Matteo; Sere, Yves Y.; Leszyk, John D.; Alterman, Julia F.; Godinho, Bruno M. D. C.; Hassler, Matthew R.; Wollacott, Rachel; Wang, Yan; Shaffer, Scott A.; Aronin, Neil; and Khvorova, Anastasia, "Serum Deprivation of Mesenchymal Stem Cells Improves Exosome Activity and Alters Lipid and Protein Composition" (2019). Open Access Articles. 3848.
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This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
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