GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.
Dar, Ghulam Hassan
Mendes, Cláudia C
Lobo, Miguel J
Springer Science and Business Media LLC
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Dar, G. H., Mendes, C. C., Kuan, W., Speciale, A. A., Conceição, M., Görgens, A., Uliyakina, I., et al. (2021). GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain.. Nat Commun, 12 (1) https://doi.org/10.1038/s41467-021-27056-3
Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington's disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain.
Article, /631/61/391/3932, /631/80/86/820, /13, /13/89, /14, /38, /42, /42/89, /59, /59/5, /64, /64/60, article
Medical Research Council (MR/M007715/1)
External DOI: https://doi.org/10.1038/s41467-021-27056-3
This record's URL: https://www.repository.cam.ac.uk/handle/1810/330877