GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain

Dar, Ghulam Hassan 
Mendes, Cláudia C. 
Kuan, Wei-Li 
Speciale, Alfina A.  ORCID logo
Conceição, Mariana 

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Abstract: 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.

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Article, /631/61/391/3932, /631/80/86/820, /13, /13/89, /14, /38, /42, /42/89, /59, /59/5, /64, /64/60, article
Journal Title
Nature Communications
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Nature Publishing Group UK
RCUK | Medical Research Council (MRC) (MR/M007715/1)