Genetically engineered exosomes display RVG peptide and selectively enrich a neprilysin variant: a potential formulation for the treatment of Alzheimer's disease

Exosome is a promising next generation nano-based drug delivery vehicle. However, the unknown molecular mechanisms underlying its natural tissue tropism and the relatively low quantity of naturally enriched molecules of therapeutic value hamper exosome's clinical application. The aim of the research was to create a targeted and highly efficacious exosome formulation for the treatment of Alzheimer's disease (AD). Genetic engineering techniques combined with co-transfection of parental cells were employed to create an exosome formulation that displays RVG peptide on its surface targeting alpha 7-nAChR and simultaneously enriches a neprilysin variant with increased specificity and efficacy in degrading beta amyloid peptide (A beta). The exosome formulation was preferentially internalised into cell lines in an alpha 7-nAChR expression level-dependent manner. When incubated with A beta-producing N2a cells, it significantly decreased intracellular and secreted A beta 40 levels, a potency that is superior to exosomes derived from adipose-derived stem cell. When systemically administered into mice, the exosome formulation was preferentially targeted to the hippocampus region of the brain and significantly decreased the expression of proinflammatory genes, IL1 alpha, TNF alpha and NF-kappa B, and simultaneously increased the expression of anti-inflammatory gene, IL10. Our exosome formulation may be explored as an over-the-counter treatment for AD.