There was a paper that came out in 2011 where they loaded exosomes with siRNA and used a RVG peptide to target them to the brain after systemic delivery.

http://www.nature.com/nbt/journal/v29/n4/full/nbt.1807.html

That might be a good place to start.

The testis has a comparably "tight" tight junction barrier that forms between the Sertoli cells.  In this case, any ions, small molecules, etc. can only cross the barrier by first being endocytosed on the basal side of the Sertoli cells, then then exocytosed on the apical side.  For exosomes, you could confirm if this is the case two ways:

1) Use transmission electron microscopy to look for characteristic double membrane vesicles in the endothelial cells within the brain.

2) Express a GFP fusion protein on the membrane of the exosome, and a tdTomato or mCherry protein on the surface of the membrane of the brain endothelium.  Vesicles that are GFP and tdTomato double positive would confirm that the endothelium has endocytosed the exosome, creating a double membrane vesicle.  Even more exciting would be to do some live imaging and capture the secretion of the exosomes.

Shoichiro Tsukita did an experiment similar to this (but for different reasons) several years back: http://jcs.biologists.org/content/117/7/1247.full

The process likely involves an active migration or invasion mechanism based on the membrane components.  At least a portion of murine melanoma exosomes express an endogenous retroviral envelope (Env) (Darga, unpublished data).    Neutrophils and endothelial cells express Lsp1, a homolog of Env, is important in trans-endothelial migration.  It seems likley that exosomes are endogenous retrovirual particles co-opted for normal function, and mediators or initiators of pathogenic processes.

http://www.jimmunol.org/cgi/content/meeting_abstract/188/1_MeetingAbstracts/173.29

http://www.ncbi.nlm.nih.gov/pubmed/25234543

 Thank you for this question Abbas Raza. I have been thinking this question for quite some time and was wondering where to start. The papers shared here are very helpful. 

Also help me!Thanks!

It seems exosome trafficking across the BBB is heavily reliant on inflammatory conditions to mediate extravasation where they are absorbed by brain microvascular endothelial cells (BMEC's) via endocytosis, and are fused with BMEC endosomes where they are released into the brain. It seems the BMEC's may have to be preconditioned to endocytose the exosomes (there are many exosomes from many different cell types present in the peripheral blood) by inflammatory mediators such as TNF-a, and possibly IL-6. Other authors are also saying exosomes may facilitate metastasis in cancer through a similar method. As to the specific receptors or proteins involved on both the exosomes and endothelium, I am not sure and the latter are probably tremendously variable depending on cell type of origin.

As for the targeting and entry into specific cells within the brain, the process becomes a bit hazy. Some authors believe that the process is similar to that of viruses, where there are receptor interactions that lead to receptor mediated (clathrin-dependent) endocytosis or macropinocytosis. While studying the effect of IFN-a antiviral resistance to Hepatitis A virus, Yao et al showed that macrophage exosomes uniquely target TIM-1 to deliver exosomes to hepatocytes. Interestingly, this is the same receptor the virus uses to enter these cells. It may also be important to consider the glycosylation status of both exosomal proteins as well as those of the target cells.