“…Preliminary work demonstrates that either naturally occurring or engineered exosomes derived from stem/progenitor cells provide therapeutic benefits (139)(140)(141). However, there are multiple unanswered questions and challenges in the development of exosome therapy including the following: (a) identification of the cellular signals by which the ischemic brain is able to affect the content and quantity of exosomes released by brain parenchymal cells and by remote organs, (b) understanding how exosomal cargo affects expression of endogenous genes and proteins in recipient cells of injured brain, (c) delineation of the specific cell types that are targeted by brain parenchymal cell-derived exosomes, and (d) knowledge of the effects of sex, age, and comorbidity on the cellular generation of exosomes and their cargo and the effect of sex, age and comorbidity in response to exosome treatment after stroke.…”