Physiologic constraints of using exosomes in vivo as systemic delivery vehicles

Abstract

Systemic delivery of exosomes meets hurdles which had not been elucidated using live molecular imaging for their biodistribution. Production and uptake of endogenous exosomes are expected to be nonspecific and specific, respectively, where external stimuli of production of exosomes and their quantitative degree of productions are not understood. Despite this lack of understanding of basic physiology of in vivo behavior of exosomes including their possible paracrine or endocrine actions, many engineering efforts are taken to develop therapeutic vehicles. Especially, the fraction of exosomes’ taking the routes of waste disposal and exerting target actions are not characterized after systemic administration. Here, we reviewed the literature about in vivo distribution and disposal/excretion of exogenous or endogenous exosomes and, from these limited resources of knowledge currently available, summarized the knowledge and the uncertainties of exosomes on physiologic standpoints. An eloquent example of the investigations to understand the roles and confounders of exosomes’ action in the brain was highlighted with emphasis on the recent discovery of brain lymphatics and hypothesis of glymphatic/lymphatic clearance pathways in diseases as well as in physiologic processes. The possibility of delivering therapeutic exosomes through the systemic circulation, across blood-brain barriers and finally to target cells such as microglia, astrocytes and/or neurons is a good testbed in which the investigators can formulate problems to solve for both understanding (science) and application (engineering).