Introduction: Extracellular vesicle (EV) research is a rapidly growing field. EV biomarker discovery for diseases as well as functional studies of EVs on recipient cells have been at the forefront of attention. However, recently, research has begun to shift towards understanding the biodistribution pattern of small- and large-EVs in recipient animals – an understanding that will serve as a pivotal foundation for functional studies translating into physiological settings. Unfortunately, due to the lack of a standardized guideline, many different methodologies have arisen to study EV fate making comparison between studies a challenge. In light of this challenge, we aimed to systematically review and summarize the literature regarding the biodistribution of EVs.
Method: Systematic methodology was used to search the Biosis, Embase, and Medline databases using the terms “extracellular vesicle” and “biodistribution” or “targeting” and their synonyms. This search identified 34,502 publications. Following screening, 50 studies were eligible for inclusion in this review. Data for the distribution of EVs to each organ was expressed as a percentage of the total (i.e. all organs combined as 100%) to allow comparison between studies. The biodistribution patterns, at several time points, following IV administration of small- and large-EVs were described.
Result: Clear differences between small- and large-EV biodistribution were evident. Small-EVs showed strong early localization to the liver with minor losses across time, while the spleen, lungs and kidneys showed moderate distribution across time. On the other hand, GI tract showed gradual increase in small-EV distribution up to 24 hours. Large-EVs showed an inverse distribution pattern between the liver and the lungs: as large EVs localization to the liver increased, localization to the lungs decreased.
Conclusion: Regardless of the differing methodologies used by different studies, IV administration generally resulted in both small- and large-EVs initially localizing to the lungs. However, the lungs do not appear to have as great a retention capacity as the liver. Multiple factors could be responsible for differential retention including; differing affinities of ligands in the lungs and liver, differing numbers of phagocytes resident in the different organs and different processing times of the same EV in different organs.