title: Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting.
abstract: Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in a diverse range of biological processes. For future therapeutic applications and for EV biology research in general, understanding the in vivo fate of EVs is of utmost importance. Here we studied biodistribution of EVs in mice after systemic delivery. EVs were isolated from 3 different mouse cell sources, including dendritic cells (DCs) derived from bone marrow, and labelled with a near-infrared lipophilic dye. Xenotransplantation of EVs was further carried out for cross-species comparison. The reliability of the labelling technique was confirmed by sucrose gradient fractionation, organ perfusion and further supported by immunohistochemical staining using CD63-EGFP probed vesicles. While vesicles accumulated mainly in liver, spleen, gastrointestinal tract and lungs, differences related to EV cell origin were detected. EVs accumulated in the tumour tissue of tumour-bearing mice and, after introduction of the rabies virus glycoprotein-targeting moiety, they were found more readily in acetylcholine-receptor-rich organs. In addition, the route of administration and the dose of injected EVs influenced the biodistribution pattern. This is the first extensive biodistribution investigation of EVs comparing the impact of several different variables, the results of which have implications for the design and feasibility of therapeutic studies using EVs.
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Oscar P B
authors.initials: OP
authors.lastname: Wiklander
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Joel Z
authors.initials: JZ
authors.lastname: Nordin
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Aisling
authors.initials: A
authors.lastname: O'Loughlin
authors.affiliation: Advanced Centre for Translational Regenerative Medicine, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ylva
authors.initials: Y
authors.lastname: Gustafsson
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Giulia
authors.initials: G
authors.lastname: Corso
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.|Institute of Technology, University of Tartu, Tartu, Estonia.
authors.forename: Imre
authors.initials: I
authors.lastname: Mäger
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Pieter
authors.initials: P
authors.lastname: Vader
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Sork
authors.affiliation: Molecular Engineering Laboratory, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Yiqi
authors.initials: Y
authors.lastname: Seow
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Heldring
authors.affiliation: Department of Clinical Neuroscience, Institute of Neurology, University College London, London, United Kingdom.
authors.forename: Lydia
authors.initials: L
authors.lastname: Alvarez-Erviti
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: C I Edvard
authors.initials: CI
authors.lastname: Smith
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Haematology Centre, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Le Blanc
authors.affiliation: Advanced Centre for Translational Regenerative Medicine, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Paolo
authors.initials: P
authors.lastname: Macchiarini
authors.affiliation: Advanced Centre for Translational Regenerative Medicine, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.|Department of Thoracic Surgery, Thoraxklinik, Heidelberg University, Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jungebluth
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom; Samir.El-Andaloussi@ki.se.
authors.forename: Samir El
authors.initials: SE
authors.lastname: Andaloussi
keywords: biodistribution; drug delivery; exosomes; extracellular vesicles; microvesicles; nanotechnology; tissue targeting