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Review
. 2019 May 15;11(492):eaav8521.
doi: 10.1126/scitranslmed.aav8521.

Advances in therapeutic applications of extracellular vesicles

Oscar P B Wiklander  1   2 , Meadhbh Á Brennan  3   4   5 , Jan Lötvall  6 , Xandra O Breakefield  4 , Samir El Andaloussi  1   2
Affiliations
Review

Advances in therapeutic applications of extracellular vesicles

Oscar P B Wiklander et al. Sci Transl Med. .

Abstract

Extracellular vesicles (EVs) are nanometer-sized, lipid membrane-enclosed vesicles secreted by most, if not all, cells and contain lipids, proteins, and various nucleic acid species of the source cell. EVs act as important mediators of intercellular communication that influence both physiological and pathological conditions. Given their ability to transfer bioactive components and surmount biological barriers, EVs are increasingly being explored as potential therapeutic agents. EVs can potentiate tissue regeneration, participate in immune modulation, and function as potential alternatives to stem cell therapy, and bioengineered EVs can act as delivery vehicles for therapeutic agents. Here, we cover recent approaches and advances of EV-based therapies.

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Conflict of interest statement

Competing interests: O.P.B.W. and S.EL.A. have equity in and are consultants for Evox Therapeutics Ltd. and have patents for using EVs as therapeutics. J.L. has equity in Codiak Biosciences and patents for using EVs as diagnostics and therapeutics, has been consulting for Oncorus Inc., and held an employment at Codiak Biosciences Inc. from 2016 to 2018. X.O.B. is on the Scientific Advisory Boards of Evox and Exocyte.

Figures

Fig. 1.
Fig. 1.. EV biogenesis, general EV composition, and uptake.
EVs are formed by two mechanisms. Exosomes are formed by the endocytic pathway through invagination of the endosomal membrane, which forms multivesicular bodies (MVBs) that can fuse with the plasma membrane to release exosomes into the extracellular milieu. Microvesicles (MVs) arise from the outward budding and fission of the plasma membrane. All subtypes of EVs share a general composition of an outer lipid bilayer and various proteins, lipids, and nucleic acids carried by the vesicles. The specific content of EVs is largely dependent on biogenesis, cell source, and culture conditions. EVs have been suggested to be internalized into target cells by various uptake mechanisms including membrane fusion (171) and different endocytic pathways including phagocytosis (172), receptor-mediated endocytosis (173), lipid raft–mediated endocytosis (174), clathrin-mediated endocytosis (175), caveolin-mediated endocytosis (176), and macropinocytosis (176).
Fig. 2.
Fig. 2.. EV engineering and loading strategies.
EVs can be loaded with therapeutic entities such as RNA species, proteins, and small-molecule drugs through exogenous loading (loading of isolated EVs) or endogenous loading (loading during EV biogenesis). The producer cell can further be engineered to express EVs displaying therapeutic proteins or targeting peptides via chimeric proteins consisting of an EV-sorting domain fused to the protein of interest. Similarly, RNA-binding proteins (RBPs) can be explored to bind therapeutic RNA. RNA aptamers or therapeutic RNA can also be attached to EVs by hydrophobic modifications.
Fig. 3.
Fig. 3.
Flowchart illustrating important considerations for developing EV therapeutics.
See this image and copyright information in PMC

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