Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading

Abstract

Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.

Keywords: EV therapeutics; drug loading; exosomes; extracellular vesicles; microvesicles.

Figure 1

Biogenesis of Extracellular vesicles. Exosome biogenesis begins with the invagination of the plasma membrane followed by the inward budding of the endosome to form multivesicular bodies (MVBs) which then fuse with the plasma membrane to release these smaller types of EVs. Microvesicles on the other hand are formed directly by the outward budding of the plasma membrane.

Figure 2

Different approaches to load EV therapeutics. EVs could be therapeutically loaded using endogenous and exogenous loading techniques. Endogenous approach involves overexpressing therapeutic cargo within the donor cells, which eventually gets loaded within the EVs. Exogenous approach includes the loading of therapeutic cargo within EVs once they are isolated. Depending upon the specific loading technique through which the cargo is loaded inside of the EVs, they could be further sub-classified into active and passive loading.