Extracellular vesicle-based therapeutics: natural versus engineered targeting and trafficking

Abstract

Extracellular vesicles (EVs) are increasingly being recognized as mediators of intercellular signaling via the delivery of effector molecules. Interestingly, certain types of EVs are also capable of inducing therapeutic responses. For these reasons, the therapeutic potential of EVs is a topic of intense research, both in the context of drug delivery and regenerative medicine. However, to fully utilize EVs for therapeutic purposes, an improved understanding of the mechanisms by which they function would be highly advantageous. Here, the current state of knowledge regarding the cellular uptake and trafficking of EVs is reviewed, along with a consideration of how these pathways potentially influence the functions of therapeutic EVs. Furthermore, the natural cell-targeting abilities, biodistribution profiles, and pharmacokinetics of exogenously administered EVs, along with the components responsible for these features are discussed. An overview of the potential clinical applications and preclinical examples of their successful use is also provided. Finally, examples of EV modifications that have successfully been employed to improve their therapeutic characteristics receive a particular focus. We suggest that, in addition to investigation of EV cell targeting and routes of uptake, future research into the routes of intracellular trafficking in recipient cells is required to optimally utilize EVs for therapeutic purposes.

Exosomes mediate sensory hair cell protection in the inner ear

“…These data may allow for the scalable production of hair cellprotective exosomes in vitro. Exosomes have garnered significant interest in recent years for the therapeutic delivery of proteins, nucleic acids, and small molecules (69)(70)(71)(72)(73), and our data indicate that they may be leveraged as nanocarriers to deliver therapeutics to treat inner ear disorders. In contrast to viral and nonviral delivery systems, exosomes have the advantages of a large packaging capacity, biocompatibility, nonimmunogenicity, and the innate ability to cross biological membranes, including the blood-brain barrier (61).…”

Recent advances of exosomes in immune-mediated eye diseases

“…It appears that exosome targeting specificity is based on the particular combination of exosomes and acceptor cells [24]. Studies have identified that the expression of phosphatidylserine receptors, integrins, tetraspanins, lectins, glycans, and other adhesion molecules on exosome surface contributes to this process [26,27]. Exosomes can transmit information to target cells via internalization through macropinocytosis, phagocytosis, receptor-mediated endocytosis, or membrane fusion [28][29][30], or via acting on their cell surface, without delivery of their cargos [31] (Fig.…”

Safety of bovine milk derived extracellular vesicles used for delivery of RNA therapeutics in zebrafish and mice

“…As a result, EV could be used as a robust biological delivery approach for the targeted delivery of therapeutic RNA or proteins (Raimondo, Giavaresi, Lorico, & Alessandro, ). The ability to combine their biological properties coupled with their capacity to carry endogenous cargoes provides several advantages for the use of EV over other synthetic nanoparticles for drug delivery (Murphy et al, ).…”