Extracellular vesicles: The next generation in gene therapy delivery

Abstract

Extracellular vesicles (EVs) are esteemed as a promising delivery vehicle for various genetic therapeutics. They are relatively inert, non-immunogenic, biodegradable, and biocompatible. At least in rodents, they can even transit challenging bodily hurdles such as the blood-brain barrier. Constitutively shed by all cells and with the potential to interact specifically with neighboring and distant targets, EVs can be engineered to carry and deliver therapeutic molecules such as proteins and RNAs. EVs are thus emerging as an elegant in vivo gene therapy vector. Deeper understanding of basic EV biology-including cellular production, EV loading, systemic distribution, and cell delivery-is still needed for effective harnessing of these endogenous cellular nanoparticles as next-generation nanodelivery tools. However, even a perfect EV product will be challenging to produce at clinical scale. In this regard, we propose that vector transduction technologies can be used to convert cells either ex vivo or directly in vivo into EV factories for stable, safe modulation of gene expression and function. Here, we extrapolate from the current EV state of the art to a bright potential future using EVs to treat genetic diseases that are refractory to current therapeutics.

Keywords: cell targeting; ectosomes; exosomes; extracellular vesicles; nanoparticle; non-coding RNA.

Graphical abstract

Figure 1

Endogenous and engineered EV pathways Unmodified EVs are naturally generated and taken up by target cells where their payloads can be taken up, recycled, or degraded. Producer cells can be modified to generate EVs packaged with RNA, protein, and potentially even DNA payloads, and these shed EVs can be taken up by target cells where their payloads are released.