Targeting Tissues with Extracellular Vesicles

Much of cellular communication takes the form of secretion and uptake of extracellular vesicles, tiny membrane-wrapped packages of molecules. The use of these vesicles as a basis for therapy is spreading. Since first generation stem cell therapies appear to produce their benefits via the signals generated by transplanted stem cells, why not use vesicles harvested from stem cells instead the cells themselves? The logistics are far less challenging, the costs lower. Further, vesicles can be engineered to contain novel contents, or given different surface features.

Researchers here discuss the degree to which vesicles can be targeted to specific tissues via natural or artificial surface features. This is never an all or nothing proposition, but rather the case that one tissue may take up half as many or twice as vesicles of one type versus another. This is a big enough effect to be of great interest in the development of more effective therapies, however, enabling treatments with fewer side-effects.

Great strides have been made in advancing extracellular vesicles (EVs) to clinical testing. By late 2020, approximately 250 trials that utilize EVs in some way had been registered. Diagnostic, prognostic, and monitoring uses of EVs are evident in these registrations as well as applications of EVs in therapeutics. Interest in EVs stems in part from their biology. They are involved in natural processes of communication in the body and have a perceived safety profile that features low immunogenicity.

Additionally, EVs are 'targetable'. Display of specific proteins, and possibly other biomolecules, allows EVs to be sorted to certain cell types and tissues or away from undesired recipients. EV engineering, by manipulating the EV source or by altering EVs post-production, can be used to enhance such targeting. Modified EVs have been used for some time as delivery vehicles for small molecule drugs and natural products, short hairpin RNA (shRNA), short interfering RNA (siRNA), plasmid DNA, and microRNAs. However, a key factor in the success of this and other EV therapies is whether and how EVs can be targeted to, or away from, specific cells.

Targeting EVs to specific cell types could indeed be considered a holy grail of EV therapeutics, since cell specificity reduces the necessary dose and minimizes off-target effects. However, we should be clear that the word 'targeting' is used colloquially. The typical EV cannot move towards a destination as a result of interpreting signals, for example, by crawling along a chemical gradient, so the EV cannot truly 'home' to a specific cell. Instead, the word 'targeting' refers more accurately to 'selective retention' or 'capture' by the target cell.

To the extent possible, administering EVs at the site of intended action will enhance selective retention and help to avoid clearance. Many studies use intravenous delivery of EVs, but this results in delivery predominantly to just a few organs, especially lung and liver, as well as bone marrow, spleen, and kidney. Introducing EVs by different routes, or even directly to the target site by application (e.g. skin wound healing, eye) or tissue injection avoids rapid clearance and maximizes dosage.



This is an interesting review of an emerging research of a very complex processes with potentially significant clinical applications. This complexity is illustrated in our paper on skin oxidative damage protection by stem cell-derived exosome preparations "MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system" doi: 10.1016/j.biomaterials.2020.120264. It is not clear however, if, and if so, then how, the mass deployment of the artificial nanoparticles containing modified non-human RNA will affect this research.

Posted by: Baskys at March 28th, 2021 11:48 AM
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