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Somehow missed this when it first came out, but this paper from @MasaSomiya shows that delivery of cargo proteins by #ExtracellularVesicles/ #EVs/ #exosomes to the cytosol is inefficient. https://www.biorxiv.org/content/10.1101/2020.10.16.341974v1
This fits with our work on the issue of contaminating soluble factors having biological effects that get misattributed to EVs. https://www.tandfonline.com/doi/full/10.1080/20013078.2020.1807674
Also - there's evidence (which I believe has been replicated?) that #miRNAs are very rare in EVs https://www.pnas.org/content/111/41/14888.short and recently it was shown (again) that the majority of extracellular RNA is non-EV associated.
Yet so many EV studies implicate miRNA transfer as the mechanism of action. Generally confirmed by knocking out the miRNA in the producer cell - but generally without checking if knocking out that miRNA does anything to the producer cell's secretome
I also find it concerning that many studies implicate miRNA as the active agent inside the EVs but rarely agree on which miRNA is critical for a given signalling event (at least, for hMSC-EV signalling).
I'm no longer working on #exosomes so I think I'm comfortable saying this now - I think #EV/ #exosome research in general is overdue a serious reckoning. It is too easy to implicate EVs in a process. They cannot possibly be critical to every process they've been implicated in.
There are serious methodological issues around purity, dosage, and mechanism that are often acknowledged by careful use of language and discussions of limitations but not actually in experimental design. The MISEV guidelines are great but I don't see many studies that fulfil them
The field needs to be de-hyped, and become much more self-critical and demanding in terms of the level of evidence required to attribute function to EVs. Potency and mechanism matter.
The alternative is to continue to isolate EVs from this year's exciting cell source, check their markers and diameter (and little else), plonk them onto in vitro assays in absurd quantities, and link them to a new miRNA. We're spinning our wheels here, and need to re-think.
