Take a moment to pause and think about the medications that you take. Probably, regardless of what body part that medicine needs to target, you basically eat the meds, right? Aspirin for a headache - swallow it. Birth control pills - swallow it. Benadryl for nausea - swallow it. It works, but it doesn't seem terribly targeted, eh? You basically send everything through your digestive system, and cross your fingers that enough of the medication gets to the particular cells in your body that it needs to target in order to have the desired effect. Indeed it does work - but scientists are imagining different, and hopefully better, ways of targeting drugs. And one of those ways is by capitalizing on the existing postal system of cells: extracellular vesicles.
As I've written about before on Microbial Mondays, extracellular vesicles, or EVs for short, are very tiny spherical structures that are released from pretty much every known type of cell - including your own. In essence, they kind of look like mini-cells. They have a membrane made of fat that encloses whatever is contained inside. Whenever cells are just doing their cell thing (growing, eating, recycling, the usual), they will release EVs. We now think that one of the functions of EVs is basically for cells to chat with each other: so, a sort of postal system. And just like letters that you might still send if you still have an affinity for stationery as I do, EVs naturally have a structure that allows for a sort of biological postage stamp to make sure that they get to the right place. These unique characteristics of EVs, namely that they can both contain information, and that they can be stamped to ensure their delivery to a specific location, has made some scientists think that perhaps we could use EVs in a new way. Perhaps EVs could be loaded with information that we chose to post - such as specific medications - and engineered to be sent to a specific organ that those drugs need to reach. This would be a great therapeutic tool for us, and could be a jump forward in treating diseases that largely occur in hard-to-reach organs, like the brain.
But, there is a catch: the study of EVs is a relatively new (although rapidly expanding) field, and there is still a lot of research to be done in order to actually figure out how to design EVs for use as medicine. The manuscript preprint that inspired this Microbial Mondays blog post is a step towards doing exactly that. Using mice and macaques as models, these scientists figured out where exactly EVs will end up if they are administered intranasally (via the nose) or intravenously (an injection into the bloodstream). And indeed, they found several different interesting things...
Firstly, if EVs were delivered intranasally, EVs seemed to stay in and around the nose - at least they weren't found in any great numbers in the bloodstream. In contrast, as you'd expect, lots of EVs were found in the bloodstream after injection of those EVs. But, interestingly, if animals were injected with EVs multiple times, the amount of EVs found back in the blood started to decrease with the additional 'booster shots'. The authors suggest that that may be due to the immune system interpreting the EVs as dangerous! Indeed, they found that immune cells started gobbling up the EVs to clear them from the bloodstream - similarly to how immune cells react to microbes they encounter, which can be around the same size as EVs. This brings up the interesting question of why the immune system would try to "fight" the incoming EVs. What marks the EVs as "foreign", and therefore potentially dangerous? For now, we're not sure - that's a question to be answered by future research.
Secondly, the authors of the preprint also found that regardless of how the EVs were administered - either through the nose or straight into the bloodstream - very few of those EVs ended up in the brain. This is important, because it's been largely assumed by scientists until now that, well, of course EVs can enter the brain! There were a few studies previously that indicated that it was possible that EVs could get across the notoriously-hard-to-cross barrier between the brain and the rest of the body (called the "blood-brain barrier"), which led to the assumption that EVs would cross that blood-brain barrier if administered. However, this finding shows that, if we want to use EV-encapsulated medications to treat conditions in the brain, it might be an even trickier task than we expected. As the authors beautifully put it, "overall, the low levels of signal in both tissue and [cerebrospinal fluid] suggest that the EV blood-brain route in our model is more of a precarious footpath than a superhighway".
You might remember that I mentioned that the authors used both mice and macaques as models in this study. This is an interesting duo. Mice are often used in biomedical research because, well, they're relatively easy and quick to work with, compared to other animals. They are also sort of close enough to humans to make some guesses about what biomedical studies conducted in mice might mean for human biology. Macaques, on the other hand, are biologically much closer to humans - and thereby much more difficult to work with, they are slow-growing compared to mice (so it takes a long time to "grow" your model organism to adulthood), and, as you might have guessed, macaque come with additional ethical weight. In this case, comparing mice to macaques shed some interesting light on the differences between mice and close-to-man. The administered EVs did not always target to the same organs in mice and macaques. In particular, when EVs were given intranasally, some of those EVs ended up in the brains of the mice - but not in the macaques. And, remember those studies that I mentioned earlier, which suggested that it was possible for EVs to cross the blood-brain barrier? Well, they were often conducted using mice or rats. So, this data again suggests that if we want to use EV-encapsulated medications to target the brains of humans, which more like macaques than mice, we might have to re-think which administration routes will be the best.
So for now - this study is an important stepping stone, and more will surely come. It gives some clues into how we can develop new medications that capitalize on the existing postal system of cells to send meds to specific organs or specific cells. For example, one hope is that EV-encapsulated meds could help us specifically target cells that HIV is hiding in, which is pretty tricky thing to do at the moment. HIV is a master of disguise, but these EVs may be part of the answer to uncovering, and treating, its hideouts in the body. It's the start of the future!
Until next time - send a letter, too ;)
~ Alex
This Microbial Mondays post was inspired by this great read on BioRxiv - check it out:
Pharmacokinetics and biodistribution of extracellular vesicles administered intravenously and intranasally to Macaca nemestrina
Tom Driedonks, Linglei Jiang, Bess Carlson, Zheng Han, Guanshu Liu, Suzanne E. Queen, Erin N. Shirk, Olesia Gololobova, Lyle Nyberg, Gabriela Lima, Kayla Schonvisky, Natalie Castell, Mitchel Stover, Selena Guerrero-Martin, Riley Richardson, Barbara Smith, Charles P. Lai, Jessica M. Izzi, Eric K. Hutchinson, Kelly A.M. Pate, Kenneth W. Witwer
bioRxiv 2021.07.28.454192; doi: https://doi.org/10.1101/2021.07.28.454192