Exosomes as Drug Delivery Vehicles: Natural Nano-bio-drones
In the not too distant future, click ‘buy’ on an internet shopping site and an autonomous drone will be dispatched to carry your new goods directly to your doorstop. For now, drone home-delivery is still science fiction – but inside the body, targeted autonomous delivery of packages is already a reality.
Cells use nanoscale spheres called exosomes to mail out packages of proteins, RNA and other biomolecules. These 100-nanometre-sized spheres travel freely around the body, their tiny proportions ensuring they can penetrate deep into the tissues. Exosomes are often tagged for uptake by specific cell types, which can be at a distant site within the body.
Exosomes are rapidly taken up by their target cell, and the parcel’s arrival will often trigger a notable change in the cell’s behaviour as it responds to the exosomes contents.
The ease with which exosomes traverse the body to deliver their cargo has caught the eye of researchers looking for ways to selectively target drugs to particular cells.
The traditional way we take a drug is that a pill is swallowed, or a medicine is injected, and the therapeutically active compound then spreads throughout the body. This scattershot approach to drug delivery often means suboptimal amounts of the drug reach the site of need.
The drug can also cause side effects when it is absorbed by healthy cells. Some promising drug candidates, meanwhile, have failed to make it to clinical use because they degrade too quickly when injected into the body.
Encapsulating a drug within a nanoscale targeted delivery vehicle would solve all these problems. Countless existing drugs could get an efficacy boost – as well as helping new ones into the clinic that get sidelined due to their fragility or their problematic side effects. And exosomes appear to be the perfect drug delivery system.
Many synthetic nanoparticles have been trialled as drug delivery vehicles, but very few have received FDA approval for human use, Duxin Sun from the University of Michigan, US, wrote recently in the Nature journal Acta Pharmacologica Sinica1.
Researchers face two key challenges, says Sun: the materials that synthetic nanoparticles are made of tend to be cytotoxic; and the immune system rapidly mops them up and clears them from the body before they can reach their target.
Exosomes suffer neither of these problems.
These natural nanoparticles posses innate biocompatibility, are well tolerated by the immune system and have long circulation times in the body. “Several pioneering reports have shown the advantages of using exosomes as nanocarriers,” Sun reports.
Exosomes isolated from cow’s milk, for example, make effective anticancer drug delivery vehicles, boosting the potency of several drugs including paclitaxel (Taxol) and doxorubicin2. The benefit here stems from the fact the exosomes act as a slow-release reservoir of the drug inside the body, providing a steady stream of the treatment.
Other researchers have shown it is possible to exploit exosomes’ natural tendency to target certain cell types. Elena Batrakova from the University of North Caroline at Chapel Hill, US, showed exosomes isolated from macrophage immune cells selectively delivered paclitaxel to lung cancer cells3.
The exosomes were 30 times faster than synthetic nanoparticles at being taken up by the cancer cells. Other researchers have used exosome targeting to supress inflammation, for example4.
Coded messages via nano-bio-drones (exosomes)
If exosomes have shown promise for delivering conventional molecular drugs, their potential for delivering RNA- or DNA-based therapeutics is even greater.
Gene therapy is a potentially revolutionary branch of medicine in which the faulty or missing genes responsible for a patient’s condition are switched off or replaced using short DNA or RNA strands synthesised in the lab.
The great bottleneck with this research has been finding a way to safely deliver the therapeutic gene into the target cell.
Deactivated viruses have been used – in nature, viruses replicate by injecting their genetic material into their host organism’s cells. But the delivery virus can trigger a dangerous immune system response, raising serious concerns about potential side effects.
But we now know viruses aren’t the only biological entity capable of DNA injection. Within the body, exosomes ferry snippets of genetic code from cell to cell as part of their natural role as a communication system.
Oxford University researchers have engineered exosomes to target brain cells, and deliver RNA that knocks down the gene associated with Alzheimer’s disease. In animal studies, the intravenously injected exosomes accumulated in the brain and significantly lowered the production of a protein that produces amyloid beta, the molecule that appears to clog the brain of Alzheimer’s patients5.
Natural messaging with exosomes produced by stem cells
Another angle with these nano-bio-drones (exosomes) is to collect exosomes secreted by stem cells. Stem cells themselves promote regeneration and healing – and recent research shows that exosomes alone from stem cells have a similar positive effect in a number of medical conditions e.g. diabetes and autoimmune disease.
So collecting and using these exosomes secreted by stem cells can be a next-generation medical technology as a regenerative medicine.
Ready to go, but . . .
Patients are waiting but so far most patients do not have access to medicines based on this bio-nano-drone technology. Why ? The problem has been in the manufacturing (purification) of exosomes. Until now there has been no large-scale proprietary purification process that is gentle on the exosomes but yields a pharmaceutical-grade product.
Ready for prime-time
A reliable, reproducible method for producing and purifying exosomes – such as Exopharm’s LEAP technology, which the company has recently perfected6 – will become the platform that springboards these nano-bio-drones into prime-time medical treatments.
Exopharm’s LEAP technology actually purifies exosomes and is ideally suited to large-scale biomanufacturing processing. Exosomes purified by the LEAP technology are called Exomeres ™ – exosomes ideally suited for targeted exosome drug delivery or as a stem cell derived drug.
Engineering exosomes by genetically modifying the cells producing them, or directly manipulating the exosomes themselves once they have been isolated, are two approaches already being tested in the lab7.
Exosome nanomedicine looks poised to become a technology far more disruptive than drone delivery of internet shopping.
1 Luan, X. et al. Engineering exosomes as refined biological nanoplatforms for drug delivery. Acta Pharmacologica Sinica 38, 754–763 (2017)
2 Munagala, R. Aqil, F., Jeyabalan, J., Gupta, R.C. Bovine milk-derived exosomes for drug delivery. Cancer Lett 371, 48-61 (2016)
3 Kim, M. S., et al. Development of exosome-encapsulated paclitaxel to overcome MDR in cancer cells. Nanomedicine: Nanotechnology, Biology, and Medicine 12 655–664(2016)
4 Sun, D. et al. A novel nanoparticle drug delivery system: the anit-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther. 18, 1606-14 (2010)
5 Alvarez-Erviti, L. et al. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology volume 29, pages 341–345 (2011)
7 Armstrong, J. P. K., Holme, M.N. and Stevens, M.M. Re-Engineering Extracellular Vesicles as Smart Nanoscale Therapeutics. ACS Nano 11, 69−83 (2017)