Researchers led by the University of Texas MD Anderson Cancer Center have developed a delivery system for mRNA using extracellular vesicles (EVs).

The study, published in Nature Biomedical Engineering, details how the researchers used EV-encapsulated messenger RNA (mRNA) to produce collagen for numerous months in the cells of photoaged skin. The researchers claim this is the first therapy that represents a proof-of concept for using EV mRNA therapies.

EVs are small structures formed by cells that transport biomolecules and nucleic acids in the body. EVs have the ability to be modified to carry mRNAs, which then provides them with biocompatibility without causing a strong immune response, enabling them to be administered more than once. Furthermore, their size means they can move large human genes and proteins.

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Typically, mRNA therapies use a lipid nanoparticle (LNP) delivery system. However, Wen Jiang, assistant professor of radiation oncology at MD Anderson Cancer Center and co-author of the study told us “The current mRNA therapies using lipid nanoparticles face a number of hurdles.”

“For example, they have issues with target specificity due to liver uptake of LNPs. They have also had issues with immunogenicity, where they can cause anaphylaxis in patients. They also lack the ability to cross certain biological barriers such as the blood brain barrier. These are not hurdles for an mRNA vaccine, but they pose problems for more targeted mRNA therapies.”

Jiang says the EV technique can overcome the challenges associated with other delivery methods used in mRNA therapies.

“The first is that the EVs are not taken up nearly as much as LNPs by the liver, so it allows the mRNA cargo to be delivered to the target site. Also, they do not face any issues with immunogenicity as EVs are biologically produced [compared to] LNPs, which are synthetic. EVs are also inherently capable of crossing biological barriers.”

A wider application

While the study investigated collagen production in cells, the team believe the EV delivery system has the potential to be successful for a number of different mRNA therapies.

“This is an entirely new modality for delivering mRNA,” co-author and professor of Neurosurgery at MD Anderson Cancer Center, Betty Kim said.

“We used it in our study to initiate collagen production in cells, but it has the potential to be a delivery system for a number of mRNA therapies that currently have no good method for being delivered.”

The success of collagen production in cells could even lead to the therapy potentially being approved for use in the cosmetic industry. While the team “really set out with that intent, collagen replacement ended up being a good test case for this delivery system, but it does work in reducing wrinkles so we wouldn’t be surprised at all to see it used in the cosmetic field,” said Jiang.

He continued: “The next applications that we are working on include rare genetic diseases caused by the body’s inability to produce certain proteins. There are a number of these, for example, cystic fibrosis and epidermolysis bullosa. We are also exploring applications of EV mRNAs in cancer therapy. Immunotherapy is an exciting front in the fight against cancer, and EV mRNAs could give us another tool in being able to reprogram the body’s natural immune defenses to fight cancer cells.”

mRNA-based firm Moderna transferred personalized cancer vaccine capabilities to its production facility in Norwood, Massachusetts in March 2019 for its cancer vaccine, mRNA-4157, which is set to move into Phase III clinical trials this year.

The team is planning a Phase I trial where the overall aim is to test the toxicity of its dermal delivery systems of mRNA EVs.