Aldevron Breakthrough Blog

Holding It All Together

April 12, 2023 / by Yasser Kehail

Encapsulation and mRNA

Imagine trying to hold water in a shape without it being in a container. That essentially summarizes mRNA without encapsulation. mRNA is, by nature, very fragile, so you need to protect it so that it can reach its targeted location when it goes into a body. Without that protection, mRNA will be quickly denatured or hydrolyzed. That’s why encapsulation is so important when developing mRNA-based therapeutics.

The current state of the technology has four main types of encapsulation in use: liposomes, exosomes, polymers and lipid nano particles (LNPs). In this post, I’ll give a short summary of each and how it relates to the distribution of mRNA.

A traditional approach
When people have traditionally thought of encapsulation, they’ve been talking about liposomes. It is an older technology that’s been used in traditional vaccines, microbials and chemotherapeutics. The issue with this technology is that, while liposomes can work with mRNA, they don’t allow for targeting, plus the production process itself can be complex. Additionally, they don’t carry a cationic charge.

The exo factor
Another rather new technology is using exosomes for encapsulation. Exosomes are biologically derived, coming from HEK cell lines. But being new, there are some issues that need to be dealt with. For example, there is a lot of batch-to-batch variability and exosomes are extremely expensive to manufacture. Additionally, there is no clinical product approval as of yet.

What the industry is trying to do with this approach is to move forward with the synthetic part to move into more of a small molecule route rather than adding another biological raw material into the process. While it does show promise, it’s unlikely the exosome approach will soon be seen in the clinic when concerning mRNA.

Polymer technology
There’s also a lot of development in polymer approaches, though they are in the early stages. One area in particular that might be able to benefit from this approach would be for chemotherapy, especially as the polymer approach can operate with an extended, controlled release.

While the polymers would be non-organic, they would be soluble. Of note concerning the polymer technology is that, recently, the Massachusetts Institute of Technology (MIT) presented what it calls polymer nanoparticles (PNP) for use in encapsulation, which is a further advance in the field.

Lipid targeting
Finally, LNPs are a very promising means of encapsulating and protecting mRNA. Of particular note is that this approach can have targeted delivery. Varying the formulation of the lipids used (ionizable lipids, phospholids, cholesterol, PEG-lipids) not only protects the mRNA, but directs it to the proper target.

Since each of those lipids has a different function, we can fine-tune where the mRNA ends up. To me, the LNP approach seems to be the best fit with mRNA therapeutics, since our ultimate goal is to get the mRNA to a specific place, rather than a general distribution throughout a body.

It’s important to note that getting the right means of encapsulating in place is just one of the many steps in developing mRNA therapeutics, such as how to encapsulate the mRNA and the technologies that are used to do so. My colleagues and I are continually evaluating these approaches and developing guidance for our clients to ensure each project has the proper technology in use.

ABOUT THE AUTHOR

Yasser Kehail
Yasser Kehail

Yasser Kehail leads the product management area for Aldevron’s mRNA business unit, where he is responsible for expanding RNA service offerings, building client partnerships, and ensuring successful scale up and tech transfer. Yasser started his career at Biogen, then worked at Cytiva managing the Upstream and Single Use Bioreactor portfolio. Yasser has a Masters in Bioprocessing from Northeastern University in Boston, and has been in the bioprocess industry for more than 13 years supporting different therapeutic modalities.