MIT Engineers Design Bio-Inspired Synthetic mRNA Delivery System
Because of its safe and effective protein expression profile, the in-vitro transcribed messenger RNA represents a promising candidate in the development of novel therapeutics for genetic diseases, vaccines or gene editing strategies, especially when its inherent shortcomings have been partially addressed via structural modifications.
Now, a team of MIT chemical engineers inspired by the way that cells translate their own mRNA into proteins, has designed a synthetic delivery system that is four times more effective than delivering mRNA on its own.
“If we want to be able to deliver mRNA, then we need a mechanism to be more effective at it because everything that’s been used so far gives you a very small fraction of what would be the optimal efficiency,” says Paula Hammond, a David H. Koch Professor in Engineering, the head of MIT’s Department of Chemical Engineering, and a member of MIT’s Koch Institute for Integrative Cancer Research.
The messenger RNA is an ideal vehicle to deliver vaccines or treat diseases since it degrades after it carries out its intended work. For this process to proceed, the mRNA has to get into cells efficiently, and once there, it needs to
reach the ribosomes to be translated into protein.Therefore, the researchers at MIT improved the rate of mRNA translation by attaching a protein cap to one end of the mRNA strand. This cap helps mRNA to form a complex that is needed to initiate translation.
Naturally occurring mRNA usually has a long “poly-A tail,” made up of a long sequence of adenosine repeats, that stabilizes the molecule and helps it to resist being broken down by enzymes in the cell. The MIT team attached a protein called a poly-A binding protein to this tail. They then coated this complex with a type of polymer known as a polypeptide, which is a sequence of modified amino acids strung together in a chain. This polypeptide serves as a scaffold to hold the poly-A binding protein and mRNA in close contact, and it helps to neutralize the negatively charged mRNA.
And once the polymer-coated mRNA enters a cell, the poly-A binding protein protects it from being broken down and helps it to link up with ribosomes. The mRNA forms a closed loop so that a ribosome can cycle through it many times, producing many copies of the target protein. In this way, the effect of mRNA, which is a very costly genetic therapeutic, can be significantly enhanced by combination with much cheaper synthetic polypeptides and proteins.
The researchers tested this system by delivering mRNA that encodes the gene for luciferase, a glowing protein, into the lungs of mice. They found that with this type of delivery, cells produced four times as much protein as they did when only mRNA was packaged with the same polypeptide for delivery.
The MIT approach also helps to overcome another challenge to delivering mRNA, which is that the molecules are very large, says Peixuan Guo, a professor of pharmaceutics and drug delivery systems at Ohio State University.
In this study, the mRNA particles accumulated in the lungs because of the polypeptide’s positive charge, which allowed the particles to attach to red blood cells and catch a ride to the lungs. However, the researchers now plan to explore modifying the particles with polymers that will direct them to other locations in the body, including tumors.
