New materials to improve delivery of therapeutic messenger RNA

Polymeric nanoparticles can efficiently administer mRNA to cells of the lungs, liver, and other organs.

MIT researchers have designed nanoparticles that can deliver messenger RNA to specific organs. In this image, lung cells expressing the synthetic mRNA show up as red. Image: Piotr Kowalski
MIT researchers have designed nanoparticles that can deliver messenger RNA to specific organs. In this image, lung cells expressing the synthetic mRNA show up as red. Image: Piotr Kowalski

Messenger RNA, a huge nucleic corrosive that encodes genetic data, can guide cells to create particular proteins. Unlike DNA, mRNA isn’t for all time embedded into a cell’s genome, so it could be utilized to deliver a restorative protein that is just required briefly. It can likewise be utilized to deliver quality altering proteins that adjust a cell’s genome and after that vanish, limiting the danger of off-target impacts.

In an advance that could lead to new treatments for a variety of diseases, MIT researchers have devised a new way to deliver messenger RNA (mRNA) into cells.

Due to the large size of mRNA, it was difficult for scientists to efficiently design them within the cells. It has also been a challenge to deliver mRNA to specific organs in the body. The new MIT approach, which involves packaging mRNA into polymers called amino-polyesters, addresses both of those obstacles.

By delivering synthetic mRNA to cells, researchers hope to be able to stimulate cells to produce proteins that could be used to treat disease. Scientists have developed some effective methods for delivering smaller RNA molecules, and a number of these materials have shown potential in clinical trials.

Scientists additionally packaged mRNA into new polymers called amino-polyesters. These polymers are biodegradable and dissimilar to numerous other conveyance polymers, they don’t have a solid positive charge, which may make them less inclined to harm cells.

To demonstrate the polymers, scientists used a method that allows them to control the properties of the polymer, such as its molecular weight. This means that the quality of the polymers produced will be similar in each batch, which is important for clinical transition and often not the case with other polymer synthesis methods.

MIT researchers have designed nanoparticles that can deliver messenger RNA to specific organs, in this case, the liver. Cells expressing the synthetic mRNA show up as red. Image: Piotr Kowalski
MIT researchers have designed nanoparticles that can deliver messenger RNA to specific organs, in this case, the liver. Cells expressing the synthetic mRNA show up as red.
Image: Piotr Kowalski

Graduate student Umberto Capasso Palmiero of Politecnico di Milano said, “Being able to control the molecular weight and the properties of your material help to be able to reproducibly make nanoparticles with similar qualities, and to produce carriers starting from building blocks that are biocompatible could reduce their toxicity.”

“It makes clinical translation much harder if you don’t have control over the reproducibility of the delivery system and the released degradation products, which is a challenge for polymer-based nucleic acid delivery.”

In addition to creating polymers that varied in the composition of the amino-alcohol core and the lactone monomers, scientists also varied them in length of polymer chains and the presence of carbon atom side chains in the lactone subunits. After that, they combined the polymers with lipids, which help stabilize the particles and encapsulated mRNA within the nanoparticles.

Yizhou Dong, an associate professor of pharmaceutics and pharmaceutical chemistry at Ohio State University said, “It is challenging to achieve tissue-specific mRNA delivery. The findings in this report are very exciting and provide new insights into chemical features of polymers and their interactions with different tissues in vivo. These novel polymeric nanomaterials will facilitate systemic delivery of mRNA for therapeutic applications.”

In tests in mice, the researchers identified several particles that could effectively deliver mRNA to cells and induce the cells to synthesize the protein encoded by the mRNA. To their surprise, they also found that several of the nanoparticles appeared to preferentially accumulate in certain organs, including the liver, lungs, heart, and spleen. This kind of selectivity may allow researchers to deliver specific therapies to certain locations in the body.

Daniel Anderson, an associate professor in MIT’s Department of Chemical Engineering, is the senior author of the paper, which appears in the journal Advanced Materials. The paper’s lead authors are MIT postdoc Piotr Kowalski and former visiting graduate student Umberto Capasso Palmiero of Politecnico di Milano. Other authors are research associate Yuxuan Huang, postdoc Arnab Rudra, and David H. Koch Institute, Professor Robert Langer.

Kowalski said, “The researchers did not investigate what makes different nanoparticles go to different organs, but they hope to further study that question. Particles that specifically target different organs could be very useful for treating lung diseases such as pulmonary hypertension, or for delivering vaccines to immune cells in the spleen. Another possible application is using the particles to deliver mRNA encoding the proteins required for the genome-editing technique known as CRISPR-Cas9, which can make permanent additions or deletions to a cell’s genome.”

“There is definitely a potential to increase the efficacy of these materials by further modifications, and also there is potential to hopefully find particles with different organ-specificity by extending the library.”

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