This simple 3-amino acid trick boosts mRNA therapy 20-fold

However, progress has been slowed by a persistent challenge. For LNPs to work inside the body, they must merge with cell membranes and release their cargo. While this process works efficiently in laboratory experiments, it is far less effective in real biological conditions.

Scientists Discover a Simple Amino Acid Solution

A research team at Biohub has identified an unexpectedly straightforward way to improve this process. In a study published in Science Translational Medicine, researchers led by Daniel Zongjie Wang, PhD, and Shana O. Kelley, Ph.D., showed that adding three common amino acids -- methionine, arginine, and serine -- alongside LNPs can dramatically enhance performance. This combination increased mRNA delivery by up to 20-fold and raised CRISPR gene editing efficiency from about 25 percent to nearly 90 percent after a single dose.

"Gene editing and mRNA-based therapies will play increasing roles in the medicine of the future, but they require LNPs to reach and enter cells," said Kelley, president of bioengineering at Biohub and head of Biohub, Chicago, where scientists are decoding the inflammatory processes that drive a wide range of diseases. "Any LNP formulation being developed today could potentially benefit from our approach."

The finding stems from the team's broader strategy of studying biology under conditions that better reflect the human body. "That's exactly what led us here," said Wang, who leads Biohub's Spatiotemporal Omics Group. "By asking why LNPs perform so differently in the physiological milieu of the body, we found a surprisingly simple answer that could make a wide range of mRNA and gene editing therapies substantially more effective."

A Metabolic Barrier Inside Cells

Until now, most efforts to improve LNP performance have focused on redesigning the nanoparticles themselves. Scientists have tested hundreds of new lipid combinations and used artificial intelligence to explore countless formulations. Despite these efforts, clinical results have remained underwhelming.

The Biohub researchers took a different approach. Instead of modifying the delivery system, they investigated whether the cells themselves were limiting uptake. They explored whether it might be possible to encourage cells to more readily absorb LNPs.

"The field has spent enormous effort engineering nanoparticles," said Wang. "We found, however, that the cell's own metabolic state is an equally important -- and addressable -- part of the equation."

Their work revealed that metabolism plays a key role. Standard lab-grown cells are exposed to nutrient-rich conditions that differ significantly from those inside the human body. When the team grew cells in a medium that more closely resembles human blood plasma, LNP uptake dropped sharply by 50 to 80 percent.

Further analysis showed that several amino acid-related metabolic pathways were less active under these more realistic conditions. This suggests that cells in the body operate with fewer available nutrients, which limits their ability to absorb nanoparticles.

A Simple Fix With Powerful Effects

To address this limitation, the researchers developed a targeted supplement containing methionine, arginine, and serine. When this mixture was given together with LNPs, the results were striking. Protein production from delivered mRNA increased between 5- and 20-fold across multiple cell types, both in laboratory experiments and in living animals.

The improvement held true across different delivery methods -- intramuscular, intratracheal, and intravenous -- and worked regardless of the specific nanoparticle design or genetic material being delivered. Additional studies showed that the amino acids enhance a cellular pathway that allows nanoparticles to enter cells more efficiently.

Dramatic Improvements in Animal Studies

The team tested the approach in disease models using both mRNA therapies and CRISPR gene editing.

In a mouse model of acetaminophen-induced acute liver failure -- the leading cause of drug-induced liver failure in human patients -- mice treated with growth hormone mRNA delivered by LNPs alone had a survival rate of just 33 percent. When the same treatment was combined with the amino acid supplement, survival rose to 100 percent. Levels of the therapeutic protein increased nearly ninefold, while indicators of liver damage and inflammation dropped to near-normal levels.

In another experiment, the researchers delivered CRISPR-Cas9 components to mouse lungs. Without the supplement, gene editing efficiency ranged from 20 to 30 percent. With the amino acid mixture, efficiency climbed to between 85 and 90 percent after a single dose. This level of improvement could be especially important for conditions such as cystic fibrosis, where effective gene correction in lung tissue is essential.

A Practical Path Toward Clinical Use

One of the most promising aspects of this discovery is how easy it may be to apply in real-world treatments. The supplement uses amino acids that are already produced at large scale and are considered safe. Unlike other strategies that require altering the nanoparticles or genetically modifying cells, this approach could simply be added to existing formulations.

By focusing on the biology of the cell rather than redesigning the delivery system, researchers may have found a practical way to unlock the full potential of mRNA therapies and gene editing technologies.