A small metabolic tweak may unlock the full potential of RNA medicines.
Lipid nanoparticles, or LNPs, are best known as the delivery system used in the COVID-19 mRNA vaccines given to billions of people worldwide. Scientists are now exploring their potential far beyond vaccines. Researchers hope to use these particles to carry therapeutic mRNA into cells to treat cancer and inflammatory diseases, and to deliver CRISPR gene editing tools that can repair harmful genetic mutations.
A major challenge has slowed progress. For LNP therapies to work, the particles must release their cargo by fusing with cell membranes. This step happens efficiently in laboratory experiments but far less reliably inside the human body.
Scientists at Biohub have now identified a simple strategy that may solve this problem. According to a study published in Science Translational Medicine, researchers led by Daniel Zongjie Wang, PhD, and Shana O. Kelley, PhD, discovered that giving three common amino acids together with LNPs can dramatically improve delivery. The amino acids methionine, arginine, and serine increased mRNA delivery by as much as 20 times and raised CRISPR gene editing efficiency from about 25 percent to nearly 90 percent after a single treatment.
“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 grew out of a broader research strategy used by Kelley’s team. Their work focuses on studying biological processes at the molecular and tissue levels under conditions that better resemble those inside 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 roadblock
Many scientists have assumed that the limits of LNP performance come from the particles themselves. This belief has driven major efforts to engineer improved nanoparticles. Researchers have screened hundreds of new lipid molecules and used artificial intelligence to analyze billions of possible combinations in search of better formulations.
Despite these efforts, clinical delivery efficiency has remained limited.
The Biohub team took a different approach. Instead of focusing on the nanoparticles, they examined whether the cells themselves might be limiting the process. They investigated whether altering cellular behavior could help cells fuse with LNPs more easily and absorb their contents.
“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 experiments pointed to metabolism as the key factor. Standard cell culture media used in laboratories were designed decades ago to maximize cell growth. These solutions contain nutrient levels far higher than those found in human blood. Under these rich conditions, LNPs work very well.
However, when the researchers grew cells in a special human plasma-like medium that closely mimics the body’s metabolic environment, LNP uptake fell sharply. Delivery dropped by 50 to 80 percent.
Further metabolic and genetic analyses revealed why. Cells grown in the plasma-like environment showed reduced activity in several metabolic pathways related to amino acids. The researchers concluded that cells inside the body operate under leaner metabolic conditions, which reduces their ability to internalize nanoparticles.
Simple fix, outsized results
To overcome this limitation, the researchers systematically screened potential metabolic supplements. This work led them to a mixture of three amino acids: methionine, arginine, and serine.
Adding this amino acid combination alongside LNP treatments produced dramatic improvements. Across many types of cells, the method increased target protein production by five to 20 times in both cell experiments and living animals.
The effect was consistent across several delivery methods, including intramuscular, intratracheal, and intravenous administration. The improvement also did not depend on the specific lipid formulation or the type of mRNA cargo being delivered.
Further experiments showed that the amino acid mixture activates a specific cellular uptake pathway. In effect, it makes it easier for nanoparticles to enter cells.
The team then tested the strategy using both mRNA therapy and CRISPR gene editing.
In one experiment, researchers used a mouse model of acetaminophen-induced acute liver failure, the leading cause of drug-induced liver failure in human patients. Mice treated with LNPs carrying growth hormone mRNA had a survival rate of only 33 percent. When the same treatment was combined with the amino acid supplement, all of the mice survived.
Levels of the therapeutic protein in the blood increased almost nine times, while indicators of liver injury and inflammation dropped to levels close to those seen in healthy animals.
In another experiment, the scientists tested CRISPR Cas9 gene editing in mouse lungs using LNP delivery. Without the amino acid supplement, a single treatment produced editing efficiencies of about 20 to 30 percent, similar to previous studies.
When the amino acids were included, gene editing efficiency rose to 85 to 90 percent after just one dose. Such improvements could be especially important for diseases like cystic fibrosis, which require efficient correction of genes in lung tissue.
The researchers say the simplicity of the method makes it attractive for clinical use. The supplement uses pharmaceutical-grade amino acids that are already produced at a large scale and are widely considered safe.
Rather than redesigning nanoparticles or genetically modifying cells, the approach could be implemented simply by adding the amino acid mixture to the injection buffer used with existing LNP treatments.
Reference: “Amino acid supplementation enhances in vivo efficacy of lipid nanoparticle–mediated mRNA delivery in preclinical models” by Kangfu Chen, Wenhan Wang, Amber Lennon, Ryan A. McClure, Aleksandra Vuchkovska, Shana O. Kelley and Zongjie Wang, 11 March 2026, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adx4097
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