New lipid delivery systems aim to improve potency and reduce side effects As any dietician will tell you, some fats are good—and that is surely true of the little fatty balls found in two of the world’s most widely used COVID-19 vaccines. Known as lipid nanoparticles (LNP), these tiny bubbles of fat encase messenger RNA (mRNA) that encodes a viral protein, helping ferry it into cells and shield it from destructive enzymes. The technology was key to the success of COVID-19 shots from Moderna and the Pfizer-Bio N Tech collaboration. But as beneficial as these fats are, there is plenty of room for improvement.
The nanoparticles are a major source of unwanted side effects when they spread through the body, triggering the aches and inflammation many people experience after vaccination. They do a poor job of unloading their cargo once inside cells, a necessary step for the protein making machinery to turn the mRNA sequences into immune-priming signals. And because they tend to fall apart when warm, they have to be stored at low temperatures, limiting their global use.
“This is a system that clearly has legs,” says biochemist Pieter of the University of British Columbia (UBC), Vancouver, who created the first LNP, but “we still need to increase the efficiency of LNP—that’s for sure.”
A new generation of LNP with greater potency, fewer side effects, increased stability, and more precise tissue-targeting properties is now under development at big pharma and biotech startups. Big money is at stake: These improved nanoparticles could lead to better mRNA vaccines for COVID-19 and other diseases. They might also help mRNA deliver on its promise as a therapeutic tool to treat disease. “There are innovations on delivery that certainly could change the game,” says Philip Santangelo, a biomedical engineer at the Georgia Institute of Technology who has collaborated with several mRNA companies.
Developed the first LNP about 20 years ago to carry gene-silencing drugs into cells. He and others later tailored the LNP four lipid components to deliver disease-correcting mRNA to faulty cells. Now that they are being put to a new use, in vaccines, “There is still so much optimization and development that needs to happen,” says UBC bioengineer Anna co-founder of the RNA vaccine company Vaccine Equity. And when it comes to understanding how cells interact with the nanoparticles, “it’s just this big question mark,” she adds.
One clue emerged earlier this year when Genentech scientists showed how nanoparticles activate a particular inflammatory pathway, the interleukin-1 axis, which is critical to generating protective immune responses but can also spur side effects. Among the LNP tested, one made with SM-102, an “ionizable” lipid that helps bind and package mRNA into LNP, proved an especially strong instigator of this pathway. That could help explain why Moderna’s shot, which relies on SM-102, is both highly effective and prone to making people feel icky.
Unlike DNA, however, RNA is most often single-stranded. An RNA molecule has a backbone made of alternating phosphate groups and the sugar ribose, rather than the deoxyribose found in DNA.
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