BETHESDA, MD – The tiny fatty capsules that delivered COVID-19 mRNA vaccines into billions of arms may work better when they’re a little disorganized. That’s the surprising finding from researchers who developed a new way to examine these drug-delivery vehicles one particle at a time—revealing that cramming in more medicine doesn't always mean better results. The research will be presented at the 70th Biophysical Society Annual Meeting in San Francisco from February 21–25, 2026.
Lipid nanoparticles, or LNPs, are microscopic bubbles of fat that can ferry fragile RNA molecules into cells. They were crucial to the success of mRNA vaccines, and scientists are now working to use them to deliver treatments for cancer, genetic diseases, and other conditions. But there’s a problem: only about 1 to 5 percent of the cargo inside LNPs actually gets released inside cells.
“This low efficiency limits what we can do with LNPs as therapeutics,” said Artu Breuer, a researcher at the University of Copenhagen. “For example, in cancer treatment where cells are dividing rapidly, if you deliver too little RNA, the cells outpace the therapy.”
To understand why delivery efficiency varies so much, Breuer and colleagues developed a high-throughput method that can measure individual nanoparticles—about a million at a time—rather than just looking at the average properties of a batch. They measured both the size of each particle and how much cargo it contained.
“Instead of assuming that every nanoparticle in a batch is the same, we found enormous variation,” Breuer said. “And we discovered two distinct subpopulations: organized particles where the cargo is neatly structured, and amorphous particles where it’s more disorganized. The surprise was that the messy ones actually work better inside cells.”
The finding upends conventional wisdom. Drug developers have focused on loading as much medicine as possible into each nanoparticle and packing it as efficiently as they can. But Breuer and colleagues found that highly organized particles—structured like the layers of an onion—may actually resist releasing their cargo once inside cells.
“Think of it this way: in an organized nanoparticle, the positively charged lipids are tightly bound to the negatively charged RNA,” Breuer explained. “When the particle enters a cell, even though conditions change, those attractions hold everything together. But in a disorganized particle, there’s some separation between the charges. When conditions change inside the cell, the positive charges repel each other, and the particle falls apart—releasing the medicine.”
The results suggest a paradigm shift in how scientists design these delivery vehicles. Rather than maximizing how much cargo each particle carries, researchers may need to focus on maintaining a disorganized internal structure that allows the cargo to escape once it reaches its destination.
“We’re aiming in the opposite direction of what the field has been pursuing,” Breuer said. “I’m not saying we should have empty nanoparticles, but we need to find ways to load enough RNA while still keeping that disorganized structure that’s more effective inside cells.”
Their new single-nanoparticle measurement tool gives researchers a way to screen LNP formulations and understand which structural features actually matter for delivery—potentially accelerating the development of more effective RNA-based medicines.
Image Caption
Organized lipid nanoparticles in which the cargo is neatly structured are shown on the right, and amorphous lipid nanoparticles where cargo is more disorganized are shown on the left. Surprisingly, researchers discovered that the more disorganized lipid nanoparticles delivered drugs more effectively.
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