Messy Nanoparticles Beat Tidy Ones at Drug Delivery, Study Finds

When scientists packed lipid nanoparticles with as much mRNA as possible for the COVID-19 vaccines, they were following a seemingly obvious principle: more cargo, more delivery. What they may not have fully appreciated is that maximum packing density and maximum delivery efficiency are not the same thing - and may actually work against each other.

That is one implication of new research from the University of Copenhagen, where Artu Breuer and colleagues developed a method to examine roughly one million lipid nanoparticles at once, one particle at a time. What they found contradicts the prevailing design logic of the field. The research was presented at the 70th Biophysical Society Annual Meeting in San Francisco in February 2026.

The 1 to 5 Percent Problem

Lipid nanoparticles - microscopic fatty bubbles that ferry RNA molecules into cells - were central to the success of the COVID-19 mRNA vaccines and are now the leading platform for RNA-based therapeutics targeting cancer, rare genetic diseases, and other conditions. But they have a fundamental inefficiency problem: only about 1 to 5 percent of the RNA cargo actually escapes into the cell interior where it can do its job. The remaining 95 to 99 percent gets trapped and degraded.

"This low efficiency limits what we can do with LNPs as therapeutics," said Breuer. "For example, in cancer treatment where cells are dividing rapidly, if you deliver too little RNA, the cells outpace the therapy."

Most research aimed at improving this efficiency has focused on tweaking lipid compositions, adjusting the ratio of different lipid types, or optimizing the charge balance between the positively charged lipids and the negatively charged RNA. What has been harder to examine is the physical structure of individual particles within a batch - because standard analytical methods report averages across millions of particles, hiding the variation within.

Measuring One at a Time

Breuer's team built a high-throughput single-particle measurement platform capable of characterizing both the size and RNA content of individual nanoparticles at scale - roughly a million particles per experiment. That resolution revealed something previous batch-level analyses had missed: enormous particle-to-particle variability, and within that variability, two distinct structural populations.

Some particles were organized, their RNA cargo neatly arranged in layered, onion-like structures where the positively charged lipids and negatively charged RNA are tightly interleaved. Others were amorphous - disorganized internally, with more separation between the charge groups.

"The surprise was that the messy ones actually work better inside cells," Breuer said.

Why Structure Governs Release

The mechanism appears to follow from basic electrostatics. In an organized particle, the positively charged lipids are tightly bound to the negatively charged RNA - a stable ionic pairing that holds the structure together. When the particle enters a cell's endosome, conditions change: the compartment acidifies, and the lipid composition shifts. In a disorganized particle, that shift is enough to create repulsion between positively charged lipids that are no longer neutralized by closely positioned RNA, causing the particle to rupture and release its cargo.

In a tightly organized particle, the ionic bonds are strong enough to resist this disruption. The particle stays intact, the cargo remains trapped, and the cell eventually degrades the whole complex without ever accessing the RNA.

"Think of it this way: in an organized nanoparticle, the positively charged lipids are tightly bound to the negatively charged RNA," Breuer explained. "When conditions change inside the cell, the positive charges repel each other, and the particle falls apart - releasing the medicine. But in an organized particle, those attractions hold everything together even when conditions change."

Rethinking the Design Logic

The finding challenges a basic assumption driving nanoparticle design: that tighter packing is better packing. Drug developers have invested considerable effort in maximizing RNA loading and minimizing structural disorder, on the assumption that well-organized particles would be more stable and more effective. These results suggest the opposite may be true for intracellular delivery.

"We're aiming in the opposite direction of what the field has been pursuing," said Breuer. "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."

The single-particle measurement tool the team developed gives researchers a new way to screen LNP formulations and correlate structural features with delivery outcomes - something that was not possible with bulk measurement approaches that average across the full population of particles in a batch.

Limitations remain. The study examined delivery efficiency in cell culture conditions, and whether the same structural effects hold in tissues - where particles must navigate more complex biological environments before reaching their target cells - requires further investigation. The precise lipid compositions that produce the most favorable amorphous structures, and how to reliably manufacture particles with those properties at scale, represent open engineering problems.

But the conceptual shift the findings introduce is clear. The goal may not be to build the most perfect nanoparticle. It may be to build one that falls apart at precisely the right moment.