Engineers at the University of Pennsylvania have reworked the tiny fat bubbles that carry mRNA vaccines so they home in on lymph nodes and largely avoid the liver. The advance could make future vaccines and mRNA therapies more precise, effective and easier on the body.
Engineers at the University of Pennsylvania have redesigned the tiny delivery vehicles behind mRNA vaccines so they head straight for the body’s immune hubs, potentially making future shots more powerful at lower doses and with fewer side effects.
The team focused on lipid nanoparticles, or LNPs, the microscopic fat bubbles that protect fragile strands of mRNA and ferry them into cells. In current mRNA vaccines, many of these particles end up in the liver, not in the lymph nodes where immune cells are trained to recognize threats.
The new particles, called aroLNPs, are built to do the opposite: avoid the liver and accumulate in lymph nodes while still sparking strong immune responses.
The goal was to make every dose count, according to senior author Michael J. Mitchell, an associate professor of bioengineering at Penn.
“The more particles that reach the lymph nodes, the fewer particles each dose needs,” he said in a new release.
Lymph nodes are small, bean-shaped organs scattered throughout the body that act as training grounds for the immune system. When the body encounters a virus or other invader, immune cells carry pieces of it to the lymph nodes and show them to other immune cells, which then learn what to attack.
mRNA vaccines tap into this system by delivering genetic instructions that tell cells to make a harmless fragment of a virus or other target. That fragment is then presented to the immune system, priming it for future encounters.
“The lymph nodes are key to this process,” added first author Hannah Yamagata, a doctoral student in bioengineering. “That’s where the mRNA vaccine teaches the immune system what to guard against.”
But in practice, many LNPs never reach those immune hubs. Instead, they are swept up by the liver, a major filtering organ for substances in the bloodstream. That off-target delivery means higher doses are often needed to get enough mRNA into the right place.
“Even with proven mRNA vaccines, not every nanoparticle ends up in the lymph nodes,” Yamagata added.“If we can make the delivery process more precise, we can potentially lower the dose needed to achieve immunity.”
To change where the particles go, the Penn team zeroed in on a key ingredient in LNPs known as an ionizable lipid. This component helps the nanoparticle fuse with cell membranes and release its mRNA cargo, and its exact chemical structure strongly influences how the particle behaves in the body.
Several years ago, other scientists had found that adding a particular square-shaped chemical feature, known as an aromatic compound, to the ionizable lipid could improve LNP performance. In chemistry, “aromatic” refers to a stable ring of atoms that affects how molecules interact with each other and with their surroundings.
The Penn researchers wondered how far that idea could be pushed. They designed a library of new ionizable lipids that included benzene rings, a classic aromatic ring structure, and then made small, systematic tweaks to where different chemical groups sat around the ring.
The work shows how sensitive these systems are to tiny design changes, according to co-author Marshall Padilla, a postdoctoral fellow in bioengineering.
“Small changes in molecular structure can dramatically alter how nanoparticles behave,” he said in the news release.
The team also built in bioreducible disulfide bonds, chemical links that can break apart inside cells. These bonds have been shown in earlier work to help nanoparticles release their cargo more efficiently and reduce toxicity.
“To our knowledge, this is the first time aromatic rings and bioreducible disulfide bonds have been combined in this way within lipid nanoparticles,” Padilla added.
To see which designs worked best, the researchers loaded the different nanoparticles with mRNA encoding luciferase, a protein that produces light. By tracking the glow in animal models, they could see where the mRNA ended up.
“We were initially just trying to make better-performing lipids,” added Yamagata. “When we looked at where the LNPs were going, the shift away from the liver was striking.”
The top-performing aroLNPs delivered at least 10 times less mRNA to the liver than LNPs made with the ionizable lipid used in the Moderna COVID-19 vaccine, according to the study. At the same time, they reached the lymph nodes just as effectively, boosting the ratio of lymph-node to liver delivery by five- to tenfold.
Importantly, that shift in targeting did not weaken the immune response. In a vaccine model, aroLNPs triggered antibody levels comparable to those produced by clinically used formulations. Antibodies are Y-shaped proteins that recognize and bind to specific threats, marking them for destruction.
The new particles also caused only minimal increases in proinflammatory cytokines, immune signaling proteins that are often responsible for common vaccine side effects such as fever, fatigue and muscle aches. That pattern suggests the redesigned nanoparticles could help reduce the short-term discomfort that sometimes follows vaccination.
“What’s exciting is that we were able to redirect where the particles go without losing immune potency, and even reducing side effects,” Yamagata added. “That suggests we can design vaccines that are more precise, better tolerated and more efficient.”
Beyond infectious disease vaccines, the researchers see broad potential for the technology. Many emerging mRNA therapies aim to either ramp up the immune system, as in cancer vaccines, or dial it down in conditions such as autoimmune disease. Both approaches require careful control over where and how strongly the immune system is activated.
“More precise nanoparticle delivery gives us a new level of control over immune activation,” Mitchell said.
“This is really about precision,” he added. “If we can control where mRNA goes in the body, we can begin to tailor immune responses more deliberately, whether that means turning them up, turning them down or directing them toward a specific target.”
The work, carried out at the University of Pennsylvania School of Engineering and Applied Science with collaborators from Penn Medicine, is published in the Journal of the American Chemical Society. The team has filed a provisional patent application based on the aroLNPs, underscoring their belief that this design strategy could help shape the next generation of vaccines and mRNA-based treatments.
Source: University of Pennsylvania School of Engineering and Applied Science