If you’ve had an mRNA vaccine — like the COVID-19 shots — you probably remember the side effects: fever, soreness, maybe even a day or two of exhaustion. For hundreds of millions around the world, it was the price to pay for pandemic protection. But what if that toll could be reduced — or even eliminated — while making the vaccine more effective?
Researchers at the University of Pennsylvania believe they’ve done exactly that. In a study published in Nature Biomedical Engineering, the team unveiled a game-changing innovation: a new type of lipid nanoparticle (LNP) that causes far less inflammation and delivers stronger therapeutic results.
Their key ingredient? A group of natural compounds found in olive oil.
A Mediterranean Twist on Vaccine Science
The breakthrough centers around phenols, plant-derived molecules known for their anti-inflammatory and antioxidant properties. These compounds — found in extra virgin olive oil, fruits, and vegetables — are now being engineered into the lipid shells that carry mRNA into the body.
These lipid nanoparticles are critical in mRNA vaccine delivery. They protect fragile mRNA strands, help them cross cell membranes, and control how and where the genetic instructions are released. But the LNPs used in most current vaccines are also responsible for triggering inflammatory side effects — a byproduct of how the body recognizes and reacts to the synthetic materials.
By incorporating phenols into the structure of ionizable lipids, the most biologically active part of LNPs, the Penn team has crafted a solution that both dampens immune overreaction and enhances delivery.
“We essentially rewrote the recipe,” said Dr. Michael Mitchell, associate professor of bioengineering and lead author. “It’s a win-win: lower inflammation and higher effectiveness.”
Reviving a Forgotten Chemical Reaction
To create this new class of LNPs, the researchers went deep into chemistry history. They used a century-old process known as the Mannich reaction, developed by German chemist Carl Mannich. Unlike conventional methods that combine two components, the Mannich reaction fuses three molecules, enabling richer chemical diversity.
The team synthesized hundreds of new lipids, exploring which variations had the most desirable biological effects. One stood out — dubbed C-a16 — a phenol-enriched lipid with remarkable anti-inflammatory properties and delivery potential.
“It’s like discovering a secret sauce that transforms everything,” said Dr. Mitchell.
What Phenols Actually Do
Phenols work by neutralizing free radicals — unstable molecules that can damage cells and DNA. When too many free radicals build up in the body (a state known as oxidative stress), inflammation spikes and immune function falters. Phenols counteract this, restoring balance and reducing tissue stress.
When tested in lab settings, the new phenol-infused lipid not only caused less inflammation than those used in today’s COVID-19 vaccines, but also outperformed them in gene delivery and therapeutic action.
Glowing Results in Mice
In one early experiment, researchers delivered a gene that causes fireflies to glow into mice using the new LNPs. The result? Mice injected with the phenol-enhanced formulation glowed 15 times brighter than those that received current-generation vaccine particles — a vivid sign of more efficient genetic transfer.
That same formulation, C-a16, also doubled the effectiveness of CRISPR gene editing in correcting transthyretin amyloidosis, a rare and fatal liver disease caused by a single faulty gene.
A New Weapon Against Cancer
The team then tested C-a16 on melanoma, the deadliest form of skin cancer. Mice treated with a C-a16-based mRNA cancer vaccine showed tumor shrinkage three times greater than those treated with current LNP formulations. The new particles also supercharged immune T-cells, empowering them to better recognize and destroy cancer cells.
Importantly, this enhanced performance came with significantly reduced oxidative stress — suggesting the body was working more efficiently, not just harder.
Stronger Protection Against COVID-19
Finally, the researchers reformulated an mRNA COVID-19 vaccine using the new lipids. The result: a fivefold increase in immune response compared to conventional vaccine delivery systems.
“This isn’t just about one disease,” said Emily Han, a PhD candidate and co-author of the study. “It’s a platform technology — a way to improve everything from vaccines to genetic medicine.”
Rediscovering the Past to Power the Future
The team at UPenn is already exploring other long-overlooked chemical reactions in hopes of discovering new lipid structures. The goal? Unlock better, safer, and more adaptable drug delivery systems that can accelerate everything from pandemic responses to cancer immunotherapies.
“We revived a chemical reaction that’s more than 100 years old — and it’s transforming some of the most advanced medical technologies of our time,” said Dr. Mitchell. “Who knows what else we’ve missed in the past that could shape the future.”