As millions of individuals have experienced, the most common side effect of mRNA vaccines, such as those for COVID-19, is inflammation, which manifests as soreness, redness, and a brief period of malaise. However, what if mRNA vaccines could be re-engineered to completely avoid this response?
In a groundbreaking study published in Nature Biomedical Engineering, researchers from the University of Pennsylvania have demonstrated that modifying the structure of ionizable lipids, a crucial component of the lipid nanoparticles (LNPs) that deliver mRNA, not only reduces inflammation but also enhances the vaccine’s effectiveness in preventing or treating a variety of diseases, including COVID-19 and cancer.
The Role of Phenol Groups in Reducing Inflammation
The pivotal change involves the addition of phenol groups, chemical compounds with well-known anti-inflammatory properties found in foods like olive oil. “By essentially changing the recipe for these lipids, we were able to make them work better with fewer side effects,” explains Michael J. Mitchell, Associate Professor in Bioengineering and the study’s senior author. “It’s a win-win.”
Traditionally, the ionizable lipids in LNPs—one of four types of lipids in these nanoparticles—have been synthesized using chemical reactions that combine two components into a new molecule, akin to assembling two halves of a sandwich. “Because these processes have been so successful, there hasn’t been much effort to look for alternatives,” notes Ninqiang Gong, a former postdoctoral fellow in the Mitchell Lab and co-first author of the paper.
Exploring New Chemical Reactions
Upon revisiting the history of chemistry, the research team identified an alternative approach: the Mannich reaction, named after the German chemist who discovered it over a century ago. Unlike traditional methods, the Mannich reaction combines three precursors, allowing for a broader range of molecular outcomes. “We were able to create hundreds of new lipids,” says Gong.
Through this exploration, the team discovered that incorporating a phenol group—a combination of hydrogen and oxygen connected to a ring of carbon molecules—significantly reduced inflammation. “It’s kind of like the secret sauce,” Gong adds. “The phenol group not only reduces the side effects associated with LNPs but also improves their efficacy.”
Phenol Groups and Oxidative Stress
Previous studies have shown that phenol-containing compounds mitigate inflammation by counteracting the harmful effects of free radicals, molecules with unpaired electrons that can disrupt the body’s chemistry. An excess of free radicals and a deficiency of antioxidants lead to “oxidative stress,” which degrades proteins, damages genetic material, and can even kill cells.
By examining various markers associated with oxidative stress, the researchers compared the inflammatory effects of LNPs formulated with different lipids. “The best-performing LNP, which we built using a phenol-containing ionizable lipid produced by the Mannich reaction, actually caused less inflammation,” states Emily Han, a doctoral student in Bioengineering and co-author of the paper.
Enhancing Vaccine Performance
With promising signs of reduced inflammation, the researchers proceeded to test whether the new lipids also improved vaccine performance. Across multiple experiments, C-a16 LNPs, which incorporated the most anti-inflammatory lipid, outperformed LNPs used in current mRNA technologies. “Lowering oxidative stress makes it easier for LNPs to do their job,” explains Dongyoon Kim, a postdoctoral fellow in the Mitchell Lab and co-first author of the paper.
C-a16 LNPs not only produced longer-lasting effects but also enhanced the efficacy of gene-editing tools like CRISPR and the potency of vaccines for treating cancer.
Testing in Animal Models
To evaluate the effectiveness of the new C-a16 lipids in an animal model, the researchers first used them to deliver the gene that makes fireflies glow—a classic experiment for assessing the strength of genetic instructions. The glow in mice was approximately 15 times brighter compared to the LNPs used in Onpattro, an FDA-approved treatment for hereditary transthyretin amyloidosis (hATTR), a rare genetic liver disease.
The C-a16 lipids also improved the performance of gene-editing tools like CRISPR in correcting the faulty gene that causes hATTR, more than doubling the treatment’s effectiveness in a mouse model compared to current delivery methods.
Implications for Cancer and COVID-19 Treatments
In cancer treatments, the results were equally impressive. In an animal model of melanoma, an mRNA cancer treatment delivered with C-a16 lipids reduced tumor size three times more effectively than the same treatment delivered with the LNPs used in COVID-19 vaccines. The new lipids also enhanced the function of cancer-fighting T cells, enabling them to recognize and destroy tumor cells more efficiently and with less oxidative stress.
Finally, when the team used the C-a16 lipids for preparing COVID-19 mRNA vaccines, the immune response in animal models was five times stronger than with standard formulations. “By causing less disruption to cellular machinery, the new, phenol-containing lipids can enhance a wide range of LNP applications,” says Kim.
Future Directions
Beyond investigating the immediate potential of the new lipids to reduce side effects in mRNA vaccines, the researchers are eager to explore how overlooked chemical processes like the Mannich reaction can unlock new LNP-enhancing recipes. “We tried applying one reaction discovered a century ago and found it could drastically improve cutting-edge medical treatments,” Mitchell remarks. “It’s exciting to imagine what else remains to be rediscovered.”
For more information, refer to the study titled “Mannich reaction-based combinatorial libraries identify antioxidant ionizable lipids for mRNA delivery with reduced immunogenicity,” published in Nature Biomedical Engineering (2025). DOI: 10.1038/s41551-025-01422-8
🔗 **Fuente:** https://medicalxpress.com/news/2025-07-pain-gain-phenol-groups-recipe.html