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Liver Kupffer cells and endothelial cells were labelled with F4\/80 and CD31 antibodies, respectively (green, upper panels for F4\/80, lower panels for CD31). (CREDIT: Nature Biomedical Engineering)<\/p>\n
Instead of using the traditional method, the scientists turned to an older chemical reaction called the Mannich reaction. Invented as a tribute to a German chemist, the reaction uses three components instead of two. That sounds like a small difference, but it opens up many new possibilities for designing lipids. Using this strategy, the scientists designed hundreds of new molecules.<\/p>\n
The Secret Power of Phenols<\/p>\n
Among the numerous new lipids that have been tested, one emerged as standout \u2014 a molecule the researchers dubbed C-a16. What distinguished it was a mere chemical addition: a phenol group. Phenols are natural molecules with antioxidant abilities, famously being present in foods such as olive oil.<\/p>\n
By incorporating a phenol unit, the researchers created an ionizable lipid that could suppress inflammation in the body. Phenols<\/a> are also antifoods for oxidative stress, a harmful process in which molecules called free radicals oxidize DNA, proteins, and even whole cells. Vaccines and treatments by mRNA cause some degree of this stress usually. It causes inflammation, which has side effects like soreness and fatigue.<\/p>\n Emily Han, a graduate student in the Mitchell Lab, helped measure the levels of oxidative stress in cells treated with different LNPs. The C-a16 LNPs caused much lower stress levels compared to commercial ones, fewer side effects, and safer delivery. \u201cThe most effective LNP, which we built using a phenol-containing ionizable lipid that was made by the Mannich reaction, actually caused less inflammation,\u201d Han said.<\/p>\n Synthesis and evaluation of six combinatorial libraries of Mannich ionizable lipids for mRNA delivery. (CREDIT: Michael Mitchell, et al.)<\/p>\n Stronger and Longer-Lasting Effects<\/p>\n Silencing inflammation was just the beginning. The researchers also wanted to know whether the new LNPs did better overall. In a wide range of experiments, the response was a resounding yes.<\/p>\n In mice, LNPs that bore C-a16 delivered mRNA instructions that lasted much longer than with lipids from current vaccine technologies. They also made gene-editing agents like CRISPR work better<\/a>. Co-lead author and postdoctoral fellow Dongyoon Kim clarified that minimizing oxidative stress gave the freedom for LNPs to act more efficiently. \u201cReducing oxidative stress makes it easier for LNPs to get the job done,\u201d he continued.<\/p>\n The effect was evident when scientists injected mice with the new lipids and a glowing gene from fireflies. Those mice given the C-a16 version glowed far brighter than the ones given traditional lipid formulations. Actually, the glow was approximately 15 times stronger than with the LNPs used in Onpattro \u2014 an FDA-approved medication to treat a rare liver disease known as hereditary transthyretin amyloidosis (hATTR).<\/p>\n Still more impressive, when the identical new lipids were used with CRISPR to edit out the faulty gene causing hATTR, efficiency of editing was more than double. That might mean more successful treatments for inherited disorders with fewer doses and less side effects.<\/p>\n Inhibition of tumour growth by C-a16 LNP encapsulating an OVA mRNA or a neoantigen mRNA. (CREDIT: Michael Mitchell, et al.)<\/p>\n Defeating Tumors and Viruses<\/p>\n The C-a16 lipid did not just work well against inherited illnesses. It also showed excellent performance in cancer and infectious disease models. In melanoma-bearing mice, an mRNA-based cancer therapy<\/a> delivered using the new LNPs inhibited tumors threefold more potently than with standard formulations.<\/p>\n This innovation wasn\u2019t solely about the drug reaching the tumor. It was also about the body\u2019s immune system response. T cells that battle cancer with the C-a16 LNPs were enhanced at targeting and killing tumor cells. In doing so, they experienced less stress, so they were healthier and lasted longer.<\/p>\n The exact same lipid came in handy when used to make COVID-19 vaccines. Test subjects who received the C-a16-based vaccine gained immunity five times higher than that provided in current mRNA vaccines. This could potentially teach your body how to defeat viruses with even fewer side effects.<\/p>\n The benefits did not stop there. In subsequent experiments, LNPs loaded with C-a16 also promoted expression of fibroblast growth<\/a> factor 21, a protein involved in regulating the metabolism. Levels of protein were 3.6 times higher with the new lipid compared with conventional LNPs. Michael Mitchell summarized the study as follows: \u201cBy basically adjusting the recipe for these lipids, we were able to get them to work better with fewer side effects. It\u2019s a win-win.\u201d<\/p>\n In the Direction of mRNA Medicine of the Future<\/p>\n The results of this study could have a long-term effect on how scientists design mRNA vaccines<\/a> and gene therapies. By lowering the stress response of the immune system, C-a16 opens the door to longer-lasting, more effective treatments for a wide range of illnesses.<\/p>\n The subsequent steps are additional testing to confirm safety and efficacy in humans. But already the research shows that a slight difference in chemistry \u2014 putting on one group of atoms \u2014 can have a gigantic impact.<\/p>\n As the world looks to mRNA not just for vaccines, but for gene therapy, cancer immunotherapy, and beyond, innovations like this may be the way forward.<\/p>\n Research findings are available online in the journal Nature Biomedical Engineering<\/a>.<\/p>\n Related Stories<\/p>\n![\"Synthesis](\"https:\/\/www.newsbeep.com\/us\/wp-content\/uploads\/2025\/09\/6f2e90fe69d3856b70f3c7000cb1ffc3.jpeg\"\/)
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