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Researchers spearheaded by Dr. KIM V. Narry, the director of the Center for RNA Research at the Institute for Basic Science (IBS), have unveiled a significant cellular mechanism that influences the efficacy of mRNA vaccines and therapeutics. Their recent publication in Science marks a pivotal advancement in understanding how mRNA vaccines are transported, processed, and ultimately degraded in cells, potentially leading to the development of more effective vaccines and RNA-based therapies.
Messenger RNA (mRNA) serves as the genetic instruction manual for protein synthesis within cells, playing a critical role in the operation of mRNA vaccines, like those developed for COVID-19. It also emerges as a promising avenue for treating various conditions such as cancer and genetic disorders. For mRNA vaccines to be effective, the foreign mRNA must evade the body’s built-in defense mechanisms. However, the specific processes that regulate mRNA within cells had remained largely obscure until now.
To elucidate these processes, the research team utilized CRISPR-based knockout screening, which enabled them to pinpoint cellular components that contribute to the entry of mRNA into cells. Using a comprehensive CRISPR library aimed at over 19,000 genes, they identified three crucial factors that facilitate the internalization or oversight of external mRNA.
– The first significant finding was the role of heparan sulfate (HSPG), a sulfated glycoprotein located on the cell surface that is essential for attracting lipid nanoparticles (LNPs) and promoting the entry of mRNA into cells.
– Second, they found that V-ATPase, a proton pump located within the endosome, is responsible for acidifying the vesicle, which in turn causes LNPs to acquire a positive charge. This alteration allows them to temporarily disrupt the endosomal membrane, facilitating the release of mRNA into the cytoplasm for protein expression.
– Lastly, the study highlighted TRIM25, a protein integral to the cellular defense system, which binds to and leads to the rapid degradation of foreign mRNA, thus impeding its function.
So, what mechanisms allow mRNA vaccines to bypass this cellular defense? A standout discovery was that mRNA with a specific modification known as N1-methylpseudouridine (m1Ψ)—recognized with the award of the 2023 Nobel Prize in Physiology or Medicine—successfully evades TRIM25. This modification prevents TRIM25 from interacting with the mRNA and consequently enhances its stability and effectiveness. This finding not only clarifies how mRNA vaccines can circumvent cellular surveillance but also underscores the modification’s significance in boosting the efficacy of mRNA-based therapies.
Furthermore, the study shed light on the critical involvement of proton ions in this entire process. When lipid nanoparticles rupture the endosomal membrane, proton ions spill into the cytoplasm, where they activate TRIM25. These protons signal the cell about the presence of foreign RNA, inciting a defensive reaction. Notably, this is the first research to establish that proton ions function as immune signaling molecules, providing an innovative perspective on how cells safeguard themselves against foreign RNA intrusions.
Dr. KIM V. Narry emphasized the necessity of comprehending these processes, stating, “Understanding how cells respond to mRNA vaccines is key to improving mRNA therapeutics. To develop effective RNA treatments, we need to find ways to bypass the cellular defense mechanisms and harness the endosomal system effectively.”
This research, featured in Science on April 3rd, establishes a foundation for enhancing mRNA vaccine delivery methods and sets the stage for the next generation of RNA-based therapies. It highlights the pivotal role of early medical intervention and opens new avenues for creating more impactful treatments across various diseases.
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