A study led by V. Narry Kim from the Institute for Basic Science provides a detailed understanding of how mRNA vaccines and therapeutics are delivered, processed, and degraded within cells. Published in Science, the research identifies key cellular factors influencing the effectiveness of mRNA-based treatments.

Messenger RNA (mRNA) acts as a genetic blueprint that instructs cells to produce proteins. It is central to mRNA vaccines, such as those for COVID-19, and holds potential for treating diseases like cancer and genetic disorders. However, foreign mRNA must overcome cellular defenses to function effectively.

Using CRISPR-based knockout screening on over 19,000 genes, the researchers identified several critical factors involved in mRNA delivery and regulation. Heparan sulfate, a glycoprotein on the cell surface, plays a crucial role in attracting lipid nanoparticles (LNPs) containing mRNA, facilitating their entry into cells. Additionally, V-ATPase, a proton pump in endosomes, acidifies vesicles, causing LNPs to become positively charged and enabling them to disrupt the endosomal membrane and release mRNA into the cytoplasm for protein expression.

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The study also highlighted the role of TRIM25, a protein involved in cellular defense that binds to foreign mRNAs, triggering their rapid degradation and preventing their function. However, mRNA vaccines can evade this degradation through a chemical modification called N1-methylpseudouridine (m1Ψ), which prevents TRIM25 from binding to mRNA, enhancing vaccine stability and effectiveness.

Furthermore, the researchers discovered that proton ions released during endosomal rupture serve as immune signaling molecules, activating TRIM25 and alerting cells to foreign RNA.

Dr. Kim emphasized the importance of understanding 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."