Domestic researchers have newly discovered the proteins involved in the delivery and degradation of mRNA (messenger ribonucleic acid) vaccines in cells. Regulating these proteins is expected to significantly aid in developing safe and effective vaccines or therapeutics by enhancing the efficacy and longevity of therapeutic mRNA.
Professor Kim Bit-naeri, chair of the Department of Life Sciences at Seoul National University and head of the RNA Research Center at the Institute for Basic Science, noted on the 4th, "We have revealed the key proteins and regulation pathways involved in the entry and degradation of mRNA into cells." The research findings were published online that day in the international journal Science.
The mRNA vaccine and therapeutic market has been rapidly growing since the COVID-19 pandemic. According to market research firm Mordor Intelligence, the market size is expected to increase from approximately $63.9 billion (about 92.8 trillion won) this year to $138.9 billion (201.7 trillion won) by 2030.
◇Decoding the process of mRNA's entry into cells
Humans have genetic material in the form of DNA (deoxyribonucleic acid). Coronaviruses have it in RNA (ribonucleic acid). Living organisms copy certain information from genes into mRNA to produce the desired proteins. Proteins govern all phenomena in living organisms. If genes are a storage of information about proteins, mRNA is the blueprint for producing the desired proteins. The vaccine that saved humanity during the COVID-19 pandemic was created using mRNA.
Professor Kim's research team decoded the process by which the mRNA of the vaccine enters the human body. At that time, they replaced the natural nucleotide components constituting the mRNA with a synthetic nucleotide called N1-methylpseudouridine to avoid excessive immune responses and ensure proper protein production. The research team revealed how this modified nucleotide enhanced the efficacy of the vaccine and what the underlying principles were.
The research team used CRISPR gene-editing technology to systematically remove genes one by one to identify those influencing specific traits or cellular responses. Gene scissors are enzyme complexes that cut desired genes. The team analyzed over 20,000 genes.
The experimental results confirmed that heparan sulfate molecules on the cell membrane facilitate the entry of mRNA protected by lipid nanoparticles from the vaccine into cells. Heparan sulfate is a glycoprotein with sulfate groups, serving as a mediator for the influx of external substances into the cell.
Lipid nanoparticles containing mRNA enter the cell and into vesicles that transport materials, where they temporarily disrupt the vesicle membrane. Thanks to this disruption, mRNA is released into the cytoplasm, leading to protein synthesis.
The research team also identified proteins that inhibit mRNA. The 'TRIM25' protein found in the cytoplasm recognizes and removes mRNA as an intruder. However, it was also discovered that the modified mRNA of the vaccine, which had its natural nucleotides replaced with N1-methylpseudouridine, does not easily bind to this protein and cannot be cut or degraded. The N1-methylpseudouridine modified nucleotide was essentially the 'kick' that enabled the COVID-19 mRNA vaccine.
◇Possibility of developing efficient and long-lasting mRNA vaccines
mRNA research has changed the paradigm of vaccine development. Previously, vaccines induced immune responses through injections of inactivated viruses or specific proteins, whereas mRNA vaccines deliver genetic information that allows the human body to directly synthesize viral proteins and produce antibodies in response. Katalin Kariko and Drew Weissman received the 2023 Nobel Prize in Physiology or Medicine for their contributions to the development of mRNA vaccines.
Using mRNA allows for quicker vaccine development without needing to neutralize the virus's toxicity or create proteins individually. Furthermore, if mutant viruses arise, mRNA information can be updated immediately to respond effectively. The research findings by Professor Kim Bit-naeri's team clarify the process by which mRNA is delivered to cells from vaccines and is not degraded by enzymes, which can significantly enhance the efficacy of mRNA vaccines and therapeutics in the future.
Professor Kim said, "If we develop technology that utilizes heparan sulfate to assist in mRNA delivery, we can improve the delivery efficiency of mRNA, and conversely, if we develop technology to evade TRIM25, a substance that destroys mRNA, we can increase the stability of mRNA."
This would allow obtaining the desired immune response with lower doses of mRNA. Professor Kim said, "When developing vaccines or therapeutics, there will be no need to inject large amounts of mRNA, allowing for the creation of effective vaccines and therapeutics with minimal side effects." Professor Kim Bit-naeri previously contributed to COVID vaccine development by completing a high-resolution genetic map of the coronavirus in 2020.
mRNA vaccines have emerged as a powerful tool for humanity in conquering rare diseases and cancer since the COVID-19 pandemic. BioNTech, which introduced the COVID-19 vaccine, entered clinical trials last year for the mRNA vaccine "BNT116," which can prevent the recurrence of lung cancer. Similarly, Moderna, which also developed a COVID mRNA vaccine, is conducting clinical trials for the vaccine "mRNA-4157," aimed at preventing melanoma, in collaboration with Merck & Co. (MSD).
References
Science(2025), DOI: https://www.science.org/doi/10.1126/science.ads4539
Cell(2020), DOI: https://doi.org/10.1016/j.cell.2020.04.011