South Korean researchers have, for the first time in the world, uncovered how messenger ribonucleic acid (mRNA) vaccines enter human cells, function inside the body, and are blocked by certain proteins — a breakthrough that could significantly accelerate the broader application and commercialization of mRNA vaccine technology.
The research team, led by Kim V. Narry, director of the RNA Research Center at the Institute for Basic Science (IBS) and a distinguished professor at Seoul National University, used gene-editing tools to test nearly 20,000 genes.
Through this large-scale screening, they identified molecules that assist mRNA in entering cells and proteins that interfere with its function. By pinpointing key factors that affect cellular uptake and sustained efficacy — two of the biggest hurdles in expanding mRNA vaccine applications to treat a wide range of diseases — the team has clarified critical biological mechanisms that had long remained elusive.
“We have identified the proteins that control the delivery and degradation of mRNA vaccines within cells and clarified how they function,” Kim’s team said.
Experts say the findings could prove to be a game changer, potentially speeding up the path toward the widespread commercial use of mRNA vaccines. The study was published April 4 in the international journal Science.
mRNA plays a central role in translating genetic information from DNA into functional proteins. After copying the genetic code, it delivers the instructions to ribosomes inside the cell, where proteins are synthesized — much like a factory receiving a blueprint for production.
COVID-19 vaccines harnessed this process by injecting synthetic mRNA that codes for a viral protein, thereby training the immune system to produce antibodies. This novel approach allowed developers to compress the traditional vaccine development timeline — typically more than 10 years — into just 11 months.
Companies such as Pfizer and Moderna enveloped the mRNA in lipid nanoparticles and chemically modified one of its nucleosides to prevent unwanted immune responses. However, until now, it had remained unclear what mechanisms enabled mRNA to enter cells, how it was released into the cytoplasm, and what factors influenced its stability or degradation.
To answer these questions, the research team used CRISPR gene-editing technology to deactivate individual genes in cells, one by one, across 20,000 candidates. They then introduced fluorescent mRNA into the edited cells to observe which molecules either supported or interfered with its function.
Their analysis revealed that heparan sulfate — a glycoprotein found on the cell surface — facilitates mRNA entry into the cell. Once inside, the mRNA reaches endosomes, and a protein complex called V-ATPase breaks open the endosomal membrane. This process allows the mRNA to escape into the cytoplasm, where it can begin directing the production of proteins.
The team also discovered how the body’s immune system detects and responds to foreign mRNA — and how modified mRNA vaccines evade that response.
A cytoplasmic protein called TRIM25 was found to recognize unmodified mRNA as a foreign substance, binding to it with other nucleases to break it down. In contrast, the chemically modified mRNA used in COVID-19 vaccines was able to bypass this immune surveillance and successfully produce proteins.
“This reveals the mechanism by which mRNA vaccines avoid immune detection and function effectively within the body,” the researchers explained.
In 2023, scientists who contributed to improving the performance of mRNA vaccines during the pandemic were awarded the Nobel Prize in Physiology or Medicine. However, many aspects of how mRNA functions at the cellular level remained unresolved. The new findings address some of those unanswered questions, drawing attention from the global scientific community.
The study is also expected to boost international interest in Kim V. Narry, who has long been regarded as a leading authority in RNA biology and has often been mentioned as a potential Nobel Prize candidate.
“This research provides a theoretical foundation for enhancing the stability of mRNA and increasing its efficiency in producing proteins,” Kim said. “We hope it will contribute to the development of next-generation mRNA vaccines.”
