A molecular swap may improve protein production.
BALTIMORE, UNITED STATES
Scientists have identified a chemical modification that could help future mRNA medicines produce more protein while reducing translation errors. The experimental approach uses N4 acetylcytidine, known as ac4C, instead of N1 methylpseudouridine, the modification commonly incorporated into current mRNA platforms. Researchers tested the strategy in laboratory cell lines, human dendritic cells and mouse liver tissue. The findings remain preclinical and do not establish that ac4C is safer or more effective in patients.
Messenger RNA medicines work by delivering temporary genetic instructions that cells use to manufacture a selected protein. Ribosomes read those instructions and assemble the protein, but the chemical composition of the mRNA can influence the speed and accuracy of that process. In the study, ribosomes moved along ac4C modified mRNA almost twice as fast as they did along mRNA containing the established modification. This faster movement increased protein production and appeared to prevent molecular congestion caused by ribosomes colliding on the same strand.
The researchers also found that ac4C suppressed inflammatory responses as effectively as the current standard under the experimental conditions. Meanwhile, mRNA containing N1 methylpseudouridine was associated with slower translation, more ribosome collisions and a greater likelihood of errors such as premature termination or shifts in the genetic reading frame. Those mistakes can generate unintended proteins, making translation accuracy particularly important for vaccines, gene editing and protein replacement therapies. However, the results do not invalidate existing mRNA vaccines, whose design and safety profiles are supported by extensive clinical evidence.
If confirmed in additional studies, ac4C could allow developers to obtain the desired protein output from smaller quantities of mRNA. That possibility could influence experimental treatments for infectious diseases, cancer and autoimmune disorders, although each application would require separate testing. Researchers must still determine how the modification behaves in different organs, delivery systems and dosing schedules, as well as whether repeated administration creates unexpected immune or toxic effects. Human clinical trials and rigorous manufacturing assessments will be necessary before ac4C can become part of an approved medicine.
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