This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: In a new study, scientists from Johns Hopkins Medicine report that an experimental mRNA-based platform has the potential to help deliver next-generation mRNA therapeutics, including vaccines to fight infectious diseases, cancer and autoimmune conditions, faster and more efficiently than the industry standard. In experiments with cells from people and mice, researchers at Johns Hopkins Medicine and the National Institutes of Health (NIH) compared an experimental mRNA platform, N4-acetylcytidine (ac4C), with the industry-standard mRNA platform, N1-Methylpseudouridine (m1Ψ).
The chemical modification used in COVID-19 mRNA vaccines is being widely studied for delivering potential cancer and autoimmune disease vaccines. The study was published July 1 in Nature. "Our results show that ac4C causes cells to produce more therapeutic proteins to fight disease than the industry-standard mRNA platform," says Bin Wu, Ph.D., associate professor of biophysics and biophysical chemistry at the Johns Hopkins University School of Medicine.
"This may eventually lead to more efficient drugs that require smaller doses." There are more than 170 known RNA modifications, but only a small subset has been studied for mRNA therapeutic purposes, Wu says. In experiments, NIH scientists had previously demonstrated how ac4C, a naturally occurring modification, may enhance mRNA translation, potentially speeding up protein production. Wu says this research began when co-corresponding author Shalini Oberdoerffer, Ph.D., senior investigator in the Laboratory of Receptor Biology and Gene Expression at the National Cancer Institute, gave a talk about ac4C at Johns Hopkins University in 2024.
Wu, who uses biophysics to study mechanisms of mRNA modifications, proposed a research collaboration to better understand the behavior of individual RNA molecules. While m1Ψ is a safe and effective mechanism for drug delivery, the researchers say the study reveals how ribosomes that travel along single strands of mRNA containing m1Ψ may slow down and cause traffic jams, which in turn produce fewer proteins that trigger an immune response, Wu says. In their experiments, the scientists used lipid nanoparticles to mimic how vaccines work, inserting mRNA with the ac4C and industry-standard m1Ψ modifications into cultured human dendritic cells derived from monocytes, or white blood cells that support the immune system, and mouse liver cells.
Comparing the two mRNA modifications, the scientists used an imaging technique developed by Wu's lab, called single-molecule imaging of nascent peptides, and an advanced microscope to track individual mRNAs as they produced therapeutic proteins within cells. "Our imaging revealed that ribosomes travel nearly twice as fast on the ac4C-modified mRNA, preventing the ribosomal traffic jam we may encounter with the industry-standard mRNA platform," Wu says. Further, Wu says, the imaging demonstrated that irregularly translated ribosomes on the m1Ψ platform caused premature termination or frameshifting, producing fewer or compromised proteins.
In contrast, the ac4C platform resulted in smoother mRNA translation, preventing ribosomal roadblocks and producing more and better proteins that may boost therapeutic effects, Wu says. "We propose this ribosome collision as a model for why the industry standard may produce fewer proteins," Wu says. "In the future, this could help us investigate potential therapeutics that require smaller doses but create more protein and a better immune response." Sarah Schiffers et al, N4-Acetylcytidine enhances synthetic mRNA translation yield and fidelity, Nature (2026).
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