A virus can copy itself with astonishing accuracy inside host cells. Researchers at San Diego State University and Michigan State University, reporting in Proceedings of the National Academy of Sciences, have now revealed how bacteriophage MS2 achieves its near-perfect feat of genetic packaging.
Their study shows that instead of relying on a single molecular “switch,” viral coat proteins selectively package genetic cargo using a network of RNA features. And this breakthrough could shape the future of gene therapies and antiviral design.
Many viruses like MS2 invade bacteria such as Escherichia coli, hijacking host machinery to mass-produce new viral particles. When packaging their genome, MS2 must distinguish its own RNA from the cell’s, despite the crowded intracellular environment. Historically, scientists thought one specific stem-loop structure in the viral RNA, the TR loop, acted as a packaging signal, a kind of molecular signpost guiding viral coat proteins to the right spot. But using in-cell experiments with systematically scrambled RNA sequences, the researchers showed that selective packaging is driven instead by the collective action of many stem-loop structures spread throughout the genome, along with features like length and sequence.
“MS2 coat proteins alone are capable of selectively packaging MS2 RNA, achieving packaging fractions as high as 97% under the conditions tested,” the scientists wrote.
To explore this process, the team inserted modified RNA constructs into bacteria and tracked how different RNA shapes and lengths competed for entry into viral shells. The outcome: while physical compactness had a modest effect, the number and arrangement of stem-loops governed how well viral RNA was distinguished from host transcripts. These results challenge old models and clarify that packaging signals are distributed—no single loop, not even the famous TR loop, is strictly essential for selectivity if others remain intact.
Understanding these molecular rules has major implications beyond basic science. Synthetic viral shells could become tools for delivering genetic cargo in gene therapy, CRISPR gene-editing systems, or messenger RNA vaccines. By mastering selective genome packaging, bioengineers may tune virus-like particles to treat diseases or create next-generation RNA-based therapeutics.
Viruses like MS2 exemplify the abundance and diversity of RNA viruses on Earth. The World Health Organization (WHO) notes their vast presence in natural ecosystems, while researchers continue to discover foundational principles of viral biology (PMC: Introduction to RNA Viruses). By showing how packaging selectivity arises from the “collective code” of RNA structure and sequence, the new findings point to exciting possibilities for health and biotechnology in the years ahead.
Proceedings of the National Academy of Sciences, August 11, 2025, DOI: 10.1073/pnas.2505190122
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