Genome biology · 2026
Directed evolution of compact RNA-guided nucleases for enhanced activity in mammalian cells.
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Gorbenko Fedor, Sala Irene, Lee Young-Yoon, van de Venn Lilly, Yeh Charles D, Tálas András, Karvelis Tautvydas, Druteika Gytis, Bechter Luca V, Vykhlyantseva Iryna, Schröder Markus S, Gvozdenovic Ana, Schwank Gerald, Siksnys Virginijus, Corn Jacob E
Аннотация
BACKGROUND: RNA-guided nucleases enable DNA editing and offer promise for treating genetic diseases, particularly when used for precise sequence replacement. However, many of the most effective enzymes, such as Streptococcus pyogenes Cas9, are too large for delivery using vectors like adeno-associated virus. This has prompted interest in smaller alternatives from the Cas12f and TnpB families. Yet, these nucleases often show low activity in mammalian cells, limiting their utility.
RESULTS: We use directed evolution in human cells to select variants with greatly improved activity. The resulting variants, Cas12f1Super and TnpBSuper, exhibit up to 11-fold increase in editing efficiency without increased off-target effects. When tested as a base editor, Cas12f1Super shows up to tenfold improvement relative to the previously engineered CasMINI, suggesting utility beyond nuclease-related activities.
CONCLUSIONS: These compact and efficient genome editors expand the current toolkit and hold promise for both research and therapeutic use in mammalian systems.
RESULTS: We use directed evolution in human cells to select variants with greatly improved activity. The resulting variants, Cas12f1Super and TnpBSuper, exhibit up to 11-fold increase in editing efficiency without increased off-target effects. When tested as a base editor, Cas12f1Super shows up to tenfold improvement relative to the previously engineered CasMINI, suggesting utility beyond nuclease-related activities.
CONCLUSIONS: These compact and efficient genome editors expand the current toolkit and hold promise for both research and therapeutic use in mammalian systems.