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Article Abstract
Eukaryotic transposon-encoded Fanzor proteins hold great promise for genome-engineering applications as a result of their compact size and mechanistic resemblance to TnpB. However, the unmodified Fanzor systems show extremely low activity in mammalian cells. Guided by the predicted structure of a Fanzor2 complex using AlphaFold3, we engineered the NlovFz2 nuclease and its cognate ωRNA to create an evolved enNlovFz2 system, with an expanded target-adjacent motif (TAM) recognition scope (5'-NMYG) and a substantially improved genome-editing efficiency, achieving an 11.1-fold increase over the wild-type NlovFz2, comparable to two previously reported IS200 or IS605 transposon-encoded TnpBs and two CRISPR-Cas12f1 nucleases. Notably, enNlovFz2 efficiently mediated gene disruption in mouse embryos and restored dystrophin expression in a humanized Duchenne muscular dystrophy mouse model with single adeno-associated virus delivery. Our findings underscore the potential of eukaryotic RNA-guided Fanzor2 nucleases as a versatile toolbox for both biological research and therapeutic applications.
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