RNA-guided bridge recombinases expand the scope of genome editing

Programmable genome editing has advanced rapidly, but efficient control of large-scale structural DNA changes remains a major challenge. Nuclease-based systems enable broad genome manipulation but rely on double-strand breaks and error-prone repair. Base editors and prime editors improve precision, yet are better suited to local sequence changes than to large insertions or chromosomal rearrangements. Other emerging platforms, including PCE/RePCE, amplification editing, and engineered R2 retrotransposons, expand the scope of structural editing but remain functionally specialized. RNA-guided bridge recombinases introduce a distinct strategy for programmable insertion, excision, and inversion at endogenous loci. Derived from IS110-family elements, these systems use a bridge RNA to specify both genomic target and donor sequences, coupling recombinase-mediated DNA mobility with RNA programmability. Recent studies identified and optimized ISCro4 for activity in human cells, enabling targeted DNA insertion, deletion, and inversion without detectable on-target indels. Further engineering of the recombinase and bridge RNA improved performance, supporting insertion efficiencies up to 20%, specificity up to 82% at selected loci, scarless inversions approaching 0.93 Mb, and excisions exceeding 0.13 Mb. These advances establish bridge recombinases as promising tools for structural genome engineering, while guide design, genomic-context dependence, and off-target recombination remain important challenges.