A University of Pennsylvania team reported that hybrid guide RNAs—gRNAs with select DNA nucleotide substitutions—boost adenine base editor (ABE) performance by reducing off‑target and bystander edits while improving correction efficiency for disease‑causing A>G mutations. The work, published in Nature Biomedical Engineering, demonstrated improved editing in hepatocyte models and humanized mouse systems for disorders such as PKU, PXE and HT1. Investigators used ONE‑seq to map off‑target sites, validated candidates in cells, and screened 21 synthetic hybrid gRNAs. Selected designs packaged with ABE8.8 in lipid nanoparticles yielded more accurate in vivo editing of target adenines while suppressing unintended edits. The approach is compatible with mRNA‑LNP delivery and could enable safer base‑editing therapeutics for autosomal recessive diseases. For readers: hybrid gRNAs substitute a few RNA bases with DNA to alter binding kinetics and nuclease activity, a practical lever to tune editor specificity.