Scientists used directed evolution and 3′‑extended guide RNAs to sharpen adenine base editor specificity, reducing bystander edits that hinder clinical applicability. The Nature Biotechnology report documents engineered editor variants with narrower editing windows and improved on‑target:bystander ratios. The optimized editors were validated across disease‑relevant targets, demonstrating fewer unintended edits without compromising on‑target efficiency. Developers working on therapeutic base editing can use these evolved enzymes and guide modifications to improve safety margins for candidate programs.