Core Viewpoint - The article discusses advancements in base editing technology, specifically focusing on a new method to minimize bystander editing while maintaining high editing efficiency, which addresses significant challenges in genome editing applications [1][2][9]. Group 1: Research Findings - The research team from Harvard University developed a multi-faceted approach to enhance base editing precision by optimizing gRNA and deaminases, thereby minimizing bystander editing [2][5]. - A library of approximately 60,000 different 3' extended sgRNAs was designed and tested to improve the precision of adenine base editors (ABE), leading to the identification of promising agRNA candidates [6]. - The V28C variant, evolved through phage-assisted non-continuous evolution (PANCE), demonstrated a significant increase in editing efficiency at target sites while substantially reducing bystander editing, achieving precision two to three times greater than ABE8e with a 20% efficiency improvement [6][7]. Group 2: Methodologies - The study integrated three complementary technologies: engineering gRNA to reduce bystander editing, using PANCE to evolve more precise base editors, and employing protein language models (PLM) for rational design of optimized deaminases [5][9]. - The M151E mutation, identified through PLM, significantly narrowed the editing window and improved target site editing efficiency [7]. Group 3: Clinical Applications - The performance of the evolved base editors was validated in two clinically relevant scenarios, showing high efficiency and precision in editing cardiovascular disease-related target PCSK9 and early-onset Parkinson's disease-related mutation SNCA E46K [7].