Core Viewpoint - The research led by Zhang Feng's team presents a novel gene editing tool, NovaIscB, which significantly enhances gene editing efficiency and specificity compared to existing tools, paving the way for advanced applications in gene and epigenetic editing [3][19]. Group 1: Development of NovaIscB - The NovaIscB system was created through evolutionary and structural-guided protein engineering, achieving up to 40% insertion/deletion editing activity in the human genome, which is approximately 100 times more efficient than the wild-type OgeuIscB [3][19]. - The research utilized a combination of natural selection, structural grafting, directed evolution, and RNA engineering to optimize the IscB protein, resulting in a compact system that can be delivered via a single AAV vector [10][14]. Group 2: OMEGAoff System - The NovaIscB was fused with a methyltransferase to create the programmable epigenetic editing system OMEGAoff, which can achieve persistent gene suppression, notably reducing PCSK9 gene expression and cholesterol levels for over six months [3][16]. - The OMEGAoff system demonstrated significant potential for long-lasting gene suppression and epigenetic editing, with no observed toxicity in the tested subjects [16][19]. Group 3: Implications and Future Applications - The study introduces a new framework for optimizing protein functions that extends beyond genome editing, suggesting broad potential applications in various fields [4][19]. - The compact nature of the NovaIscB system allows for easier delivery into cells, addressing a major challenge in the gene editing field [7][8].