Precision Control of Cell Type‐Specific Behavior via RNA Sensing and Editing

Abstract In the realms of bioengineering and biopharmaceuticals, there exists a critical demand for advanced genetic tools that can interact with specific cell signaling pathways to accurately identify and target various cell types. This research introduces the innovative CRISPR‐ADAReader system, which enables precise manipulation of cell activity through sensing target RNA. Featuring both positive and negative feedback loops, the system allows for tailored regulation across different cell types in response to various internal signals, showcasing exceptional programmability, specificity, and sensitivity. By choosing distinct RNAs as activation signals, the CRISPR‐ADAReader efficiently monitors and alters targeted cell behaviors. In a case study focusing on retinoblastoma treatment, the system distinctively initiates positive feedback and self‐silencing actions by detecting MCYN and Rb transcripts, thus safeguarding normal retinal pigment epithelial cells while promoting apoptosis in cancer cells. Moreover, the CRISPR‐ADAReader demonstrates significant anti‐tumor effectiveness in live models, markedly reducing retinoblastoma cell proliferation through the activation of several cancer‐suppression pathways, outperforming the capabilities of the ADAR‐sensor. Notably, the system also shows an excellent in vivo safety profile. In conclusion, the CRISPR‐ADAReader system represents a groundbreaking method for the detection and editing of RNA, offering a potent instrument for the customized and precise governance of cell behavior.