Programmable Transcriptional-Translation Active Sensors for miRNA-Responsive Gene Imaging and Theranostics in Mammalians

Synthetic gene circuits are logical circuits constructed by various biological elements based on engineering principles. However, the majority of current synthetic gene circuits are modulated through exogenous factors or endogenous inhibitory substances, which results in redundant structures and low efficiency, thereby greatly limiting their application scenarios. In this study, we developed a miCU sensor system comprising the Gal4-VP16 gene element, which enables real-time targeted monitoring of miR-9 and miR-124a during neural differentiation through transcriptional-translation two-step active regulation with a relatively low background signal. Additionally, the functional gene was replaced by P21 through the programmability of miCU, thereby achieving miRNA-mediated cell cycle arrest and suppression of cell migration in tumor cells. Furthermore, by strategically substituting the target miRNA with miR-155 and concurrently introducing the therapeutic gene Nrf2 into the miCU system, the integration of disease diagnosis and treatment in lipopolysaccharide (LPS)-induced acute liver injury (ALI) mouse models has been successfully achieved. Our study presented a programmable miRNA-responsive gene regulation platform, which may offer a robust tool for precise diagnosis and treatment in disease settings.