Programming Next-Generation Synthetic Biosensors by Genetic Circuit Design.

Synthetic biology employs engineering principles to construct genetic circuits with customized functionality, empowering unprecedented control over biological systems. By harnessing this capability to precisely manipulate biological systems, synthetic biosensors are being developed as promising biosensing platforms for on-site, sustainable, affordable, and easy-to-use detection across diverse scenarios, such as environmental monitoring, disease diagnosis, food safety control, and bioproduction optimization. However, the field deployment and real-world application of synthetic biosensors face considerable challenges in biosensing sensitivity, specificity, speed, stability, and biosafety. This review summarizes recent advancements of genetic circuit-enabled synthetic biosensors, focusing on their sensory mechanisms, designs, and applications. Moreover, the design principles, enabling tools, and engineering strategies for creating a high-performing synthetic biosensor are analyzed. In particular, methods for tuning various characteristics of the dose-response curve, including detection limit, detection threshold, operating range, dynamic range, and leakiness, are thoroughly examined. Finally, this review discusses the functional extension of biosensors by customizing signal-processing and output modules, and outlines future directions to expedite the transition of synthetic biosensors from laboratory settings to field applications. Genetic circuit-enabled synthetic biosensors, in collaboration with materials science, electronic engineering, and artificial intelligence, will tremendously expand the application space of synthetic biology.