Designing high performance whole-cell biosensors by integrating Synthetic Biology with Control Engineering

Transcription-based whole-cell biosensors (WCBs) are cells engineered with an analyte-responsive promoter that regulates the expression of a reporter gene, enabling continuous monitoring of specific biomolecules in vitro and in vivo. Despite their significant potential, the design of WCBs often involves a time-consuming trial-and-error process, resulting in suboptimal sensor performance. To overcome these challenges, we propose a theory-driven approach that integrates Synthetic Biology and Control Theory to enhance the biosensor performance by means of biomolecularcircuits. Specifically, we first defined five main features of a biosensor from its input-output response (leakiness, fold-change, sensitivity, operating range and linearity). We then show how to optimize each feature by designing alternative biomolecular circuits to obtain a final configuration that closely approximates the characteristics of an ideal biosensor.