Engineering sensor-based antithetic integral controllers for enhanced dynamic performance and noise attenuation

Effective cellular regulation relies on feedback control mechanisms to maintain homeostasis and mitigate environmental fluctuations. We develop and analyze a sensor-based antithetic integral feedback (sAIF) controller that achieves this by embedding proportional and integral actions within a minimal genetic architecture. Arising from a single modification to the classical antithetic control motif, this sAIF architecture intrinsically incorporates proportional feedback without requiring additional circuitry. Control-theoretic and stochastic analyses show that this proportional action speeds up the system's dynamic response and counteracts the noise amplification typical of pure integral feedback, enabling both improved speed and reduced cellular variability. Using intein-mediated splicing, we implement sAIF in E. coli and demonstrate robust perfect adaptation, strong disturbance rejection, and favorable noise properties. These findings establish a generalizable design principle for engineering high-performance biological controllers, with broad implications for synthetic biology, metabolic engineering, and cell-based therapies. A record of this paper's transparent peer review process is included in the supplemental information.