The use of intracellular, biosensor-based dynamic regulation strategies to regulate and improve the production of useful compounds have progressed significantly over previous decades. By employing such an approach, it is possible to simultaneously realize high productivity and optimum growth states. However, industrial fermentation conditions contain a mixture of high- and low-performance non-genetic variants, as well as young and aged cells at all growth phases. Such significant individual variations would hinder the precise controlling of metabolic flux at the single-cell level to achieve high productivity at the macroscopic population level. Intracellular biosensors, as the regulatory centers of metabolic networks, can real-time sense intra- and extracellular conditions and, thus, could be synthetically adapted to balance the biomass formation and overproduction of compounds by individual cells. Herein, we highlight advances in the designing and engineering approaches to intracellular biosensors. Then, the spatiotemporal properties of biosensors associated with the distribution of inducers are compared. Also discussed is the use of such biosensors to dynamically control the cellular metabolic flux. Such biosensors could achieve single-cell regulation or collective regulation goals, depending on whether or not the inducer distribution is only intracellular.
Keywords: Dynamic regulation; extracellular metabolite; intracellular metabolite; microdroplet; riboswitch; non-genetic variants; single-cell regulation.