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Biomolecule delivery systems are often plagued by problems such as non-specific targeting and low bioavailability. We sought to design a novel system that can sense and respond to specific stimuli present in the microenvironment of pathogenic cells. We engineered a dual-sensor bacterium that can sense increased metabolite levels in its microenvironment and then respond by delivering biomolecules into target cells. As a proof-of-concept, we engineered Escherichia coli to detect increased level of lactate in biological fluid, then respond by attaching itself to a cancer cell marker, and subsequently release biomolecules into the cell. A biosafety kill switch will be activated when there is insufficient lactate present, thus minimizing non-specific targeting.

Our proposed system has the flexibility to be engineered to detect other metabolites by changing the gene promoter and also detect different cell types by targeting other cell receptors. In addition, the modular nature of our system also allows part of the lactate sensing mechanism to be used as a diagnostic kit, especially for detecting for elevated levels of lactate in biological fluids such as blood or serum from patients with suspected cases of sepsis or lactic acidosis. This method of detection can be carried out without any specialized equipment or impoverished areas.