Tunable thermal bioswitches for in vivo control of microbial therapeutics

Temperature is a unique input signal that could be used by engineered microbial therapeutics to sense and respond to host conditions or spatially targeted external triggers such as focused ultrasound. To enable these possibilities, we present two families of tunable, orthogonal, temperature-dependent transcriptional repressors providing switch-like control of bacterial gene expression at thresholds spanning the biomedically relevant range of 32-46 degrees C. We integrate these molecular bioswitches into thermal logic circuits and demonstrate their utility in three in vivo microbial therapy scenarios, including spatially precise activation using focused ultrasound, modulation of activity in response to a host fever, and self-destruction after fecal elimination to prevent environmental escape. This technology provides a critical capability for coupling endogenous or applied thermal signals to cellular function in basic research, biomedical and industrial applications.