Engineered probiotics to sense and respond to inflammation

Le résumé fourni par la source

Engineered probiotics represent a powerful new frontier in diagnostics and immunotherapy, with the potential to detect and treat disease directly at the site of pathology. However, practical deployment remains constrained by the need for biosensors responsive to physiologically relevant biomarkers, strategies for controllable therapeutic delivery, and consistent performance within complex host environments. In the first part of this work, we develop a platform for sensing and responding to intestinal inflammation in situ using the probiotic strain Escherichia coli Nissle 1917 (EcN). We establish the transcriptional regulator KynR as a dual-ligand biosensor that detects the inflammation-associated metabolite kynurenine and is selectively inhibited by tryptophan. Structural modeling, biochemical binding assays, and genetic knockout studies reveal the molecular basis of this dual-ligand regulation. Localized cytokine delivery offers a strategy to resolve inflammation at its source while avoiding the systemic side effects that limit conventional immunotherapies. To this end, we integrate a YebF-based protein secretion system into EcN and construct a closed-loop genetic circuit that links biosensing to therapeutic cytokine release, advancing the development of autonomous microbial theranostics. In the second part of this work, we engineer a hydrogel encapsulation platform to enhance oral delivery and in vivo performance of probiotic biosensors. This system preserves bacterial viability, limits off-target dispersal, and enables robust diagnostic function in the gastrointestinal tract. We validate the approach by combining it with a previously characterized bacterial biosensor of intestinal inflammation in a rat model of colitis. Encapsulated bacteria remain viable post-transit and report disease severity with high fidelity. To improve safety, we embed UV-absorbing nanoparticles within the hydrogel matrix to enable targeted sterilization of the capsule surface without compromising internal bacterial viability. We further reinforce the hydrogel with a polymer network that improves biocontainment. Together, these technologies establish a foundation for safe, programmable, and responsive living therapeutics with diagnostic and therapeutic capabilities suited to complex host environments.

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