Genetic Entanglement Enables Ultrastable Biocontainment in the Mammalian Gut.

ABSTRACT: Imbalances in the mammalian gut are associated with acute and chronic conditions, and using engineered probiotic strains to deliver synthetic constructs to treat them is a promising strategy. However, high rates of mutational escape and genetic instability in vivo limit the effectiveness of biocontainment circuits needed for safe and effective use. Here, we describe STALEMATE (Sequence enTAngLEd Multi lAyered geneTic buffEring), a dual-layered failsafe biocontainment strategy that entangles genetic sequences to create pseudoessentiality and buffer against mutations. We entangled the colicin E9 immunity protein (Im9) with a thermoregulated meganuclease (TSM) by overlapping the reading frames. Mutations that disrupted this entanglement

SUBMITTER: Foo GW 

PROVIDER: S-EPMC12455656 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature