Genetic principles enabling the creation of bacteria-based therapeutics.

Genetic engineering can transform bacteria (including Salmonella, Escherichia coli, Listeria, and Yersinia) from naturally occurring microbes into programmable therapeutics. Unlike passive platforms, engineered bacteria can localize to defined biological niches, sense environmental cues, regulate programmed activity in situ, interact with host tissues in novel ways, and persist for controlled periods. These properties make bacteria versatile medicines but require genetic control of precision, safety, stability, and activity under clinical conditions. Major design layers include strain or "chassis" selection, attenuation and biocontainment, control of therapeutic activity, targeting and persistence, and genotype-to-phenotype stability during manufacturing and in vivo use. These features also create liabilities, including off-target behavior, unstable expression, and evolutionary loss of function under selection. Progress depends on safe, clinically translatable chassis with integrated, bounded, and durable behaviors. This review examines the genetic design principles and liabilities of bacteria-based therapeutics, approaches used to produce clinical and near-clinical candidates, and the emergence of programmed bacteria delivering complete gene editing systems to therapeutically relevant cells.