Engineering microbes to modulate innate immune signaling: strategies for host–microbe interactions

The human gastrointestinal tract hosts a dense microbial community that closely interfaces with the mucosal immune system to preserve homeostasis. While dysregulation of this interaction contributes to certain disease states, through targeted microbial engineering, these interactions can be modulated for therapeutic benefit. Although engineered microbial therapeutics have shown encouraging preclinical results, few approaches have progressed into clinical pipelines. This gap highlights the need for engineered microbes with greater precision, reliability, and context-dependent control. The innate immune system is primed to rapidly sense microbial signals through pattern recognition receptors and provides accessible and tractable targets for such interventions. This review highlights four strategies that have used engineered probiotics to modulate innate immunity: (1) direct immune cell engagement through surface-display, (2) production of soluble immune effectors, (3) extracellular vesicles for delivery of immune modulators, and (4) environmentally responsive systems to enable spatial and temporal control over immune modulation. Bridging microbial engineering with mucosal immunology can enable engineered probiotics to function as dynamic, context-aware immunomodulators.