Programmed Probiotics Generate Interleukin-37b-Bearing Nanovesicles In Situ for Precision Immunomodulation in Colitis.

Genetically engineered probiotic bacteria are promising living therapeutics. However, their therapeutic potential is frequently confined to their colonization sites, and limitations in efficacy, controllability, and robustness remain major barriers to translation. Anti-inflammatory cytokines play a crucial role in mitigating the pathogenesis of inflammation-related diseases, yet their application is limited by their vulnerability in the mammalian gastrointestinal tract. In this regard, we first found that interleukin-37b (IL-37b) mitigated inflammatory responses at picogram concentrations in primary intestinal cells, supporting its translational potential for the oral treatment of inflammatory diseases. Then, we harnessed the probiotic bacterium Escherichia coli Nissle 1917 as a chassis and further engineered it into a hypervesiculating strain, ΔECIL-37b, capable of efficiently secreting IL-37b-bearing bacterial outer membrane vesicles (OMVs) in situ. These OMVs facilitated IL-37b penetration across the intestinal barrier, enabling it to reach the inflamed mucosa and interact with target cells. In both acute and chronic murine colitis models, we demonstrated that ΔECIL-37b achieved anti-inflammatory efficacy comparable to direct IL-37b injection while enabling local intestinal delivery. Mechanistically, ΔECIL-37b exerted anti-inflammatory effects by attenuating myeloid differentiation primary response 88 (MyD88)-related downstream extracellular-signal-regulated kinase/nuclear factor κB signaling and inflammatory-immune cross-talk. Together, these findings provide a proof-of-concept strategy to harness the anti-inflammatory activity of IL-37b via probiotic-derived OMV delivery and offer insights into a precision anti-inflammatory approach integrating cytokine and probiotic functions.