Recombination of miR-146b by Lactococcus lactis for Remolding Macrophages and the Microbiome in the Treatment of Murine Colitis

MicroRNA 146b (miR-146b) mitigates the progression of inflammatory bowel disease (IBD) by reprogramming macrophage polarization through the induction of interleukin-10 (IL-10), thereby eliciting an anti-inflammatory response, but its application is currently hindered by the lack of safe delivery systems that allow sustained miR-146b expression. Inspired by the probiotic Lactococcus lactis, which can produce extracellular vesicles (EVs) that carry a variety of biomolecules, we successfully constructed a genetically modified L. lactis strain that expresses miR-146b (LL-miR-146b) in a nisin-dependent manner and found that its administration eliminated intestinal inflammation in a murine IBD model. Furthermore, LL-miR-146b remodeled the proinflammatory microenvironment, enhanced the integrity of the intestinal barrier, and manipulated the gut microbiota. We then confirmed that the LL-miR-146b-induced reduction in intestinal inflammation was partially dependent on EVs that contained miR-146b, which modulated the activation of classically activated macrophages (M1 macrophages). Importantly, this treatment showed no significant systemic toxicity. In conclusion, we developed a safe and effective vector for IBD treatment by integrating a strategy for calming cytokine storms with biotherapy.