Sonogenetic Control of Engineered Probiotics for the Treatment of MASH by Modulating the Gut‐Liver Axis

ABSTRACT Metabolic dysfunction‐associated steatohepatitis (MASH) currently lacks effective targeted therapeutics, while interleukin‐22 (IL‐22) as a potential treatment approach faces challenges in the clinical translation due to off‐target risks associated with systemic delivery. To address this limitation, we developed an intelligent oral biologics platform centered on an engineered probiotic strain ( Escherichia coli Nissle 1917) capable of producing therapeutic IL‐22 in situ, encapsulated within an inulin hydrogel to resist gastric degradation. Critically, we integrated a sonogenetic control module that enables non‐invasive, spatiotemporally precise activation of IL‐22 expression in the gut via remote ultrasound stimulation. In MASH model, this targeted, on‐demand IL‐22 delivery effectively remodeled the gut microbiota and improved intestinal barrier function. This led to significantly reduced portal lipopolysaccharide (LPS) levels, which in turn decreased hepatic IL‐6 production. Mechanistically, this strategy inhibited the pathological overactivation of the PI3K‐AKT‐mTOR signaling pathway, thereby markedly ameliorating hepatic steatosis, inflammation, and fibrosis. Notably, by confining IL‐22 production to the gut, this strategy completely circumvented the off‐target effects of conventional IL‐22 therapy. We observed reversal of MASH‐associated cognitive impairment, highlighting systemic benefits of restoring gut‐liver axis homeostasis. This study establishes a transformative, multi‐beneficial MASH therapy paradigm by modulating the gut‐liver axis, offering a safe, effective, clinically translatable strategy.