Targeted colonic delivery of AET-1 encapsulated in hydrogel-liposome microspheres ameliorates NAFLD through modulation of the gut microbiota

To overcome the poor bioavailability of AET-1, a bioactive compound from Brassica rapa L., we developed a food-grade colon-targeted delivery system (AET-1 A) to treat non-alcoholic fatty liver disease (NAFLD). AET-1 was encapsulated into liposomes and embedded within pH-responsive alginate-hyaluronic acid microspheres. Efficacy and mechanisms were evaluated using a high-fat diet (HFD)-induced mouse model, HepG2 cells, 16S rRNA sequencing, and metabolomics. In vitro digestion confirmed colonic targeted release. Notably, AET-1 A lacked direct lipid-lowering effects in isolated HepG2 cells but significantly reduced hepatic steatosis, oxidative stress, and inflammation in HFD-fed mice. Multi-omics analyses revealed that AET-1 A restored hepatic metabolic homeostasis (including bile acids and vitamins) and remodeled gut microbiota, specifically enriching Akkermansia muciniphila and elevating fecal acetate. AET-1 A ameliorates NAFLD primarily via microbiome modulation and the gut-liver axis, providing a novel targeted nutraceutical strategy for metabolic disorders.