Colon-Targeted astragalus polysaccharide nanoparticles prevent NAFLD-Driven hepatocarcinogenesis via microbiota remodeling and NF-κB Inhibition.

Hepatocellular carcinoma (HCC), often arising from liver fibrosis in nonalcoholic fatty liver disease (NAFLD), remains a leading cause of cancer-related death. Targeting the gut-liver axis offers new therapeutic opportunities to prevent this progression. In this study, colon-targeted chitosan/pectin-based nanoparticles loaded with Astragalus polysaccharide (APs-CS/PT-NPs) were developed to modulate gut microbiota and inhibit liver tumorigenesis. The nanoparticles exhibited robust physicochemical stability and pH-responsive release. In vivo, oral administration of APs-CS/PT-NPs attenuated hepatic steatosis, reduced inflammatory cytokines, and suppressed NAFLD-induced HCC development. 16 S rRNA sequencing revealed restoration of microbial diversity and enhanced production of short-chain fatty acids, especially acetate. Mechanistically, transcriptomic profiling and functional analysis identified acetate as a key mediator, acting via G-protein-coupled receptor 43 (GPR43) to inhibit the NF-κB pathway. These results highlight the therapeutic potential of APs-CS/PT-NPs in modulating the gut-liver axis, rebalancing intestinal microbiota, and suppressing pro-inflammatory signaling. This nanoparticle-based strategy offers a promising food-derived preventive intervention for liver fibrosis-HCC transition.