Honeysuckle-derived exosome-like nanovesicles ameliorate metabolic-associated fatty liver disease by modulating gut microbiota and its metabolites

Metabolic-associated fatty liver disease (MAFLD), a global health burden with limited therapeutic options beyond lifestyle changes, urgently needs novel strategies. We engineered&nbsp;exosome-like nanovesicles (HNVs)&nbsp;from dried honeysuckle (<em>Lonicera japonica</em>), exhibiting&nbsp;significantly more uniform size distribution than conventional herbal extracts&nbsp;and characteristic nanovesicle morphology. Orally delivered HNVs, enriched with bioactive metabolites,&nbsp;dramatically inhibited increased fat vacuoles, lipid droplet deposition, and collagen fibrosis in the livers of mice with MAFLD induced by high-fat diet (HFD). Mechanistically, HNVs orchestrate a dual gut-liver intervention:&nbsp;(1)&nbsp;Restoring gut barrier integrity, slashing serum LPS by 1.58-fold and quelling hepatic inflammation; (2)&nbsp;Remodeling gut microbiota&nbsp;to suppress bile salt hydrolase (BSH), elevating taurochenodeoxycholic acid (TCDCA) 2.07-fold. This microbial shift&nbsp;reprograms enterohepatic signaling by inhibiting the FXR-FGF15-FGFR4 axis, thereby&nbsp;boosting hepatic cholesterol catabolism via bile acid synthases.&nbsp;Critically, efficacy is strictly microbiota-dependent:&nbsp;abolished by antibiotics and&nbsp;fully transferable via fecal microbiota transplantation (FMT)&nbsp;from HNV-treated donors. Presenting the&nbsp;first natural nanovesicle platform that concurrently targets gut barrier repair and metabolic reprogramming, HNVs establish a&nbsp;pioneering, multi-targeted therapeutic paradigm&nbsp;for MAFLD, directly linking gut microbial ecology to hepatic pathophysiology with high translational potential.