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

Transmucosal drug administration represents a potential strategy for enhancing treatment efficacy and reducing side effects by avoiding the first-pass effect into the systemic circulation and delivering therapeutics directly to the target disease site. However, many challenges still remain in its clinical application, including low drug availability and limited retention time in the mucosa. The burgeoning advancement of nanotechnologies offers great potential to overcome the above limitations, leveraging their distinct advantages of high drug-loading capacity and strong permeability. In this review, the latest developments of nanoparticles (NPs) in transmucosal drug delivery as well as their clinical applications are discussed.