Oral co-delivery of quercetin and anthocyanins via dual-ligand nanoparticles alleviate obesity and associated metabolic disorders.

Obesity is a global epidemic driven in part by poor oral bioavailability of bioactive food compounds. Here, we develop dual-ligand-functionalized nanoparticles (NPs) for the oral co-delivery of hydrophilic anthocyanins (ACN) and hydrophobic quercetin (Que) to combat obesity. The system is assembled from lactobionic acid-modified chitosan (LACS) and glycyrrhetinic acid-modified casein (GACA), forming a core-shell structure that protects both compounds against gastrointestinal degradation and affords pH-responsive colloidal stability. In Caco-2/HT29-MTX-E12 co-culture models, the LACS-ACN-GACA-Que NPs enhance intestinal absorption via energy-dependent endocytosis, facilitate transcellular transport, and achieve sustained intracellular accumulation. Orally administered to high-fat diet-induced obese mice, the NPs surpass both the unencapsulated bioactive mixture and the clinical drug atorvastatin in reducing body weight gain, white adipose tissue hypertrophy, hepatic steatosis, and systemic inflammation. These anti-obesity benefits are accompanied by favorable gut microbiota remodeling: enrichment of short-chain fatty acid-producing taxa (Oscillospiraceae, Ruminococcaceae, Lachnospiraceae) and suppression of pro-inflammatory lineages (Erysipelotrichaceae). Collectively, this dual-ligand strategy establishes a versatile oral delivery platform that protects and synergistically delivers disparate bioactive compounds, offering a promising approach for obesity management.