Supramolecular engineering of a ferulic acid-puerarin co-amorphous system via intermolecular hydrogen bonding: Mechanism, enhanced bioavailability, and synergistic lipid-lowering efficacy.

Hyperlipidemia poses a major cardiovascular threat requiring safe, long-term therapies. Ferulic acid (FA) and Puerarin (PUE), "medicine-food homology" compounds with synergistic lipid-lowering effects, suffer from poor physicochemical properties and low bioavailability. Here, we engineered a novel FA-PUE co-amorphous system (COA) via supramolecular assembly. PXRD and DSC confirmed amorphous phase formation, while molecular dynamics simulations and FT-IR revealed stabilization through intermolecular hydrogen bonds (C=O···H-O) between FA's carbonyl and PUE's hydroxyl groups. The COA exhibited significantly enhanced solubility, dissolution rate, membrane permeability, and antioxidant capacity compared to crystalline drugs. In vivo pharmacokinetics showed 2.32-fold and 2.21-fold increases in oral bioavailability of FA and PUE, respectively. Evaluation in cellular lipid-overload models and high-fat diet-induced hyperlipidemic rats demonstrated that COA markedly reduced lipid accumulation and alleviated hepatic steatosis. This study highlights supramolecular engineering's potential to enhance therapeutic efficacy of food-derived bioactives for cardiovascular disease management.