Punicic acid ethyl ester, a superior absorption-enhancer over pomegranate seed oil, dramatically improves quercetin bioavailability via strong interaction and rapid lipolysis

Low oral bioavailability remains a major challenge for drug delivery. Fatty acids (FAs) and vegetable oils have attracted great interest as absorption enhancers due to their excellent compatibility. However, the difference in absorption-enhancing efficiency of various FA chemical forms and the underlying mechanisms remain unclear. In vegetable oils, FAs are confined within rigid triglyceride structures, whereas free FAs or their monoesters possess flexible carbon chains. We hypothesize that such molecular flexibility facilitates stronger drug interactions, resulting in greater absorption-enhancing capacity for FAs or their monoesters compared with parent oils. To validate this, punicic acid (PA) was isolated from pomegranate seed oil (PSO) and converted into its ethyl ester (PAEE). Employing quercetin (QU) as the model drug and oleic acid (OA) as a control, we systematically evaluated the effect of PAEE, PSO, OA, and their nanoemulsions (NE) on QU physiochemical characteristics. In vitro , the antibacterial activity followed the order of QU-PAEE > QU-PSO > QU-OA > QU. Among the oils, PAEE showed strongest protection on QU in gastrointestinal fluid, the greatest interaction with QU, and significantly faster lipolysis than PSO. NE formulations further amplified these effects. In vivo , PAEE, PSO, and OA increased QU oral bioavailability by 4.57-, 3.49-, and 3.07- fold, respectively, whereas their NE achieved 20.66-, 6.42-, and 6.19- fold increases. This study identifies PAEE as a highly efficient and safe absorption-enhancer and, more importantly, demonstrates that FA monoesters present markedly stronger absorption-enhancing efficiency than their parent oils, providing new insights for the design of lipid-based drug carriers. • PAEE outperforms parent oil as a potent absorption enhancer for drug delivery. • PAEE's efficacy stems from its long, flexible hydrophobic chain. • PAEE's chain improved QU protection and accelerates lipolysis. • PAEE NE enhanced QU oral bioavailability by 20.7- fold. • PAEE exhibited superior antibacterial activity over PSO and OA.