Plant sterol ester-modified naringenin liposomes: A novel strategy for effectively penetrating the mucus barrier.

Liposomes (LPs) have attracted attention for their potential in oral drug delivery, including the delivery of compounds like naringenin (Nar), a flavonoid found in citrus fruits. However, they encounter obstacles when crossing the mucus and epithelial barriers of the gastrointestinal tract. Plant sterol esters (SE), beyond their antioxidant and immunomodulatory properties, demonstrate unique capabilities in modulating phospholipid bilayer characteristics. Herein, we have developed a Nar loaded SE-LP (SE-Nar-LP) utilizing SE as a cholesterol substitute to effectively overcome the obstacles faced by common LPs and to improve the effective delivery of Nar. SE-Nar-LP was prepared by ethanol injection with a particle size of 179.50 ± 3.96 nm and a polydispersion index of 0.22 ± 0.02. SE-Nar-LP was superior in drug loading and stability to cholesterol Nar liposome (CH-Nar-LP). Compared to CH-Nar-LP, SE-Nar-LP demonstrated superior drug loading and stability. Furthermore, SE-Nar-LP exhibited greater rigidity, which enhanced its ability to penetrate the mucus barrier more effectively. This increased rigidity favors rotational motion, facilitating both the avoidance of mucus diffusion and the prevention of epithelial absorption issues. In rat models, oral administration of SE-Nar-LP successfully bypassed both mucus and intestinal barriers, leading to a significant increase in the bioavailability of Nar compared to cholesterol-stabilized LPs. These findings suggest that SE can serve as an effective alternative to cholesterol for stabilizing LPs, influencing their biomechanical rigidity, and enhancing mucus penetration. SE-Nar-LP thus presents a promising strategy for overcoming the challenges of oral drug delivery.