Lymph-Targeted Delivery of CUR-NLCs Enhances Oral Bioavailability: Evidence from a Double-Catheterized Rat Model

Background/Objectives: Curcumin (CUR), a natural polyphenol with poor solubility and significant first-pass metabolism, shows extremely low oral bioavailability. Although CUR-loaded nanostructured lipid carriers (CUR-NLCs) have demonstrated potential in enhancing oral absorption, direct evidence regarding their intestinal lymphatic transport mechanism remains insufficient, and current understanding largely relies on indirect speculation. Methods: CUR-NLCs were prepared by emulsion-ultrasonication and evaluated for their physicochemical properties including particle size, zeta potential, polydispersity index, encapsulation efficiency, drug loading, stability and release profile. A mesenteric lymph duct-jugular vein shunt rat model combined with transmission electron microscopy was employed to assess the pharmacokinetic behavior and lymphatic transport pathway. Results: CUR-NLCs had a mean size of 117.28 ± 1.32 nm, 99.99% encapsulation efficiency, and 1.73% drug loading. They exhibited good gastrointestinal stability and sustained release (<55% in 24 h). CUR-NLCs significantly enhanced oral absorption versus free CUR, with 5.13-fold higher relative bioavailability, 5.25-fold greater Cmax, and extended half-life (33.49 ± 3.15 h). CUR was detected only in the lymph of the CUR-NLCs group, confirming intestinal lymphatic transport. TEM revealed abundant chylomicrons (0.1–2 μm) in jejunal epithelial cells, providing morphological support. Conclusions: This study directly demonstrates that CUR-NLCs improve oral bioavailability via intestinal lymphatic absorption, offering a viable strategy for delivering poorly soluble hydrophobic drugs.