Brucea javanica-Derived Natural Lipid Droplets: Selective Oral Lymph Targeting and Endocytic Transport Mechanisms

Background: Brucea javanica oil (BJO) suffers from poor oral bioavailability due to oxidative degradation and hepatic first-pass effect. Methods: Here, we report a one-step, solvent-free isolation of endogenous Brucea javanica lipid droplets (BJLDs) that function as a "drug-in-carrier" delivery platform. Results: BJLDs exhibited a uniform size distribution and superior oxidative stability. In vitro digestion showed 80% long-chain fatty acids released within 4 h following first-order kinetics. Caco-2 transport studies revealed caveolin-dependent endocytosis as the dominant uptake route and a 2.3-fold increase in rhodamine 123 accumulation versus free drug, indicating potent P-gp inhibition. A cycloheximide-blocked rat model quantified the intestinal lymphatic transport rate at 89.73%. Plasma t_1/2 and MRT of linoleic acid were 8.44 ± 3.16 h and 11.45 ± 2.72 h, respectively. LC-MS/MS confirmed retention of brusatol and bruceine inside BJLDs. Conclusions: This study provides direct evidence that micron-sized lipid droplets derived from plants can achieve >80% lymphatic targeting after oral administration, offering a green and scalable alternative to conventional BJO formulations.