Abstract Wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles (WGA-LPNs) promote cellular uptake after oral delivery via receptor-mediated endocytosis and bioadhesion. Understanding the mucosal transport of WGA-LPNs would help to improve bioavailability and ensure therapeutic efficacy. In this study, WGA-LPNs interacted with mucin, forming larger agglomerates with intact core-shell structure. The interaction of WGA-LPNs with mucin improved enterocyte endocytosis in Caco-2 cells. An in situ intestinal diffusion study in mice confirmed that WGA-LPNs reached enterocytes and underwent endocytosis, despite interference from mucin. Importantly, oral bioavailability of oridonin-loaded WGA-LPNs increased by 1.96-fold compared with that of LPNs. Furthermore, oral administration of WGA-LPNs inhibited tumor growth in HepG2 xenograft nude mice. In addition to elucidating interactions between WGA-LPNs and mucin, these results indicated WGA-LPNs might act as promising nanocarriers for oral delivery of drugs.