Transporters are traditionally considered to transport small molecules rather than large-sized nanoparticles due to their small pores. In this study, we demonstrate that the upregulated intestinal transporter (PCFT), which reaches a maximum of 12.3-fold expression in the intestinal epithelial cells of diabetic rats, mediates the uptake of the folic acid-grafted nanoparticles (FNP). Specifically, the upregulated PCFT could exert its function to mediate the endocytosis of FNP and efficiently stimulate the traverse of FNP across enterocytes by the lysosome-evading pathway, Golgi-targeting pathway and basolateral exocytosis, featuring a high oral insulin bioavailability of 14.4% in the diabetic rats. Conversely, in cells with relatively low PCFT expression, the positive surface charge contributes to the cellular uptake of FNP, and FNP are mainly degraded in the lysosomes. Overall, we emphasize that the upregulated intestinal transporters could direct the uptake of ligand-modified nanoparticles by mediating the endocytosis and intracellular trafficking of ligand-modified nanoparticles via the transporter-mediated pathway. This study may also theoretically provide insightful guidelines for the rational design of transporter-targeted nanoparticles to achieve efficient drug delivery in diverse diseases.

As our ongoing research project on Ban Lan Gen (Isatis tinctoria roots), a total of 23 alkaloids were obtained. Compounds 1 and 2 contain an unusual C–C bond between the 2(1H)-quinolinone moiety and the phenol moiety and between the 2(1H)-quinolinone moiety and the 1H-indole moiety, respectively. Compound 3 possesses an unusual carbon skeleton and its putative biosynthetic pathway was discussed, and Compound 23 was deduced as a new indole alkaloid glycoside. Compounds 4–7 were identified as four new natural products by extensive spectroscopic experiments. Additionally, the anti-inflammatory activity was assessed based on nitric oxide (NO) production using Lipopolysaccharide-stimulated RAW264.7 macrophages. Compounds 9, 15, and 17 showed inhibitory effects with IC₅₀ values of 1.2, 5.0, and 74.4 μM.