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.

由于它们的小孔，转运蛋白传统上被认为是运输小分子而不是大尺寸的纳米颗粒。在这项研究中，我们证明了在糖尿病大鼠肠上皮细胞中表达最多 12.3 倍的上调肠道转运蛋白 (PCFT) 介导了叶酸接枝纳米粒子 (FNP) 的摄取。具体而言，上调的 PCFT 可发挥其介导 FNP 内吞作用的功能，并通过溶酶体逃避途径、高尔基体靶向途径和基底外侧胞吐作用有效刺激 FNP 穿过肠细胞，其口服胰岛素生物利用度高达 14.4%。糖尿病大鼠。相反，在 PCFT 表达相对较低的细胞中，正表面电荷有助于细胞摄取 FNP，FNP 主要在溶酶体中降解。总的来说，我们强调上调的肠道转运蛋白可以通过介导配体修饰的纳米颗粒的内吞作用和细胞内运输来指导配体修饰的纳米颗粒的摄取。通过转运蛋白介导的途径。该研究还可以在理论上为转运蛋白靶向纳米粒子的合理设计提供有见地的指导，以实现在多种疾病中的有效药物递送。