Transferrin Functionization Elevates Transcytosis of Nanogranules across Epithelium by Triggering Polarity-Associated Transport Flow and Positive Cellular Feedback Loop

作者：Dan Yang, Dechun Liu, Hailiang Deng, Jian Zhang, Mengmeng Qin, Lan Yuan, Xiajuan Zou, Bin Shao, Huiping Li, Wenbing Dai, Hua Zhang, Xueqing Wang, Bing He, Xing Tang, Qiang Zhang · 发表于：ACS Nano · 年份：2019 · DOI：10.1021/acsnano.8b07231 · 被引用次数：72 · 研究领域：Nanocluster Synthesis and Applications、Nanoparticle-Based Drug Delivery、Gold and Silver Nanoparticles Synthesis and Applications

Overcoming the epithelial barriers to enhance drug transport is a focused topic for gastrointestinal, intratracheal, intranasal, vaginal, and intrauterine delivery. Nanomedicines with targeting functionization promote such a process owing to specific ligand-receptor interaction. However, compared to the cell uptake of targeting nanotherapies, currently few studies concentrate on their transcytosis including endocytosis for "in" and exocytosis for "out". In fact, the cellular regulatory mechanism for these pathways as well as the principle of ligand's effect on the transcytosis are almost ignored. Here, we fabricated transferrin (Tf) functionalized nanogranules (Tf-NG) as the nanomedicine model and confirmed the difference in polar distributions of Tf receptors (TfRs) between two epithelium models (bipolarity for Caco-2 and unipolarity for MDCK cells). Compared to the nonspecific reference, Tf-conjugation boosted the endocytosis by different pathways in two cell models and transformed the intracellular route of Tf-NG in both cells differently, affecting exocytosis, recycling, and degradation but not the secretion pathway. Only bipolar cells could establish a complete transport flow from "in" to "out", leading to the enhanced transcytosis of Tf-NG. Importantly, epithelia could make responses to Tf-NG transcytosis. Based on the quantitative proteomics, the intracellular trafficking of Tf-NG altered the protein expression profiles, in which the endocytosis- and transcytosis-relat...