Transferrin Functionization Elevates Transcytosis of Nanogranules across Epithelium by Triggering Polarity-Associated Transport Flow and Positive Cellular Feedback Loop
Transferrin Functionization Elevates Transcytosis of Nanogranules across Epithelium by Triggering Polarity-Associated Transport Flow and Positive Cellular Feedback Loop
复制标题
转铁蛋白功能化通过触发极性相关的传输流和正细胞反馈环来提高纳米颗粒跨上皮的转胞吞作用
DOI：
10.1021/acsnano.8b07231
复制
发表时间：
2019-05-01
期刊：
影响因子：
17.1
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Yang, Dan;Liu, Dechun;Zhang, Qiang
克服上皮屏障以增强药物转运是胃肠道、气管内、鼻腔、阴道和宫内分娩的一个重点主题。具有靶向功能的纳米药物通过特定的配体受体相互作用促进了这一过程。然而，与靶向纳米疗法的细胞摄取相比，目前很少有研究集中在它们的跨细胞作用上，包括内吞作用和胞吐作用。事实上，这些途径的细胞调控机制以及配体对跨细胞作用的作用原理几乎被忽略了。在这里，我们制备了转铁蛋白功能化纳米颗粒(TF-NG)作为纳米医学模型，并证实了两种上皮模型(Caco-2细胞的双极性和MDCK细胞的单极性)中TF受体(TFR)的极性分布的差异。与非特异性参照物相比，在两种细胞模型中，TF偶联通过不同的途径促进胞吞作用，并改变了两种细胞中TF-NG的胞内途径，影响胞吐、循环和降解，但不影响分泌途径。只有双极细胞才能建立从“内”到“外”的完整转运流，导致TF-NG的跨细胞作用增强。重要的是，上皮细胞可以对TF-NG的转胞反应产生反应。在定量蛋白质组学的基础上，Ting的细胞内转运改变了蛋白质表达谱，其中内吞和跨细胞相关蛋白特异性上调。特别是，只有双极细胞才能通过加速随后的TF-NG跨细胞转运而正向反馈这种转运。在此，Tf-NG的所有细胞转运都是极性相关的。综上所述，TF修饰通过触发与极性相关的运输流和正细胞反馈环，增加了TF-NG跨上皮细胞的转运。这些发现为靶向纳米递送有效地通过上皮屏障提供了洞察力。
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 TING altered the protein expression profiles, in which the endocytosis-and transcytosis-related proteins were specifically upregulated. Particularly, only bipolar cells could positively feed back to such trafficking via accelerating the subsequent Tf-NG transcytosis. Here, all the cell transport of Tf-NG was polarity associated. In summary, Tf modification elevated the transcytosis of Tf-NG across the epithelium by triggering the polarity-associated transport flow and positive cell feedback loop. These findings provided an insight into the targeting nanodelivery for efficient transport through epithelial barriers.