Transformable Dual‐Inhibition System Effectively Suppresses Renal Cancer Metastasis through Blocking Endothelial Cells and Cancer Stem Cells

• Published in: Small (Weinheim an der Bergstrasse, Germany) Germany), 2020-10, Vol.16 (40), p.e2004548-n/a
• Main Authors: Wang, Lu, Lv, Yulin, Li, Cong, Yang, Guang, Fu, Bo, Peng, Qiang, Jian, Lingrui, Hou, Dayong, Wang, Jiaqi, Zhao, Changhao, Yang, Peipei, Zhang, Kuo, Wang, Lei, Wang, Ziqi, Wang, Hao, Xu, Wanhai
• Format: Article
• Language: English
• Subjects: Angiogenesis; Cancer; cancer stem cells; Cell membranes; dual inhibition; Endothelial cells; Endothelium; Kidney cancer; Metastasis; Nanofibers; nanofibrous barriers; Nanotechnology; Nodules; Permeability; Receptors; Stem cells; Xenotransplantation
• ISSN: 1613-6810; 1613-6829
• DOI: 10.1002/smll.202004548

Tumor vasculature and cancer stem cells (CSCs) accelerate the development of metastatic renal cancer. Dual inhibition of vascular endothelium and CSCs is still a challenge due to their different pathological features. Herein, a transformable dual‐inhibition system (TDS) based on a self‐assembly peptide is proposed to construct nanofibrous barriers on the cell membrane in situ, which contributes to 1) reducing endothelial permeability and angiogenesis; and 2) inhibiting stemness and metastasis of CSCs in renal cancer. TDS specifically targets overexpressed receptor CD105 that provides the possibility to modulate both endothelial cells and CSCs for cancer therapy. Subsequently, owing to ligand—receptor interaction‐induced transformation, the nanofibers form a barrier on the cell membrane. For vascular endothelium, TDS reduces the vascular permeability to 67.0% ± 4.7% and decreases angiogenesis to 62.0% ± 4.0%, thereby preventing the renal cancer metastasis. For human‐derived CSCs, TDS inhibits stemness by reducing endogenic miR‐19b and its transportation via CSCs‐derived exosomes, which increases PTEN expression and consequently suppresses CSCs‐mediated metastasis. In patient‐derived xenograft mice, TDS significantly inhibits the tumorigenesis and angiogenesis. It also reduces the metastatic nodules in lung 5.0‐fold compared with the control group. TDS opens up a promising avenue for suppressing the metastasis of cancer. Metastatic renal cancer is highly vascularized and the abundant presence of cancer stem cells (CSCs) often leads to poor clinical outcome for patients. To inhibit this process, a transformable dual‐inhibition system based on self‐assembly peptide is proposed to in situ construct the nanofibers on both endothelium and CSC membranes simultaneously by targeting overexpressed CD105.