Attenuating endothelial leakiness with self-assembled DNA nanostructures for pulmonary arterial hypertension

作者全名："Liu, Qian; Wu, Di; He, Binfeng; Ding, Xiaotong; Xu, Yu; Wang, Ying; Zhang, Mingzhou; Qian, Hang; Leong, David Tai; Wang, Guansong"

作者地址："[Liu, Qian; Wu, Di; He, Binfeng; Ding, Xiaotong; Xu, Yu; Zhang, Mingzhou; Qian, Hang; Wang, Guansong] Third Mil Med Univ, Xinqiao Hosp, Inst Resp Dis, Chongqing 400037, Peoples R China; [Liu, Qian] Chongqing Med Univ, Lab Pharm & Chem, Chongqing 400016, Peoples R China; [Liu, Qian] Chongqing Med Univ, Management Ctr, Lab Tissue & Cell Biol, Lab Teaching, Chongqing 400016, Peoples R China; [Wang, Ying] Third Mil Med Univ, Xinqiao Hosp, Dept Cardiol, Chongqing 400037, Peoples R China; [Leong, David Tai] Natl Univ Singapore, Dept Chem & Biomol Engn, Singapore 117585, Singapore"

通信作者："Qian, H; Wang, GS (通讯作者)，Third Mil Med Univ, Xinqiao Hosp, Inst Resp Dis, Chongqing 400037, Peoples R China.; Leong, DT (通讯作者)，Natl Univ Singapore, Dept Chem & Biomol Engn, Singapore 117585, Singapore."

来源：NANOSCALE HORIZONS

ESI学科分类：Multidisciplinary

WOS号：WOS:000907181400001

JCR分区：Q1

影响因子：8

年份：2023

卷号：8

期号：2

开始页：270

结束页：278

文献类型：Article

关键词：　

摘要："Vascular endothelium dysfunction plays an important role in oncological and pulmonary diseases. Endothelial barrier dysfunction is the initial step of pulmonary vascular remodeling (PVR) and pulmonary arterial hypertension. Upregulation of a pro-autophagy protein Atg101 in the endothelial cells triggered a cascade of intracellular events that leads to endothelial dysfunction through apoptosis. Herein, we proposed a strategy that used endothelial targeting DNA nanostructures to deliver Atg101 siRNA (siAtg101) as a safe, biocompatible ""band-aid"" to restore pulmonary arterial endothelial barrier integrity within the intricate milieu of pulmonary cells and the pulmonary vasculature. The siAtg101 and aptamer conjugated DNA nanostructures were found to attenuate hypoxia-induced pulmonary endothelial leakiness with surprisingly high selectivity and efficacy. Further in vivo study revealed that functionalized DNA nanostructures likewise attenuated the vascular remodeling in a monocrotaline-induced PVR mouse model. Mechanistically, functionalized DNA nanostructures suppressed PVR by knocking down Atg101, which in turn, downregulated Beclin-1 and subsequently upregulated VE-cadherin to restore endothelial cells' adherin junctions. This work opened a new window for future nanomaterial design that directly addresses the interfacial endothelial cell layer that often stands between the blood and many diseased sites of nanotherapeutic interest."

基金机构："National Natural Science Foundation of China; Natural Science Foundation of Chongqing, China; [81670047]; [32071379]; [cstc2020jcyj-msxmX0622]; [cstc2021jcyj-msxmX1179]"

基金资助正文："This work is funded by the National Natural Science Foundation of China (81670047 and 32071379) and the Natural Science Foundation of Chongqing, China (No. cstc2020jcyj-msxmX0622, cstc2021jcyj-msxmX1179). Qian Liu and Di Wu contributed equally to this work."