Targeted Dual Small Interfering Ribonucleic Acid Delivery via Non‐Viral Polymeric Vectors for Pulmonary Fibrosis Therapy,Advanced Materials

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Targeted Dual Small Interfering Ribonucleic Acid Delivery via Non‐Viral Polymeric Vectors for Pulmonary Fibrosis Therapy
Advanced Materials ( IF 27.4 ) Pub Date : 2021-02-19 , DOI: 10.1002/adma.202007798
Qijian Ji _{1,

2} , Jiwei Hou _{3,

4} , Xueqing Yong ₅ , Guangming Gong ₆ , Mohd Muddassir ₇ , Tianyu Tang ₈ , Jinbing Xie ₈ , Wenpei Fan ₉ , Xiaoyuan Chen ₁₀

Affiliation

Department of Critical Care Medicine, Xuyi People's Hospital, 28 Hongwu Road, Xuyi, Huai'an, Jiangsu, 211700, China.
Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China.
Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
Department of Nuclear Science & Technology, Nanjing University of Aeronautics and Astronautics, Nanjing, Jiangsu, 211106, China.
Department of Pharmaceutics, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210002, China.
Department of Chemistry, College of Science, King Saud University, Riyadh, 11451, Saudi Arabia.
Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, 87 Dingjiaqiao Road, Nanjing, Jiangsu, 210009, China.
State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Advanced Pharmaceuticals and Biomaterials, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore, 119228, Singapore.

Inhibiting the myofibroblast differentiation of lung‐resident mesenchymal stem cells (LR‐MSCs) is a promising yet challenging approach for pulmonary fibrosis (PF) therapy. Here, micelles formed by a graft copolymer of multiple PEGs modified branched polyethylenimine are used for delivering runt‐related transcription factor‐1 (RUNX1) small interfering RNA (siRNA) (siRUNX1) to the lung, aiming to inhibit the myofibroblast differentiation of LR‐MSCs. LR‐MSC targeting is achieved by functionalizing the micelle surface with an anti‐stem‐cell antigen‐1 antibody fragment (Fab′). Consequently, therapeutic benefits are obtained by successful suppression of myofibroblast differentiation of LR‐MSCs in bleomycin‐induced PF model mice treated with siRUNX1‐loaded micelles. Furthermore, an excellent synergistic effect of PF therapy is achieved for this micelle system loaded siRUNX1 and glioma‐associated oncogene homolog‐1 (Gli1) small interfering RNA (siGli1), a traditional anti‐PF siRNA of glioma‐associated oncogene homolog‐1. Hence, this work not only provides RUNX1 as a novel PF therapeutic target, but also as a promising dual siRNA‐loaded nanocarrier system for the therapy of PF.

中文翻译：

通过非病毒聚合载体靶向双小干扰核糖核酸递送用于肺纤维化治疗

抑制肺驻留间充质干细胞（LR-MSC）的肌成纤维细胞分化是肺纤维化（PF）治疗的一种有前途但具有挑战性的方法。在这里，由多个 PEG 修饰的支链聚乙烯亚胺的接枝共聚物形成的胶束用于将 runt 相关转录因子 1 (RUNX1) 小干扰 RNA (siRNA) (siRUNX1) 传递到肺部，旨在抑制 LR- 的肌成纤维细胞分化。间充质干细胞。 LR-MSC 靶向是通过使用抗干细胞抗原 1 抗体片段 (Fab') 功能化胶束表面来实现的。因此，在用 siRUNX1 负载的胶束治疗的博莱霉素诱导的 PF 模型小鼠中，通过成功抑制 LR-MSC 的肌成纤维细胞分化，可以获得治疗益处。此外，这种装载siRUNX1和胶质瘤相关癌基因同源物-1（Gli1）小干扰RNA（siGli1）的胶束系统实现了PF治疗的优异协同效应，小干扰RNA（siGli1）是胶质瘤相关癌基因同源物-1的传统抗PF siRNA。因此，这项工作不仅将RUNX1作为一种新型PF治疗靶点，而且作为一种有前景的双siRNA负载纳米载体系统用于治疗PF。

更新日期：2021-03-23

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