利用基于外泌体的纳米支架特异性递送 siRNA 以治疗 IPF

IF 10.7 1区 医学 Q1 PHARMACOLOGY & PHARMACY Asian Journal of Pharmaceutical Sciences Pub Date : 2024-08-01 DOI:10.1016/j.ajps.2024.100929
{"title":"利用基于外泌体的纳米支架特异性递送 siRNA 以治疗 IPF","authors":"","doi":"10.1016/j.ajps.2024.100929","DOIUrl":null,"url":null,"abstract":"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that leads to interstitial inflammation, lung damage, and eventually life-threatening complications. Among various pathologic factors, Smad4 is a pivotal molecule involved in the progression and exacerbation of IPF. It mediates nuclear transfer of Smad2/Smad3 complexes and initiates the transcription of fibrosis-promoting genes. Thus, the inhibition of Smad4 expression in pulmonary fibroblasts by small interfering RNAs (siRNAs) might be a promising therapeutic strategy for IPF. Herein, we engineered exosome membranes (EM) by cationic lipid (<em>i.e.</em>, DOTAP) to load siRNAs against Smad4 (DOTAP/siSmad4@EM), and investigated their specific delivery to pulmonary fibroblasts for treating IPF in a mouse model <em>via</em> pulmonary administration. As reference nanoscaffolds, undecorated DOTAP/siSmad4 complexes (lipoplexes, consisting of cationic lipid DOTAP and siRNAs) and siSmad4-loaded lipid nanoparticles (DOTAP/siSmad4@lipo, consisting of lipoplexes fused with DPPC<img>Chol liposomes) were also prepared. The results showed that DOTAP/siSmad4@EM exhibited a higher cellular uptake and gene silencing efficacies in mouse pulmonary fibroblasts (<em>viz.</em>, MLg2908) as compared to the two reference nanoscaffolds. Furthermore, the outcomes of the <em>in vivo</em> experiments illustrated that DOTAP/siSmad4@EM could significantly down-regulate the Smad4 expression with augmented anti-fibrosis efficiency. Additionally, the DOTAP/siSmad4@EM conferred excellent biocompatibility with low cytokine levels in bronchoalveolar lavage fluid and proinflammatory responses in the pulmonary area. Taken together, the outcomes of our investigation imply that specific inhibition of Smad4 expression in pulmonary fibroblasts by pulmonary administrated DOTAP/siSmad4@EM is a promising therapeutic strategy for IPF, which could safely and effectively deliver siRNA drugs to the targeted site of action.</p></div>","PeriodicalId":8539,"journal":{"name":"Asian Journal of Pharmaceutical Sciences","volume":"19 4","pages":"Article 100929"},"PeriodicalIF":10.7000,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1818087624000461/pdfft?md5=c53e6242f3910800eeaba53cccde0449&pid=1-s2.0-S1818087624000461-main.pdf","citationCount":"0","resultStr":"{\"title\":\"Pulmonary fibroblast-specific delivery of siRNA exploiting exosomes-based nanoscaffolds for IPF treatment\",\"authors\":\"\",\"doi\":\"10.1016/j.ajps.2024.100929\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that leads to interstitial inflammation, lung damage, and eventually life-threatening complications. Among various pathologic factors, Smad4 is a pivotal molecule involved in the progression and exacerbation of IPF. It mediates nuclear transfer of Smad2/Smad3 complexes and initiates the transcription of fibrosis-promoting genes. Thus, the inhibition of Smad4 expression in pulmonary fibroblasts by small interfering RNAs (siRNAs) might be a promising therapeutic strategy for IPF. Herein, we engineered exosome membranes (EM) by cationic lipid (<em>i.e.</em>, DOTAP) to load siRNAs against Smad4 (DOTAP/siSmad4@EM), and investigated their specific delivery to pulmonary fibroblasts for treating IPF in a mouse model <em>via</em> pulmonary administration. As reference nanoscaffolds, undecorated DOTAP/siSmad4 complexes (lipoplexes, consisting of cationic lipid DOTAP and siRNAs) and siSmad4-loaded lipid nanoparticles (DOTAP/siSmad4@lipo, consisting of lipoplexes fused with DPPC<img>Chol liposomes) were also prepared. The results showed that DOTAP/siSmad4@EM exhibited a higher cellular uptake and gene silencing efficacies in mouse pulmonary fibroblasts (<em>viz.</em>, MLg2908) as compared to the two reference nanoscaffolds. Furthermore, the outcomes of the <em>in vivo</em> experiments illustrated that DOTAP/siSmad4@EM could significantly down-regulate the Smad4 expression with augmented anti-fibrosis efficiency. Additionally, the DOTAP/siSmad4@EM conferred excellent biocompatibility with low cytokine levels in bronchoalveolar lavage fluid and proinflammatory responses in the pulmonary area. Taken together, the outcomes of our investigation imply that specific inhibition of Smad4 expression in pulmonary fibroblasts by pulmonary administrated DOTAP/siSmad4@EM is a promising therapeutic strategy for IPF, which could safely and effectively deliver siRNA drugs to the targeted site of action.</p></div>\",\"PeriodicalId\":8539,\"journal\":{\"name\":\"Asian Journal of Pharmaceutical Sciences\",\"volume\":\"19 4\",\"pages\":\"Article 100929\"},\"PeriodicalIF\":10.7000,\"publicationDate\":\"2024-08-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1818087624000461/pdfft?md5=c53e6242f3910800eeaba53cccde0449&pid=1-s2.0-S1818087624000461-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Asian Journal of Pharmaceutical Sciences\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1818087624000461\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Asian Journal of Pharmaceutical Sciences","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1818087624000461","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0

摘要

特发性肺纤维化(IPF)是一种进行性肺部疾病,会导致肺间质炎症、肺损伤,最终引发危及生命的并发症。在各种病理因素中,Smad4 是参与 IPF 进展和恶化的关键分子。它介导 Smad2/Smad3 复合物的核转移,并启动纤维化促进基因的转录。因此,通过小干扰 RNAs(siRNAs)抑制肺成纤维细胞中 Smad4 的表达可能是治疗 IPF 的一种有前景的策略。在此,我们用阳离子脂质(即 DOTAP)设计了外泌体膜 (EM),以装载针对 Smad4 的 siRNAs(DOTAP/siSmad4@EM),并研究了通过肺部给药将其特异性地输送到肺成纤维细胞以治疗小鼠模型中的 IPF。作为参考纳米支架,还制备了未装饰的 DOTAP/siSmad4 复合物(lipoplexes,由阳离子脂质 DOTAP 和 siRNA 组成)和 siSmad4 负载脂质纳米颗粒(DOTAP/siSmad4@lipo,由与 DPPCChol 脂质体融合的 lipoplexes 组成)。结果表明,与两种参考纳米支架相比,DOTAP/siSmad4@EM在小鼠肺成纤维细胞(即MLg2908)中表现出更高的细胞吸收率和基因沉默效率。此外,体内实验结果表明,DOTAP/siSmad4@EM 能显著下调 Smad4 的表达,提高抗纤维化效率。此外,DOTAP/siSmad4@EM 还具有良好的生物相容性,支气管肺泡灌洗液中的细胞因子水平和肺部的促炎反应较低。综上所述,我们的研究结果表明,通过肺部给药 DOTAP/siSmad4@EM 特异性抑制肺成纤维细胞中 Smad4 的表达是治疗 IPF 的一种很有前景的策略,它可以安全有效地将 siRNA 药物输送到靶向作用位点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
Pulmonary fibroblast-specific delivery of siRNA exploiting exosomes-based nanoscaffolds for IPF treatment

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease that leads to interstitial inflammation, lung damage, and eventually life-threatening complications. Among various pathologic factors, Smad4 is a pivotal molecule involved in the progression and exacerbation of IPF. It mediates nuclear transfer of Smad2/Smad3 complexes and initiates the transcription of fibrosis-promoting genes. Thus, the inhibition of Smad4 expression in pulmonary fibroblasts by small interfering RNAs (siRNAs) might be a promising therapeutic strategy for IPF. Herein, we engineered exosome membranes (EM) by cationic lipid (i.e., DOTAP) to load siRNAs against Smad4 (DOTAP/siSmad4@EM), and investigated their specific delivery to pulmonary fibroblasts for treating IPF in a mouse model via pulmonary administration. As reference nanoscaffolds, undecorated DOTAP/siSmad4 complexes (lipoplexes, consisting of cationic lipid DOTAP and siRNAs) and siSmad4-loaded lipid nanoparticles (DOTAP/siSmad4@lipo, consisting of lipoplexes fused with DPPCChol liposomes) were also prepared. The results showed that DOTAP/siSmad4@EM exhibited a higher cellular uptake and gene silencing efficacies in mouse pulmonary fibroblasts (viz., MLg2908) as compared to the two reference nanoscaffolds. Furthermore, the outcomes of the in vivo experiments illustrated that DOTAP/siSmad4@EM could significantly down-regulate the Smad4 expression with augmented anti-fibrosis efficiency. Additionally, the DOTAP/siSmad4@EM conferred excellent biocompatibility with low cytokine levels in bronchoalveolar lavage fluid and proinflammatory responses in the pulmonary area. Taken together, the outcomes of our investigation imply that specific inhibition of Smad4 expression in pulmonary fibroblasts by pulmonary administrated DOTAP/siSmad4@EM is a promising therapeutic strategy for IPF, which could safely and effectively deliver siRNA drugs to the targeted site of action.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Asian Journal of Pharmaceutical Sciences
Asian Journal of Pharmaceutical Sciences Pharmacology, Toxicology and Pharmaceutics-Pharmaceutical Science
CiteScore
18.30
自引率
2.90%
发文量
11
审稿时长
14 days
期刊介绍: The Asian Journal of Pharmaceutical Sciences (AJPS) serves as the official journal of the Asian Federation for Pharmaceutical Sciences (AFPS). Recognized by the Science Citation Index Expanded (SCIE), AJPS offers a platform for the reporting of advancements, production methodologies, technologies, initiatives, and the practical application of scientific knowledge in the field of pharmaceutics. The journal covers a wide range of topics including but not limited to controlled drug release systems, drug targeting, physical pharmacy, pharmacodynamics, pharmacokinetics, pharmacogenomics, biopharmaceutics, drug and prodrug design, pharmaceutical analysis, drug stability, quality control, pharmaceutical engineering, and material sciences.
期刊最新文献
Extracellular vesicle-functionalized bioactive scaffolds for bone regeneration Recent advances in spatio-temporally controllable systems for management of glioma Deep near infrared light-excited stable synergistic photodynamic and photothermal therapies based on P-IR890 nano-photosensitizer constructed via a non-cyanine dye Electrostatic spraying for fine-tuning particle dimensions to enhance oral bioavailability of poorly water-soluble drugs Metal-organic frameworks in oral drug delivery
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1