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
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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。

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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.

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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.
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