Targeted siRNA delivery to lung epithelia reduces airway inflammation in a mouse model of allergic asthma

IF 2.5 4区 生物学 Q3 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Irfan Ullah, Hyo Sung Choi, Changseon Choi, Kunho Chung, Jae Wook Jung, Gyeongju Yun, Seoyoun Heo, Yujong Yi, Eunhwa Kang, Sang-Heon Kim, Ho Joo Yoon, Taiyoun Rhim, Sang-Kyung Lee
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Abstract

Asthma is a chronic inflammatory disease triggered by allergic reactions in the bronchia. These reactions lead to swelling of mucous membranes, hypersecretion of mucus, and bronchoconstriction, resulting in a restricted opening of the lung airway. Allergic pulmonary inflammation and airway hyperresponsiveness are induced when Th2 cytokines, such as interleukin (IL)-4 and IL-13, bind to their cognate receptors on lung epithelial cells. Specifically, IL-13 stimulates inflammation through a multi-subunit receptor, mainly the alpha chain of the IL-4 receptor (IL-4Rα), which also plays a role in IL-4 signaling. In this study, we employed a lung epithelial cell-targeting siRNA carrier composed of a rabies virus glycoprotein-derived small peptide coupled with cationic nona-arginine and trileucine before cysteine peptide (RVG9R3LC). This carrier was complexed with siRNA, enabling targeted delivery of therapeutic siRNA to IL-4Rα (siIL4Rα) expressed in lung epithelial cells within an asthma model in vivo. Our approach demonstrated efficient gene knockdown in cultured lung epithelial cells and in vivo. Furthermore, two administrations of therapeutic siIL4Rα protected the ovalbumin-sensitized and challenged asthma mouse model from airway inflammation and excessive mucus secretion. Our findings suggest that the peptide-siRNA carrier system presents a promising therapeutic approach for respiratory inflammation.

Graphical abstract

Abstract Image

在过敏性哮喘小鼠模型中,靶向 siRNA 运送到肺上皮细胞可减少气道炎症
哮喘是一种由支气管过敏反应引发的慢性炎症性疾病。这些反应会导致粘膜肿胀、粘液分泌过多和支气管收缩,从而导致肺部气道开放受限。当白细胞介素(IL)-4 和 IL-13 等 Th2 细胞因子与肺上皮细胞上的同源受体结合时,就会诱发过敏性肺部炎症和气道高反应性。具体来说,IL-13 通过多亚基受体(主要是 IL-4 受体(IL-4Rα)的α链)刺激炎症,而α链也在 IL-4 信号转导中发挥作用。在这项研究中,我们采用了一种肺上皮细胞靶向 siRNA 载体,该载体由狂犬病毒糖蛋白衍生的小肽与阳离子壬精氨酸和半胱氨酸前三亮氨酸肽(RVG9R3LC)组成。这种载体与 siRNA 复合物结合,可将治疗用 siRNA 靶向递送至体内哮喘模型肺上皮细胞中表达的 IL-4Rα(siIL4Rα)。我们的方法在培养的肺上皮细胞和体内都能有效地敲除基因。此外,治疗性 siIL4Rα 的两次给药保护了卵清蛋白致敏和挑战性哮喘小鼠模型,使其免受气道炎症和粘液分泌过多的影响。我们的研究结果表明,多肽-siRNA 载体系统是治疗呼吸道炎症的一种很有前景的方法。
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来源期刊
Biotechnology and Bioprocess Engineering
Biotechnology and Bioprocess Engineering 工程技术-生物工程与应用微生物
CiteScore
5.00
自引率
12.50%
发文量
79
审稿时长
3 months
期刊介绍: Biotechnology and Bioprocess Engineering is an international bimonthly journal published by the Korean Society for Biotechnology and Bioengineering. BBE is devoted to the advancement in science and technology in the wide area of biotechnology, bioengineering, and (bio)medical engineering. This includes but is not limited to applied molecular and cell biology, engineered biocatalysis and biotransformation, metabolic engineering and systems biology, bioseparation and bioprocess engineering, cell culture technology, environmental and food biotechnology, pharmaceutics and biopharmaceutics, biomaterials engineering, nanobiotechnology, and biosensor and bioelectronics.
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