Biotechnology and Bioprocess Engineering 2024; 29(1): 97-108  
Targeted siRNA delivery to lung epithelia reduces airway inflammation in a mouse model of allergic asthma
Irfan Ullah1,2 · Hyo Sung Choi1 · Changseon Choi1,3 · Kunho Chung1,4 · Jae Wook Jung1 · Gyeongju Yun1 · Seoyoun Heo1 · Yujong Yi1 · Eunhwa Kang1 · Sang‑Heon Kim5 · Ho Joo Yoon5 · Taiyoun Rhim1 · Sang‑Kyung Lee1
1 Department of Bioengineering and Institute of Nanoscience and Technology, Hanyang University, Seoul 04763, Korea
2 Deparment of Internal Medicine, Yale University, New Haven, CT 06520, USA
3 Deptarment of Pharmacology, School of Medicine, Yale University, New Haven, CT 06520, USA
4 Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA
5 Department of Internal Medicine, Hanyang University School of Medicine, Seoul 04763, Korea
Correspondence to: Taiyoun Rhim
rhim@hanyang.ac.kr
Sang‑Kyung Lee
sangkyunglee@hanyang.ac.kr

Irfan Ullah and Hyo Sung Choi have contributed equally to this work.
Received: December 14, 2023; Revised: February 5, 2024; Accepted: February 6, 2024; Published online: February 21, 2024.
© The Korean Society for Biotechnology and Bioengineering. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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.
Keywords: Lung epithelial cells · Rabies virus glycoprotein · Airway inflammation · Asthma · Interleukin-4 receptor alpha · siRNA delivery


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