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

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