Cystic fibrosis (CF) results from mutations in the chloride-conducting CF transmembrane conductance regulator (CFTR) gene. Airway dehydration and impaired mucociliary clearance in CF is proposed to result in tonic epithelial sodium channel (ENaC) activity, which drives amiloride-sensitive electrogenic sodium absorption. Decreasing sodium absorption by inhibiting ENaC can reverse airway surface liquid dehydration. Here, we inhibit endogenous heterotrimeric ENaC channels by introducing inactivating mutant ENaC α mRNA (α_mutENaC). Lipid nanoparticles carrying α_mutENaC were transfected in CF-based airway cells in vitro and in vivo. We observed a significant decrease in macroscopic as well as amiloride-sensitive ENaC currents and an increase in airway surface liquid height in CF airway cells. Similarly, intranasal transfection of α_mutENaC mRNA decreased amiloride-sensitive nasal potential difference in CFTRKO mice. These data suggest that mRNA-based ENaC inhibition is a powerful strategy for reducing mucus dehydration and has therapeutic potential for treating CF in all patients, independent of genotype.

囊性纤维化 (CF) 是由传导氯离子的CF 跨膜电导调节因子( CFTR ) 基因突变引起的。建议 CF 中的气道脱水和黏膜纤毛清除受损导致强直性上皮钠通道 (ENaC) 活性，从而驱动阿米洛利敏感的电源性钠吸收。通过抑制 ENaC 减少钠吸收可以逆转气道表面液体脱水。在这里，我们通过引入失活的突变 ENaC α mRNA (α _mut ENaC) 来抑制内源性异源三聚体 ENaC 通道。_{携带 α mut}的脂质纳米颗粒ENaC 在体外和体内被转染到基于 CF 的气道细胞中。我们观察到宏观和阿米洛利敏感的 ENaC 电流显着降低，CF 气道细胞中气道表面液体高度增加。同样，α _{mut ENaC mRNA 的鼻内转染降低了}CFTR KO 小鼠的阿米洛利敏感鼻电位差。这些数据表明，基于 mRNA 的 ENaC 抑制是减少粘液脱水的有效策略，并且具有治疗所有患者 CF 的治疗潜力，与基因型无关。