Cystic fibrosis (CF), the most common lethal genetic disorder in the Caucasian population, is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-dependent chloride channel expressed in the apical membrane of epithelial cells. The disease is associated with a Na+ hyperabsorption mediated by the epithelial sodium channel (ENaC) causing an enhanced imbalance of ion and water transport. The dysregulation of these proteins leads to severe impairments in the metabolism making CF a multisystem disorder with airways and lungs being affected the most. Until now, therapy focuses on alleviating the symptoms of the disease as no treatment has been developed yet to cure the disease on a cellular level. Hence, we aim at designing a double-tracked strategy targeting both CFTR and ENaC to treat abnormal ion transports in airway epithelial cells. Recently, we established a non-viral delivery system for wtCFTR-mRNA based on chitosan (CS) to restore CFTR function1. In this work we are seeking to develop a similar system to deliver ENaC antisense oligonucleotides (ASO) to correct Na+ hyperabsorption. CS-ASO complexes were harnessed at varying charge ratios (+/-) and characterized for their physicochemical properties (e.g. size, zeta potential, stability). Most promising complexes (+/- 90, 85 mM NaCl) had an average size of 150 nm, a zeta potential of approximately +30 mV, were relatively stable in transfection medium over 24 h and were therefore chosen for in vitro transfection experiments. Primary human nasal epithelial cells grown on Transwell® permeable filters were incubated with CS-ASO complexes for 24 h (0.45 µg ASO/cm2). Afterwards, functional Ussing chamber measurements were conducted. Measurements showed decreased Na+ current mediated by ENaC (15,8%; n=6) confirming successful transfection with CS-ASO complexes. With the results presented herein we mark the start of the development of a double-tracked strategy to cure abnormal ion transports in CF.