Sphingolipids (SL) play a regulatory role in CF airway inflammation. In particular, ceramide (Cer) content was suggested to increase the pro-inflammatory state and the inflammation response to bacterial infection in CF. Recently, Cer deriving from glycosphingolipids has gained more interest, since the inhibition of enzymes of their metabolism in CF human epithelial bronchial cells (CFhEBC) results in a reduced inflammation response to P. aeruginosa. Among these enzymes, the glucocerebrosidase GBA2 seems to be directly involved; preliminary results had shown in CFhEBC infected with P. aeruginosa that the inhibition of GBA2 activity and its down-regulation by siRNA were associated with a significant reduction of IL-8 (pro-inflammatory protein), as well as a reduction of the intrinsic inflammatory state. Based on these findings, the present proposal aimed to study the link among GBA2, defective CFTR and IL-8 expression. Another aim was to develop a nanoparticle (NP)-based system to selectively delivery siRNA against GBA2 as a possible promising new anti-inflammatory therapy for CF lung disease.