RNA interference is a specific post-transcriptional gene silencing approach, which is at limelight for the treatment of severe diseases, as cystic fibrosis (CF). But up today siRNA delivery systems rely upon viral vectors and a more effective and safe tool would be advisable. The general aim of this project is the development of a formulation strategy to enable lung delivery of siRNA in CF. This objective will be pursued through the design, development and in vitro/in vivo evaluation of inhalable hybrid (made up of a combination of endogenous phospholipids and biodegradable polymers) nanoparticles (hNPs). These hNPS will deliver a siRNA against one of the most critical CF inflammatory signal, that is nuclear factor-kB (NFkB). Toxicity and efficacy of siRNA-loaded hNPs will be evaluated in different human airway cell culture models; biodistribution and biocompatibility in healthy mice; and finally the efficacy against NF-kB in an animal model of lung inflammation. One or two optimized inhalable formulations are expected to progress into pre-clinical studies.