The down-regulation of genes directly involved in the pathogenesis of severe lung diseases through pulmonary delivery of short RNA fragments, also known as siRNA, is a new therapeutic proposal in cystic fibrosis (CF). To improve the possibility that inhaled siRNA move from the laboratory to the bedside is important to set up an appropriate formulation strategy. In this context, this project aims to develop inhalable hybrid nanoparticles (hNPs) for siRNA delivery made up of a combination of endogenous phospholipids and biodegradable polymers. To provide proof-of­ concept data about this kind of approach, the in vitro/in vivo therapeutic potential of hNPs delivering a siRNA against one of the most critical signals in evoking the inflammatory response in CF, that is nuclear factor-kB (NF-kB), will be assessed. Experiments will be carried out to study optimised hNPs delivering a siRNA against NF-kB and their ability to overcome the CF mucus barrier, then their toxicity and efficacy in human airway cell culture model and finally in healthy mice and in animal models of lung inflammation. The final aim is to further the progress of formulation strategy regarding siRNA in the therapy of CF lung.