Mutations in the gene encoding the CFTR protein affect mucus-producing epithelia, including the lungs and gastrointestinal tract. In the lungs, viscous mucus obstructs the bronchi, creating an environment conducive to chronic bacterial infection, which leads to the destruction of the lung parenchyma and the death of patients with Cystic Fibrosis. To date, ~65% of patients can be treated with drugs based on Ivacaftor (ex Kaftrio). Despite significant clinical benefits, in particular respiratory, have been reported, side effects may lead to the reduction and/or discontinuation of treatment due to the hepatic and pancreatic insufficiency inherent in the disease. Moreover, ~35% of patients with very rare mutated alleles are currently without a therapeutic solution. This may explain why gene therapy is a credible option to treat all patients regardless of their mutations. Since lung failure is responsible for mortality, gene therapy must be aerosolized to deliver the transgene. However, the high viscosity of CF mucus traps both viral and non-viral vectors and limits their clinical impact. In this context, extracellular vesicles (EVs) exhibiting a natural ability to diffuse into dense extracellular matrices, are relevant candidates to diffuse into mucus. The interest of ES derived from MSCs has been established in several pulmonary pathologies, mainly due to their natural antibacterial, anti-inflammatory and anti-fibrotic effects. Few studies have reported delivery of MSC-EV to the lungs after nebulization, demonstrating their safety but also showing heterogeneous results likely due to lack of stability during nebulization. Also, our project aims to nebulize the hMSC-EVs optimized to deliver an mRNA encoding CFTR and to evaluate them in the specific CF context.