Diseases affecting the respiratory tract are numerous and many are disabling or deadly. Nucleic acids are emerging as a new tool and a new therapeutic class of compounds that could be used to address some lung diseases. However, considering the different anatomical barriers and the physicochemical behavior of nucleic acids in the blood stream, lungs are not easy to treat following a general administration. In this context, aerosol delivery is largely considered as an adapted and noninvasive approach avoiding the hepatic metabolism. This local delivery leads to a lung concentration and limits eventual side effects associated with a systemic injection. However, aerosol administration of active molecules is a real challenge due to the physical, chemical, and biological obstacles, such as respiratory movement, surfactant, or bacterial strains. Nanocomplexes have the potential to increase bioavailability and favor intracellular penetration of specific drugs into the pulmonary tissue. In this chapter, we will present our strategy to develop efficient gene carriers that, from a synthesis point of view, can be prepared on a large scale. We will discuss their use in preparing various formulations and their progressive adaptation to the airway constraints. In particular, we will focus our attention on cationic amphiphilic complexes used for aerosol gene delivery and we will present promising formulations in preclinical studies in a cystic fibrosis context.