Cystic fibrosis (CF) is a disease caused by a mutation in the CFTR gene encoding a transmembrane regulator functioning as a Cl channel within the epithelial membrane. The main mutation is linked to the loss by deletion of a Phe in position 508 (ΔF508). Among the CF pathogens, Mycobacterium abscessus (Mabs), a rapid-growing mycobacterium (RGM), is responsible for severe respiratory infections in CF patients. The specific objective of our project was to evaluate the protection induced by a Mabs virulence factor, the phospholipase C (PLC) (MAB_0555), administered under the form of a nanovectorized recombinant DNA in a model of systemic infection (intravenously) and a model of pulmonary (aerosol route) infection using as mouse model the ΔF508 CFTR mice ("CF" mice) and their wild-type counterpart (FVB genetic background Protection was evaluated by CFU counts in the spleen, liver and lungs of animals at day 1, 7, 14 and 21 for the aerosol challenge and day 1, 14 and 45 for the IV challenge. We only observed a protective effect after the aerosol challenge. After the aerosol challenge of FVB wild-type mice, no protective provided by immunization with the nanovectorized PLC gene effect was observed. However, a protective effect was observed in homozygous ΔF508 CFTR mice. A difference was observed at D7, which was confirmed at D21 (p = 0.038). In conclusion, the use of a nanovectorized gene coding for a virulence factor is able to provide local protection and accelerated clearance of M. abscessus in the lungs of “CF” mice.