Mycobacterium abscessus (Mabs) is a dangerous non-tubercular mycobacterium responsible for severe pulmonary infections in immunologically vulnerable patients, due to its wide resistance to many different antibiotics which make its therapeutic management extremely difficult. Drug nanocarriers as liposomes may represent a promising delivery strategy against pulmonary Mabs infection, due to the possibility to be aerosolically administrated and to tune their properties in order to increase nebulization resistance and retainment of encapsulated drug. In fact, liposome surface can be modified by decoration with mucoadhesive polymers to enhance its stability, mucus penetration and prolong its residence time in the lung. The aim of this work is to employ Chitosan or ε-poly-L-lysine decoration for improving the properties of a novel liposomes composed by hydrogenated phosphatidyl-choline from soybean (HSPC) and anionic 1,2-Dipalmitoyl-sn-glycero-3-phosphorylglycerol sodium salt (DPPG) able to entrap Rifampicin. A deep physicochemical characterization of polymer-decorated liposomes shows that both polymers improve mucoadhesion without affecting liposome features and Rifampicin entrapment efficiency. Therapeutic activity on Mabs-infected macrophages demonstrates an effective antibacterial effect of ε-poly-L-lysine liposomes with respect to chitosan-decorated ones. Altogether, these results suggest a possible use of ε-PLL liposomes to improve antibiotic delivery in the lung.