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BACKGROUND The liposomal inhalation of drugs has been extensively researched for the invasion of biofilms and macrophages in the infected lungs. OBJECTIVE The present study aimed to explore the in vitro and in vivo effects of surfactant-based nano-lipid vesicles of aztreonam for pulmonary delivery. METHODS Surfactant-based nano lipid vesicles of the drug were successfully prepared with the commonly abundant lung phospholipids (LIPOID S PC-3, LIPOID PC 16:0/16:0), cholesterol, and span 20. The formulations were evaluated for their physicochemical properties, in vitro diffusion, and cytotoxicity. The best formulation was subjected to stability, in vivo lung deposition, and histopathological studies. RESULTS The characterization of the lipid vesicles in terms of particle size, zeta potential, and surface morphology confirmed the formation of stable nanolipid vesicles of the drug. The presence of surfactant in the lipid vesicles exhibited high bilayer stability, entrapment, and diffusion of the drug. The in vitro diffusion study revealed the biphasic characteristic with an initial burst, followed by sustenance for 8h. A remarkable cell uptake of the drug was observed in the epithelial cell line of CHO Cricetulus griseus in the presence of surfactant. The drug was retained in mice's lungs for 8h. The histopathological study of lung tissue revealed that surfactant-based lipid vesicles could attenuate lung fibrosis significantly. CONCLUSION It can be concluded that a surfactant-based nano lipid vesicular system of aztreonam could be a paradigm for targeting and localization of the drug with a long residence time in the lungs.