<p><i>Mycoplasma pneumoniae</i> pneumonia (MPP) is a major cause of community-acquired pneumonia in children, and azithromycin (AZM) is recommended as a first-line macrolide for its treatment. However, current oral and intravenous AZM formulations require high systemic doses to achieve effective pulmonary concentrations, thereby increasing the risk of adverse effects (e.g., gastrointestinal reactions, cardiotoxicity) and antibiotic resistance. In this study, we developed an azithromycin liposomal formulation (AC-Lip) for local pulmonary administration, enabling direct targeting of pulmonary lesions while reducing the required dose and enhancing pulmonary bioavailability. To achieve efficient drug loading, an ion-pairing strategy was employed to increase the lipophilicity of AZM through complexation with cholesteryl hemisuccinate. The resulting AC-Lip displayed a spherical morphology with an average particle size of approximately 120&#xa0;nm, a high encapsulation efficiency of 89.86%, and favorable long-term stability. Pharmacokinetic analysis demonstrated that, following pulmonary administration, the absolute pulmonary bioavailability of AZM from AC-Lip was 6.52-fold higher than that of intravenous AZM injection. Preliminary nebulization stability studies further supported its feasibility as an inhalable formulation. Collectively, these findings indicate that AC-Lip enables efficient pulmonary-targeted delivery of AZM and holds substantial promise as a novel clinical therapeutic strategy for the treatment of MPP.</p>