Inhalational therapy of pulmonary infection via macrophage-targeted nanoemulsions

The dynamic immune landscape within the tuberculous (TB) granuloma microenvironment critically governs antibiotic penetration efficiency, bacterial persistence, and long-term therapeutic outcomes. Herein, we present a macrophage-targeted inhalable nanoemulsion for co-delivering rifampicin and LCL161, an inhibitor of apoptosis protein antagonists. Inhaled mannose-nanoemulsions (named RL-NE@Man) enable granuloma-targeted delivery in TB mice model, increasing infected macrophage apoptosis, remodeling the tuberculous microenvironment, and promoting T-cell immunity to synergize with antibiotics for the eradication of granulomas and persistent Mycobacterium tuberculosis . Following two-dose inhalational administration, RL-NE@Man displayed potent bactericidal activity against M. tuberculosis while concurrently alleviating pulmonary pathological lesions and hyperinflammatory responses, demonstrating superior bacterial suppression efficacy compared with that of the first-line rifampicin monotherapy. This inhaled combination therapy, which integrates immunomodulators with antibiotics to modulate the local immune landscape and synergistically enhance bactericidal efficacy, represents a novel therapeutic strategy for precision tuberculosis management. The inhaled RL-NE@Man nanoemulsion acts by targeting both M2 macrophages and dendritic cells and remodeling the granuloma microenvironment, resulting in synergistic bacterial clearance and attenuated inflammation.