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 antagonist. Inhaled mannose-nanoemulsions (named RL-NE@Man) enable granuloma-targeted delivery in TB mice model, increasing infected macrophage apoptosis, remodeling the tuberculosis microenvironment, and promoting T-cell immunity to synergize with antibiotics for the eradication of granulomas and persistent Mycobacterium tuberculosis infection. 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.

Nanoemulsions  /  Inhaled therapy  /  Mycobacterium tuberculosis  /  Rifampicin  /  LCL161  /  Macrophages  /  Antibiotic  /  Immunotherapy