Effective treatment of tuberculosis (TB) demands progression control in line with TB elimination. The objective herein is to formulate nebulized targeted antitubercular - lipid nanocarriers for TB treatment. In this context, mannosylated solid lipid nanoparticles (MN-SLNs) incorporating LNZ (LNZ) were prepared and characterized. Their nebulization efficiency and cytotoxicity were appraised. Potential internalization of LNZ-MN-SLNs in alveolar macrophages (AM) was evaluated. In vivo biodistribution was carried out following orotracheal administration to mice. Susceptibility testing to investigate antitubercular activity of LNZ formulations against Mycobacterium tuberculosis (standard strain and clinical isolates) was performed.MN-SLNs ensured ≈930 nm diameter, 5–54 mV zeta-potential and 19 %w/v LNZ loading in addition to pH-independent sustained release. Jet nebulization showed 51 % nebulization efficiency within 20 min. Viability assay on MH-S cells warranted an IC50 < 0.02 mg/mL, while no harmful effect on A549 cells was noticed. CLSM has proven phagocytosis of labelled carriers by MH-S cells as revealed by the 4-time higher fluorescence for LNZ-MN-SLNs versus LNZ-MN-NLCs. Data support 50 % reduction in MIC for LNZ-MN-SLNs versus free LNZ against standard and clinical M. tuberculosis isolates. H&E staining and bronchoalveolar lavage demonstrated in vivo accumulation of mannosylated nanocarriers in murine AM without significant histopathological/biochemical changes emphasizing their notable biosafety. The formulated nebulization therapy showed in vitro/in vivo macrophage targeting, and privileged susceptibility against TB giving promises for reduced dose and dosing frequency, evading LNZ life-threatening adverse consequences.