Surface-Engineered Ethambutol-Loaded Nanoparticles: Design, Fabrication, and In Vitro–In Vivo Evaluation for Tuberculosis Therapy

Tuberculosis (TB) remains a major global health challenge, aggravated by limitations of current chemotherapeutic regimens, including poor oral bioavailability, systemic side effects, and patient noncompliance. This study aimed to develop and evaluate macrophage-targeted, mannose-conjugated solid lipid nanoparticles (Mn-ETB-SNs) for enhanced oral delivery of ethylbutol (ETB), a first-line anti-TB drug. The Mn-ETB SNs were fabricated using high-pressure homogenization followed by surface mannosylation through Schiff's base formation between mannose and amine-functionalized nanoparticles. The prepared formulations were characterized for particle size, ζ-potential, drug loading, entrapment efficiency, morphology, and stability. <i>In vitro</i> release, GI stability, cytotoxicity, and cellular uptake studies using J774A.1 macrophages were conducted. Further, <i>in vivo</i> pharmacokinetic and biodistribution studies were performed in Sprague-Dawley rats. The optimized Mn-ETB-SNs exhibited a uniform particle size of approximately 491 nm, a high entrapment efficiency of around 84%, and spherical morphology with stable physicochemical properties under varied storage and GI conditions. Mannosylation significantly enhanced macrophage uptake by 2.02-fold compared to unconjugated nanoparticles, as confirmed through fluorescence-activated cell sorting (FACS) and fluorescence microscopy. <i>In vivo</i> pharmacokinetic studies demonstrated an 8.5-fold increase in ETB bioavailability with Mn-ETB-SNs compared to the pure drug, accompanied by prolonged circulation and reduced hepatic metabolism. Biodistribution analysis revealed preferential and sustained lung accumulation, with Mn-ETB-SNs achieving 4.74-fold higher pulmonary concentrations at 48 h compared to free drug, owing to mannose receptor-mediated uptake by alveolar macrophages. Collectively, the findings highlight the potential of orally administered Mn-ETB-SNs as a promising nanocarrier system for targeted TB therapy. The developed formulation offers improved bioavailability, site-specific drug delivery, and enhanced pulmonary targeting, addressing key limitations of conventional TB treatment.