Inhalational Delivery of β‐glucan‐chitosan‐poly(lactic co‐glycolic) acid Nanoparticles Enhance Alveolar Macrophage Rifampin Concentrations for the Treatment of Tuberculosis

Despite multiple treatments for tuberculosis (TB), there are ≈10 million new cases and 1.5 million deaths annually, warranting the need for new therapeutics. Major clinical treatment issues include the length of treatment which is associated with patient non‐compliance; and poor cellular drug penetration leading to the generation of drug‐resistant strains. This study underscores the potential of β‐glucan‐chitosan (CS) poly(lactic co‐glycolic) acid (PLGA) nanoparticles as a promising immunostimulatory adjunct for TB treatment. To facilitate drug delivery to alveolar macrophage, a CS‐PLGA nanoparticle is developed containing rifampin in the core with β‐glucan as a surface ligand, to stimulate the immune system. Mice are administered a single dose of nanoparticles or free rifampin by oropharyngeal aspiration. Pharmacokinetic investigations reveal sustained release properties of rifampin in vivo, extending over a week. Furthermore, comprehensive analysis indicates stimulation of the innate immune system, as evidenced by cytokine profiling, while concurrently revealing no detrimental effects on the alveolar epithelium, as indicated by histological examination and albumin lung leak assessment. These findings collectively establish a strong foundation for the development of a novel adjuvant immunotherapy approach for TB.