Targeted Nasal Route Delivery of Cationic Anti-TB Drug-Loaded Nano-embedded Microparticles for Mycobacterial Elimination in the CNS

Central nervous system tuberculosis (CNS-TB) is a severe and insidious form of extrapulmonary tuberculosis (TB) associated with a high mortality rate, often leading to fatal outcomes or debilitating neurological impairments. The therapeutic regimen for CNS-TB follows an approach similar to that of pulmonary TB but faces significant challenges in effectively reaching the cerebrospinal fluid and achieving therapeutic drug levels in the brain and surrounding fluids. A major obstacle in CNS-TB treatment is the difficulty in permeating the blood-brain barrier (BBB). The nasal route of drug delivery offers a promising approach for targeting anti-TB drugs directly to the infection sites, enabling higher drug concentrations while bypassing the BBB. The present study focused on the development of cationic poly(lactic-<i>co</i>-glycolic) acid (PLGA) nanoparticles (CS-PLGA NPs) loaded with anti-TB drugs (ATDs), namely, isoniazid (INH) and rifampicin (RIF). These CS-PLGA NPs were then processed into dynamic microsized nanoembedded microparticles (NEMs) using spray drying. The ATD-NEMs formulation demonstrated significantly enhanced permeation across RPMI 2650 nasal septum monolayers compared with free ATDs. Intranasal delivery of the NEM formulation to TB-infected mice over a four-week period resulted in a substantial reduction in colony-forming units (CFUs) (1.53 ± 0.50 log₁₀ CFU/gram) compared to the untreated group (4.45 ± 0.67 log₁₀ CFU/gram). Furthermore, the NEM formulation showed improved recovery in histopathological analysis, consistent with CFU reduction. Preclinical data support the feasibility of intranasally administering the NEMs formulation, demonstrating high therapeutic efficacy and the potential to address brain inflammation in the murine CNS-TB model.