Abstract

INHALABLE NANOPARTICLE DRUG DELIVERY SYSTEMS FOR MULTIDRUG-RESISTANT TUBERCULOSIS

ED Padma, Balakoti Erothi*, Varshitha Ganjam, Jagannadham Nuthana Yaswanth, K. Eswar Kumar

ABSTRACT

Tuberculosis (TB) remains the world's leading cause of death from a single infectious agent, and the persistence of multidrug-resistant and rifampicin-resistant TB (MDR/RR-TB) continues to undermine global elimination targets despite a decade of declining incidence. Conventional oral and parenteral chemotherapy is compromised by prolonged treatment duration, systemic toxicity, poor penetration into hypoxic and poorly vascularised granulomas, and the intracellular persistence of Mycobacterium tuberculosis within alveolar macrophages. Pulmonary-targeted nanoparticle delivery has emerged as a rational strategy to overcome these barriers by depositing therapeutic payloads directly at the primary site of infection while exploiting, rather than being obstructed by, macrophage phagocytic uptake. This review critically synthesises evidence across six converging nanocarrier classes, namely lipid-based nanoparticles, polymeric nanoparticles, macrophage receptor-targeted ligand-engineered carriers, metal and metal-oxide nanoparticles, biomimetic cell-membrane-camouflaged nanoplatforms, and nucleic-acid nanocarriers, with attention to aerosol engineering, preclinical efficacy, and toxicological performance. Unlike previous TB-nanomedicine reviews that treat nanoparticles primarily as passive antibiotic carriers, this review foregrounds an emerging conceptual shift toward nanoparticles as active theranostic and host-directed immunomodulatory agents, exemplified by macrophage membrane-camouflaged photothermal platforms and autophagy-modulating nanomedicines. We further provide a structured gap analysis identifying why, despite two decades of encouraging preclinical data, no inhalable nanoparticle formulation targeting Mycobacterium tuberculosis has yet entered human clinical trials, in contrast to the regulatory approval of liposomal amikacin for non-tuberculous mycobacterial lung disease. We conclude with a concrete translational roadmap spanning standardised nanotoxicology, dual-cargo antibiotic-immunomodulator platforms, and artificial-intelligence-guided formulation design, intended to move the field from mechanistic promise toward clinical validation.

Keywords: Mycobacterium tuberculosis; multidrug-resistant tuberculosis; pulmonary drug delivery; inhalable nanoparticles; macrophage targeting; biomimetic nanomedicine; nanotoxicology; host-directed therapy.