Nanoparticles for Targeted and Controlled Drug Delivery in Tuberculosis: Role of TNF-α and IFN-γ as Immunological Biomarkers

Abstract

Tuberculosis remains difficult to treat not only because Mycobacterium tuberculosis can acquire antimicrobial resistance, but because the bacillus occupies heterogeneous extracellular and intracellular niches in lungs and other tissues, including macrophages and pathologically diverse granulomas in which drug penetration, oxygen tension, pH, cellular composition and bacterial physiology vary substantially. Nanoparticle-based delivery has therefore been investigated as a means of increasing local and intracellular drug exposure, protecting unstable or poorly soluble agents, enabling controlled release and reducing systemic exposure. This critical narrative review evaluates polymeric, lipid-based and inorganic nanoparticle platforms, with emphasis on pulmonary administration, macrophage targeting, ligand-mediated uptake and stimuli-responsive release. It also examines whether tumour necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) can function as mechanistically informative biomarkers during development and evaluation of nanoparticle-based tuberculosis therapies. The literature was selected through structured searches of accessible biomedical and multidisciplinary scholarly sources from 2000 to 2 August 2026, supplemented by foundational earlier evidence and citation searching. Preclinical studies consistently show that nanocarriers can increase macrophage uptake, prolong pulmonary residence and improve intracellular delivery of rifampicin, isoniazid and other antitubercular agents. Yet translation remains limited by variable disease models, incomplete lesion-level pharmacokinetic data, manufacturing and aerosolisation constraints, uncertain long-term material safety and sparse head-to-head comparisons with optimised conventional regimens. TNF-α and IFN-γ are biologically central to antimycobacterial immunity, but neither is a stand-alone surrogate of bacterial sterilisation: concentrations are compartment-, time- and assay-dependent, and excessive or insufficient signalling may both be undesirable. The most defensible translational strategy is therefore to treat these cytokines as contextual pharmacodynamic biomarkers embedded within a multimodal framework that also measures mycobacterial burden, lesion drug exposure, pulmonary pathology and systemic safety. Future studies should prioritise clinically relevant inhaled formulations, lesion-resolved pharmacokinetics, standardised cytokine sampling and integrated exposure-response modelling before nanoparticle-based therapy can be judged superior to contemporary tuberculosis treatment.