Smart nanocarriers against MDR-tuberculosis: stimuli-responsive strategies for granuloma penetration and next generation therapy.

Multidrug-resistant tuberculosis (MDR-TB) remains a global health concern due to long treatment durations, limited drug penetration into granulomatous lesions, systemic toxicity, and the persistence of dormant Mycobacterium tuberculosis. The granuloma microenvironment, characterized by hypoxia, acidic pH, enzymatic activity, dense extracellular matrix, and redox imbalance, acts as a barrier to the effectiveness of conventional antitubercular therapy. Recent advances in nanotechnology have led to the development of stimuli-responsive nanocarriers that enable targeted, controlled, and on-demand drug delivery in response to disease-specific stimuli. This narrative review summarizes peer-reviewed literature published between 2015 and 2025 on stimuli-responsive nanocarrier systems for MDR-TB therapy, retrieved from major scientific databases, including PubMed, Scopus, Google Scholar, ScienceDirect, Web of Science, and ResearchGate, focusing on granuloma-targeted drug delivery and nanomedicine strategies. Stimuli-responsive liposomes, polymeric nanoparticles, dendrimers, and metallic nanocarriers demonstrate enhanced pulmonary accumulation with improved bacterial targeting and reduced systemic toxicity compared to free drugs. In addition, co-delivery strategies incorporating host-directed immunomodulators further improve bactericidal efficacy. Emerging approaches, including CRISPR-Cas‑based nano-therapies, RNA therapeutics, regenerative and stem cell-based strategies, artificial intelligence‑guided nanocarrier design, and biohybrid delivery systems, represent important future directions. Overall, stimuli-responsive nanocarriers, integrated with next-generation technologies, offer a promising pathway toward precise and effective MDR-TB treatment.