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

. 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.