Long-Acting Nanomedicine for Tuberculosis: A Mechanism-Informed Framework

Tuberculosis treatment remains prolonged because effective therapy must maintain coordinated multidrug exposure across heterogeneous lesions, bacterial states, and intracellular compartments. Long-acting nanomedicine may reduce adherence-related vulnerability and improve drug delivery, but prolonged release alone do not ensure lesion sterilization or treatment shortening. This review presents a mechanism-informed framework linking lesion architecture, local microenvironment, bacterial phenotypic adaptation, intracellular survival, and immunopathological organization to specific formulation functions. These include sustained active exposure, pulmonary and intralesional delivery, intracellular drug release, multidrug synchronization, and controlled host-directed therapy. Injectable depots, inhalable systems, cellular targeting, and polymeric platforms, including PLGA, other polyesters, hydrogels, natural polymers, and hybrid systems, is evaluated according to biological relevance, spatial delivery, pharmacodynamic activity, and translational feasibility. The most realistic near-term application is the development of simple, manufacturable long-acting formulations of established antimycobacterial drugs to improve exposure continuity and treatment completion. Treatment shortening will require synchronized sterilizing exposure across relevant compartments and evidence of relapse prevention.