Mycobacterial Lipid-Coated Mesoporous Silica Nanoparticles Enable “Trojan Horse” Delivery of Isoniazid for Enhanced Intracellular Mycobactericidal Activity

Tuberculosis (TB), caused by <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>), a paradigmatic intracellular pathogen that is adept at evading host defenses and establishing persistence within macrophages, poses a significant public health threat. Herein, we developed a novel nanoplatform (INH@LMSN) using lipids from <i>Mycobacterium smegmatis</i> (<i>M. smegmatis</i>), a nonpathogenic substitute for <i>Mtb</i>, to coat mesoporous silica nanoparticles (MSNs) for isoniazid (INH) delivery. This platform targets macrophages, releases INH in a pH-dependent manner, and enhances antibacterial activity <i>in vitro</i> by damaging bacterial membranes and generating reactive oxygen species (ROS). INH@LMSN also polarizes macrophages to the M1 phenotype, aiding in the intracellular <i>mycobacteria</i> clearance. In a mouse model of <i>M. smegmatis</i> infection, INH@LMSN reduced bacterial burden and alleviated pulmonary inflammation, demonstrating a dual-action strategy combining immune modulation with targeted antituberculosis drug delivery. This study provides a novel dual-action "Trojan Horse" strategy that combines pathogen lipid-mediated immune response modulation with targeted antituberculosis drug delivery, offering a promising approach to enhance intracellular mycobacterial killing and advance TB therapeutics.