Mycobacterial lipid-derived immunomodulatory drug- liposome conjugate eradicates endosome-localized mycobacteria

Tuberculosis is a challenging disease due to the intracellular residence of its pathogen, Mycobacterium tuberculosis, and modulation of the host bactericidal responses. Lipids from Mycobacterium tuberculosis regulate macrophage immune responses dependent on the infection stage and intracellular location. We show that liposomes constituted with immunostimulatory lipids from mycobacteria modulate the cellular immune response and synergize with sustained drug delivery for effective pathogen eradication. We evaluate the pH-dependent release of Rifampicin from the mycobacterial-lipid-derived liposomes intracellularly and in vitro, their cell viability, long-term stability, and antimicrobial efficacy. Intracellular drug levels were higher following liposome treatment compared with the free drug in a temporal fashion underlying a sustained release. The drug-encapsulated liposomes were taken up by clathrin-mediated endocytosis and elicited a robust pro-inflammatory immune response while localizing in the recycling and late endosomes. Notably, these were the same cellular compartments that contained the pathogen underlying localized intracellular targeting. Our results also imply a lipid-centric and species-specific selectivity of the liposomal drug formulations. This work provides a proof-of-concept for the dual-action of liposomes derived from the pathogen itself for their effective eradication, in conjunction with the attuned host immunomodulation.