Mannosamine-Modified Poly(lactic-co-glycolic acid)-Polyethylene Glycol Nanoparticles for the Targeted Delivery of Rifapentine and Isoniazid in Tuberculosis Therapy

Tuberculosis, caused by Mycobacterium tuberculosis, is the leading cause of mortality attributed to a single infectious agent. Following macrophage invasion, M. tuberculosis uses various mechanisms to evade immune responses and to resist antituberculosis drugs. This study aimed to develop a targeted drug delivery system utilizing mannosamine (MAN)-modified nanoparticles (NPs) composed of poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG), loaded with rifapentine and isoniazid, to enhance macrophage-directed therapy and enhance bacterial elimination. PLGA-PEG copolymer was modified with mannosamine through an amidation reaction. Rifapentine- and isoniazid-loaded PLGA-PEG-MAN NPs were synthesized by using the double emulsion solvent evaporation technique. The NPs exhibited an average particle size of 117.67 nm and displayed favorable physicochemical properties without evidence of cellular or hemolytic toxicity. The drug loading rates were 11.73% for rifapentine and 5.85% for isoniazid. Sustained drug release was achieved over a period exceeding 72 h, with antibacterial activity remaining intact during encapsulation. Synergistic bactericidal effects were noted. Additionally, mannosamine-modified NPs enhanced the phagocytic activity of macrophages via mannose receptor-mediated endocytosis, thereby improving drug delivery efficiency and significantly boosting the antibacterial efficacy of the NPs within macrophages. Pathological staining and biochemical analysis of rat organs following intravenous injection indicated that the NPs did not cause any significant toxic side effects in vivo. The findings of this study indicate that mannosamine-modified PLGA-PEG NPs loaded with rifapentine and isoniazid represent a promising drug delivery system for targeting macrophages to enhance the efficacy of antitubercular therapy.