Mannosamine-Engineered Nanoparticles for Precision Rifapentine Delivery to Macrophages: Advancing Targeted Therapy Against Mycobacterium Tuberculosis

Haopeng Luan,* Cong Peng,* Parhat Yasin, Qisong Shang, Wei Xiang, Xinghua Song Department of Spine Surgery, the Sixth Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xinghua Song, Tel +86 13199836661, Email [email protected]: Tuberculosis, caused by Mycobacterium tuberculosis (Mtb), remains one of the leading causes of death among infectious diseases. Enhancing the ability of anti-tuberculosis drugs to eradicate Mycobacterium tuberculosis within host cells remains a significant challenge.Methods: A mannosamine-modified nanoparticle delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) copolymers to enhance the targeted delivery of rifapentine (RPT) to macrophages. D-mannosamine was conjugated to PLGA-polyethylene glycol (PLGA-PEG) copolymers through EDC/NHS coupling chemistry, and the resultant RPT-MAN-PLGA-PEG nanoparticles (NPs) were prepared through a combination of phacoemulsification and solvent evaporation methods. The physicochemical properties, toxicity, in vitro drug release profiles, stability, cellular uptake, and anti-TB efficacy of the NPs were systematically evaluated.Results: The RPT-MAN-PLGA-PEG NPs had a mean particle size of 108.2 ± 7.2 nm, with encapsulation efficiency and drug loading rates of 81.2 ± 6.3% and 13.7 ± 0.7%, respectively. RPT release from the NPs was sustained for over 60 hours. Notably, the phagocytic uptake of the MAN-PLGA NPs by macrophages was significantly higher compared to PLGA-PEG NPs. Both NPs improved pharmacokinetic parameters without inducing significant organ toxicity. The minimum inhibitory concentration for the NPs was 0.047 μg/mL, compared to 0.2 μg/mL for free RPT.Conclusion: The engineered RPT-MAN-PLGA-PEG NPs effectively enhanced macrophage uptake in vitro and facilitated the intracellular clearance of Mtb. This nanoparticle-based delivery system offers a promising approach for improving the precision of anti-TB therapy, extending drug release, optimizing pharmacokinetic profiles, augmenting antimicrobial efficacy, and mitigating drug-related toxicities. Keywords: anti-tubercular, rifapentine, drug delivery system, nanoparticles, macrophages