Macrophage targeted graphene oxide nanosystem synergize antibiotic killing and host immune defense for Tuberculosis Therapy

Jiang Pi; Dongsheng Chen; Jiajun Wang; Enzhuo Yang; Jiayi Yang; Yilin Liu; Jiaqi Yu; Jiaojiao Xia; Xueqin Huang; Lingming Chen; Yongdui Ruan; Jun-Fa Xu; Fen Yang; Ling Shen

Pharmacological Research (Oct 2024)

Macrophage targeted graphene oxide nanosystem synergize antibiotic killing and host immune defense for Tuberculosis Therapy

Jiang Pi,
Dongsheng Chen,
Jiajun Wang,
Enzhuo Yang,
Jiayi Yang,
Yilin Liu,
Jiaqi Yu,
Jiaojiao Xia,
Xueqin Huang,
Lingming Chen,
Yongdui Ruan,
Jun-Fa Xu,
Fen Yang,
Ling Shen

Affiliations

Jiang Pi: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China; Corresponding authors at: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China.
Dongsheng Chen: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China
Jiajun Wang: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China
Enzhuo Yang: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA; Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
Jiayi Yang: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Yilin Liu: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Jiaqi Yu: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Jiaojiao Xia: Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Kunming Medical University, Kunming, China
Xueqin Huang: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Lingming Chen: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Yongdui Ruan: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China
Jun-Fa Xu: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China
Fen Yang: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China; Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics, School of Medical Technology, Guangdong Medical University, Dongguan, Guangdong, China; Corresponding authors at: Research Center of Nano Technology and Application Engineering, The First Dongguan Affiliated Hospital, Dongguan Innovation Institute, Guangdong Medical University, China.
Ling Shen: Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL 60612, USA; Corresponding author.

Journal volume & issue: Vol. 208
p. 107379

Abstract

Read online

Tuberculosis (TB), a deadly disease caused by Mycobacterium tuberculosis (Mtb) infection, remains one of the top killers among infectious diseases worldwide. How to increase targeting effects of current anti-TB chemotherapeutics and enhance anti-TB immunological responses remains a big challenge in TB and drug-resistant TB treatment. Here, mannose functionalized and polyetherimide protected graphene oxide system (GO-PEI-MAN) was designed for macrophage-targeted antibiotic (rifampicin) and autophagy inducer (carbamazepine) delivery to achieve more effective Mtb killings by combining targeted drug killing and host immunological clearance. GO-PEI-MAN system demonstrated selective uptake by in vitro macrophages and ex vivo macrophages from macaques. The endocytosed GO-PEI-MAN system would be transported into lysosomes, where the drug loaded Rif@Car@GO-PEI-MAN system would undergo accelerated drug release in acidic lysosomal conditions. Rif@Car@GO-PEI-MAN could significantly promote autophagy and apoptosis in Mtb infected macrophages, as well as induce anti-bacterial M1 polarization of Mtb infected macrophages to increase anti-bacterial IFN-γ and nitric oxide production. Collectively, Rif@Car@GO-PEI-MAN demonstrated effectively enhanced intracellular Mtb killing effects than rifampicin, carbamazepine or GO-PEI-MAN alone in Mtb infected macrophages, and could significantly reduce mycobacterial burdens in the lung of infected mice with alleviated pathology and inflammation without systemic toxicity. This macrophage targeted nanosystem synergizing increased drug killing efficiency and enhanced host immunological defense may be served as more effective therapeutics against TB and drug-resistant TB.

Published in Pharmacological Research

ISSN: 1096-1186 (Online)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.sciencedirect.com/journal/pharmacological-research

About the journal

Abstract

Keywords