Macrophage targeted iron oxide nanodecoys augment innate immunological and drug killings for more effective Mycobacterium Tuberculosis clearance

Ling Shen; Kangsheng Liao; Enzhuo Yang; Fen Yang; Wensen Lin; Jiajun Wang; Shuhao Fan; Xueqin Huang; Lingming Chen; Hongbo Shen; Hua Jin; Yongdui Ruan; Xing Liu; Gucheng Zeng; Jun-Fa Xu; Jiang Pi

doi:10.1186/s12951-023-02103-x

Macrophage targeted iron oxide nanodecoys augment innate immunological and drug killings for more effective Mycobacterium Tuberculosis clearance

J Nanobiotechnology. 2023 Oct 10;21(1):369. doi: 10.1186/s12951-023-02103-x.

Authors

Ling Shen^#¹, Kangsheng Liao^#^{2

3

4}, Enzhuo Yang^{5

6}, Fen Yang^{2

3

4}, Wensen Lin^{2

4}, Jiajun Wang^{2

4}, Shuhao Fan^{2

4}, Xueqin Huang², Lingming Chen^{2

3

4}, Hongbo Shen⁶, Hua Jin², Yongdui Ruan², Xing Liu⁷, Gucheng Zeng⁸, Jun-Fa Xu^{9

10}, Jiang Pi^#^{11

12

13}

Affiliations

¹ Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA. lshen@uic.edu.
² Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China.
³ The Marine Biomedical Research Institute of Guangdong Zhanjiang, The Marine Biomedical Research Institute of Guangdong Medical University, ZhanJiang, Guangdong, China.
⁴ Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China.
⁵ Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA.
⁶ Clinic and Research Center of Tuberculosis, Shanghai Key Lab of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
⁷ Key Laboratory of Animal Disease Diagnostics and Immunology, Ministry of Agriculture, MOE International Joint Collaborative Research Laboratory for Animal Health & Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, China.
⁸ Department of Microbiology, Zhongshan School of Medicine, Key Laboratory for Tropical Diseases Control of the Ministry of Education, Sun Yat-Sen University, Guangzhou, Guangdong, China.
⁹ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China. xujunfa@gdmu.edu.cn.
¹⁰ Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China. xujunfa@gdmu.edu.cn.
¹¹ Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, China. jiangpi@gdmu.edu.cn.
¹² The Marine Biomedical Research Institute of Guangdong Zhanjiang, The Marine Biomedical Research Institute of Guangdong Medical University, ZhanJiang, Guangdong, China. jiangpi@gdmu.edu.cn.
¹³ Institute of Laboratory Medicine, School of Medical Technology, Guangdong Medical University, Dongguan, China. jiangpi@gdmu.edu.cn.

^# Contributed equally.

Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) infection, is still one of the top killers worldwide among infectious diseases. The escape of Mtb from immunological clearance and the low targeting effects of anti-TB drugs remain the substantial challenges for TB control. Iron is particularly required for Mtb growth but also toxic for Mtb in high dosages, which makes iron an ideal toxic decoy for the 'iron-tropic' Mtb. Here, a macrophage-targeted iron oxide nanoparticles (IONPs)-derived IONPs-PAA-PEG-MAN nanodecoy is designed to augment innate immunological and drug killings against intracellular Mtb. IONPs-PAA-PEG-MAN nanodecoy exhibits preferential uptake in macrophages to significantly increase drug uptake with sustained high drug contents in host cells. Moreover, it can serve as a specific nanodecoy for the 'iron-tropic' Mtb to realize the localization of Mtb contained phagosomes surrounding the drug encapsulated nanodecoys and co-localization of Mtb with the drug encapsulated nanodecoys in lysosomes, where the incorporated rifampicin (Rif) can be readily released under acidic lysosomal condition for enhanced Mtb killing. This drug encapsulated nanodecoy can also polarize Mtb infected macrophages into anti-mycobacterial M1 phenotype and enhance M1 macrophage associated pro-inflammatory cytokine (TNF-α) production to trigger innate immunological responses against Mtb. Collectively, Rif@IONPs-PAA-PEG-MAN nanodecoy can synergistically enhance the killing efficiency of intracellular Mtb in in vitro macrophages and ex vivo monocyte-derived macrophages, and also significantly reduce the mycobacterial burdens in the lung of infected mice with alleviated pathology. These results indicate that Rif@IONPs-PAA-PEG-MAN nanodecoy may have a potential for the development of more effective therapeutic strategy against TB by manipulating augmented innate immunity and drug killings.

Keywords: Anti-microbial immunity; Macrophage-targeting; Nanodecoy; Synergistic mtb killing; Tuberculosis.

MeSH terms

Animals
Humans
Iron
Macrophages
Mice
Mycobacterium tuberculosis*
Rifampin / pharmacology
Tuberculosis* / drug therapy

Substances

ferric oxide
Rifampin
Iron

Abstract

MeSH terms

Substances

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