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Parkinson’s disease (PD) is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury. Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD. However, traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability. Herein, Cu-doping zeolite imidazolate framework-8 (ZIF-8) nanozyme is designed to simulate Cu/Zn superoxide dismutase (SOD) by biomimetic mineralization. The nanozyme composite is then integrated into thermosensitive hydrogel (poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA)) to form an effective antioxidant system (Cu-ZIF@Hydrogel). The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion, prolonging nanozyme retention time, and modulating antioxidant activity, thus significantly improving the bioavailability of nanozymes. At the cellular and animal levels of PD, we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells. Moreover, the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site. Therefore, the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.


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Bioinspired metal-organic framework nanozyme reinforced with thermosensitive hydrogel for regulating inflammatory responses in Parkinson’s disease

Show Author's information Xiaowan Fan1,3,§Tao Zhang6,§Xin Ding7,§Yushuo Gu1,3Qing Li1,3( )Wei Jiang1,2,3( )Kelong Fan3,4,5( )
Nanozyme Medical Center, Academy of Medical Science, Zhengzhou University, Zhengzhou 450001, China
Department, Central-China Branch of National Center for Cardiovascular Diseases, Hean Cardiovascular Disease Center, Fuwai Central-China Hospital, Central China Fuwai Hospital of Zhengzhou University, Zhengzhou 450046, China
Application Center for Precision Medicine, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
CAS Engineering Laboratory for Nanozyme, Key Laboratory of Protein and Peptide Pharmaceuticals, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
University of Chinese Academy of Sciences, Beijing 101408, China
Department of General Surgery, Strategic Support Force Medical Center, Beijing 100101, China
Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China

§ Xiaowan Fan, Tao Zhang, and Xin Ding contributed equally to this work.

Abstract

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder accompanied by movement disorders and neuroinflammatory injury. Anti-inflammatory intervention to regulate oxidative stress in the brain is beneficial for managing PD. However, traditional natural antioxidants have failed to meet the clinical treatment demands due to insufficient activity and sustainability. Herein, Cu-doping zeolite imidazolate framework-8 (ZIF-8) nanozyme is designed to simulate Cu/Zn superoxide dismutase (SOD) by biomimetic mineralization. The nanozyme composite is then integrated into thermosensitive hydrogel (poly (lactic-co-glycolic acid)-poly (ethylene glycol)-poly (lactic-co-glycolic acid) (PLGA-PEG-PLGA)) to form an effective antioxidant system (Cu-ZIF@Hydrogel). The thermosensitive hydrogel incorporating nanozymes demonstrate distinct viscoelastic properties aimed at enhancing local nanozyme adhesion, prolonging nanozyme retention time, and modulating antioxidant activity, thus significantly improving the bioavailability of nanozymes. At the cellular and animal levels of PD, we find that Cu-ZIF@Hydrogel bypass the blood-brain barrier and efficiently accumulate in the nerve cells. Moreover, the Cu-ZIF@Hydrogel significantly alleviate the PD’s behavioral and pathological symptoms by reducing the neuroinflammatory levels in the lesion site. Therefore, the hydrogel-incorporating nanozyme system holds great potential as a simple and reliable avenue for managing PD.

Keywords: Parkinson’s disease, oxidative stress, bioinspired nanozyme, thermosensitive hydrogel, neuroinflammatory

References(24)

[1]

Wang, Q.; Li, T.; Yang, J. Y.; Zhao, Z. N.; Tan, K. Y.; Tang, S. W.; Wan, M. M.; Mao, C. Engineered exosomes with independent module/cascading function for therapy of Parkinson's disease by multistep targeting and multistage intervention method. Adv. Mater. 2022, 34, 2201406.

[2]

Burbulla, L. F.; Song, P. P.; Mazzulli, J. R.; Zampese, E.; Wong, Y. C.; Jeon, S.; Santos, D. P.; Blanz, J.; Obermaier, C. D.; Strojny, C. et al. Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 2017, 357, 1255–1261.

[3]

Dauer, W.; Przedborski, S. Parkinson's disease: Mechanisms and models. Neuron 2003, 39, 889–909.

[4]

Shehadeh, J.; Double, K. L.; Murphy, K. E.; Bobrovskaya, L.; Reyes, S.; Dunkley, P. R.; Halliday, G. M.; Dickson, P. W. Expression of tyrosine hydroxylase isoforms and phosphorylation at serine 40 in the human nigrostriatal system in Parkinson's disease. Neurobiol. Dis. 2019, 130, 104524.

[5]

Fang, X.; Yuan, M.; Zhao, F.; Yu, A. L.; Lin, Q. Y.; Li, S. Q.; Li, H. C.; Wang, X. Y.; Yu, Y. B.; Wang, X. et al. In situ continuous Dopa supply by responsive artificial enzyme for the treatment of Parkinson's disease. Nat. Commun. 2023 , 14, 2661.

[6]

Liu, L.; Li, M. C.; Xu, M. Z.; Wang, Z.; Zeng, Z.; Li, Y. Q.; Zhang, Y.; You, R.; Li, C. H.; Guan, Y. Q. Actively targeted gold nanoparticle composites improve behavior and cognitive impairment in Parkinson's disease mice. Mater. Sci. Eng. C 2020, 114, 111028.

[7]

Liu, T. F.; Xiao, B. W.; Xiang, F.; Tan, J. L.; Chen, Z.; Zhang, X. R.; Wu, C. Z.; Mao, Z. W.; Luo, G. X.; Chen, X. Y. et al. Ultrasmall copper-based nanoparticles for reactive oxygen species scavenging and alleviation of inflammation related diseases. Nat. Commun. 2020, 11, 2788.

[8]

Hao, C. L.; Qu, A. H.; Xu, L. G.; Sun, M. Z.; Zhang, H. Y.; Xu, C. L.; Kuang, H. Chiral molecule-mediated porous Cu x O nanoparticle clusters with antioxidation activity for ameliorating Parkinson's disease. J. Am. Chem. Soc. 2019, 141, 1091–1099.

[9]

Singh, N.; Savanur, M. A.; Srivastava, S.; D'Silva, P.; Mugesh, G. A redox modulatory Mn3O4 nanozyme with multi-enzyme activity provides efficient cytoprotection to human cells in a Parkinson's disease model. Angew. Chem., Int. Ed. 2017, 56, 14267–14271.

[10]

Li, Q.; Wu, T. T.; Akakuru, O. U.; Song, N. N.; Liu, W.; Jiang, W.; Fan, K. L. A dual synergetic nanoreactor for managing Parkinson’s disease by regulating inflammation and mitigating oxidative damage. Adv. Func. Mater 2023, 33, 2214826.

[11]

Tian, R. Z.; Ma, H. Y.; Ye, W.; Li, Y. J.; Wang, S. P.; Zhang, Z. R.; Liu, S. D.; Zang, M. S.; Hou, J. X.; Xu, J. Y. et al. Se-containing MOF coated dual-Fe-atom nanozymes with multi-Enzyme cascade activities protect against cerebral ischemic reperfusion injury. Adv. Funct. Mater. 2022, 32, 2204025.

[12]

McHugh, E. A.; Liopo, A. V.; Mendoza, K.; Robertson, C. S.; Wu, G.; Wang, Z.; Chen, W. Y.; Beckham, J. L.; Derry, P. J.; Kent, T. A. et al. Oxidized activated charcoal nanozymes: Synthesis, and optimization for in vitro and in vivo bioactivity for traumatic brain injury. Adv. Mater., in press, DOI: 10.1002/adma.202211239.

[13]

Wang, Z. R.; Zhao, Y.; Hou, Y. X.; Tang, G. H.; Zhang, R. F.; Yang, Y. L.; Yan, X. Y.; Fan, K. L. A Thrombin-activated peptide-templated nanozyme for remedying ischemic stroke via thrombolytic and neuroprotective actions. Adv. Mater., in press, DOI: 10.1002/adma.202210144.

[14]

Li, Q.; Liu, Y.; Zhang, Y. R.; Jiang, W. Immunogenicity-boosted cancer immunotherapy based on nanoscale metal-organic frameworks. J. Control. Release 2022, 347, 183–198.

[15]

Cui, W. T.; Yang, X.; Chen, X. Y.; Xiao, D. X.; Zhu, J. Y.; Zhang, M.; Qin, X.; Ma, X. H.; Lin, Y. F. Treating LRRK2-related Parkinson's disease by inhibiting the mTOR signaling pathway to restore autophagy. Adv. Funct. Mater. 2021, 31, 2105152.

[16]

Wang, Q. L.; Wang, X. Y.; Feng, Y. K. Chitosan hydrogel as tissue engineering scaffolds for vascular regeneration applications. Gels 2023, 9, 373.

[17]

Adak, A.; Das, G.; Barman, S.; Mohapatra, S.; Bhunia, D.; Jana, B.; Ghosh, S. Biodegradable neuro-compatible peptide hydrogel promotes neurite outgrowth, shows significant neuroprotection, and delivers anti-Alzheimer drug. ACS Appl. Mater. Interfaces 2017, 9, 5067–5076.

[18]

Ge, P. J.; Chang, S. H.; Wang, T.; Zhao, Q.; Wang, G.; He, B. An antioxidant and antibacterial polydopamine-modified thermo-sensitive hydrogel dressing for Staphylococcus aureus-infected wound healing. Nanoscale 2023, 15, 644–656.

[19]

Yang, J.; Zhang, R. F.; Zhao, H. Q.; Qi, H. F.; Li, J. Y.; Li, J. F.; Zhou, X. Y.; Wang, A. Q.; Fan, K. L.; Yan, X. Y. et al. Bioinspired copper single-atom nanozyme as a superoxide dismutase-like antioxidant for sepsis treatment. Exploration 2022, 2, 20210267.

[20]

Chen, Z. Y.; Chen, P.; Zhu, Y. Y.; Qian, J. Y.; Huang, X. W.; Zhang, W.; Zhang, H.; Mo, Q.; Lu, Y. T.; Zhang, Y. J. 2D cobalt oxyhydroxide nanozymes inhibit inflammation by targeting the NLRP3 inflammasome. Adv. Funct. Mater. 2023, 33, 2214693.

[21]

Wu, S.; Shi, Y.; Jiang, L. T.; Bu, W. Z.; Zhang, K.; Lin, W. Z.; Pan, C.; Xu, Z. B.; Du, J. W.; Chen, H. et al. N-Acetylcysteine-derived carbon dots for free radical scavenging in intervertebral disc degeneration. Adv. Healthcare Mater. 2023 , 12, 2300533.

[22]

Jiang, Y. X.; Rong, H. T.; Wang, Y. F.; Liu, S. E.; Xu, P.; Luo, Z.; Guo, L. M.; Zhu, T.; Rong, H. P.; Wang, D. S. et al. Single-atom cobalt nanozymes promote spinal cord injury recovery by anti-oxidation and neuroprotection. Nano Res. 2023, 16, 9752–9759.

[23]

Wang, Q.; Cheng, C. Q.; Zhao, S.; Liu, Q. Y.; Zhang, Y. H.; Liu, W. L.; Zhao, X. Z.; Zhang, H.; Pu, J.; Zhang, S. et al. A valence-engineered self-cascading antioxidant nanozyme for the therapy of inflammatory bowel disease. Angew. Chem., Int. Ed. 2022, 61, e202201101.

[24]

Kelso, G. F.; Porteous, C. M.; Coulter, C. V.; Hughes, G.; Porteous, W. K.; Ledgerwood, E. C.; Smith, R. A. J.; Murphy, M. P. Selective targeting of a redox-active ubiquinone to mitochondria within cells: Antioxidant and antiapoptotic properties. J. Biol. Chem. 2001, 276, 4588–4596.

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Publication history
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Acknowledgements

Publication history

Received: 13 August 2023
Revised: 31 October 2023
Accepted: 01 November 2023
Published: 20 December 2023
Issue date: February 2024

Copyright

© Tsinghua University Press 2023

Acknowledgements

We are grateful for the financial support by the CAS Interdisciplinary Innovation Team (No. JCTD-2020-08).

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