Dual-Atom Nanozyme Eye Drops Attenuate Inflammation and Break the Vicious Cycle in Dry Eye Disease
Corresponding Author: Jingguo Li
Nano-Micro Letters,
Vol. 16 (2024), Article Number: 120
Abstract
Dry eye disease (DED) is a major ocular pathology worldwide, causing serious ocular discomfort and even visual impairment. The incidence of DED is gradually increasing with the high-frequency use of electronic products. Although inflammation is core cause of the DED vicious cycle, reactive oxygen species (ROS) play a pivotal role in the vicious cycle by regulating inflammation from upstream. Therefore, current therapies merely targeting inflammation show the failure of DED treatment. Here, a novel dual-atom nanozymes (DAN)-based eye drops are developed. The antioxidative DAN is successfully prepared by embedding Fe and Mn bimetallic single-atoms in N-doped carbon material and modifying it with a hydrophilic polymer. The in vitro and in vivo results demonstrate the DAN is endowed with superior biological activity in scavenging excessive ROS, inhibiting NLRP3 inflammasome activation, decreasing proinflammatory cytokines expression, and suppressing cell apoptosis. Consequently, the DAN effectively alleviate ocular inflammation, promote corneal epithelial repair, recover goblet cell density and tear secretion, thus breaking the DED vicious cycle. Our findings open an avenue to make the DAN as an intervention form to DED and ROS-mediated inflammatory diseases.
Highlights:
1 A dual-atom nanozyme (DAN) was successfully prepared based on Fe and Mn bimetallic single-atom embedded in N-doped carbon material and modified with hydrophilic polymer.
2 The DAN possess excellent enzyme catalytic activity and attenuate dramatically inflammation by inhibiting the reactive oxygen species (ROS)/NLRP3 signal axis.
3 The DAN break the vicious cycle in dry eye disease and is a potential strategy for treating dry eye disease.
Keywords
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- R. Zhang, M. Park, A. Richardson, N. Tedla, E. Pandzic et al., Dose-dependent benzalkonium chloride toxicity imparts ocular surface epithelial changes with features of dry eye disease. Ocul. Surf. 18(1), 158–169 (2020). https://doi.org/10.1016/j.jtos.2019.11.006
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References
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F.E. Hakim, A.V. Farooq, Dry eye disease: An update in 2022. JAMA 327(5), 478–479 (2022). https://doi.org/10.1001/jama.2021.19963
K. Walter, What is dry eye disease? JAMA 328(1), 84 (2022). https://doi.org/10.1001/jama.2022.5978
D. Wirta, Update on dry eye disease. JAMA 327(23), 2355–2356 (2022). https://doi.org/10.1001/jama.2022.6369
S.H. Liu, I.J. Saldanha, A.G. Abraham, T. Rittiphairoj, S. Hauswirth et al., Topical corticosteroids for dry eye. Cochrane Database Syst. Rev. 10, CD015070 (2022). https://doi.org/10.1002/14651858.CD015070.pub2
S.C. Pflugfelder, C.S. de Paiva, The pathophysiology of dry eye disease: what we know and future directions for research. Ophthalmology 124(11), S4–S13 (2017). https://doi.org/10.1016/j.ophtha.2017.07.010
W. Ouyang, S. Wang, D. Yan, J. Wu, Y. Zhang et al., The cGAS-STING pathway-dependent sensing of mitochondrial DNA mediates ocular surface inflammation. Signal Transduct. Target. Ther. 8, 371 (2023). https://doi.org/10.1038/s41392-023-01624-z
G.S. Shadel, T.L. Horvath, Mitochondrial ROS signaling in organismal homeostasis. Cell 163(3), 560–569 (2015). https://doi.org/10.1016/j.cell.2015.10.001
Q. Zheng, L. Li, M. Liu, B. Huang, N. Zhang et al., In situ scavenging of mitochondrial ROS by anti-oxidative MitoQ/hyaluronic acid nanops for environment-induced dry eye disease therapy. Chem. Eng. J. 398, 125621 (2020). https://doi.org/10.1016/j.cej.2020.125621
H.J. Forman, H. Zhang, Targeting oxidative stress in disease: promise and limitations of antioxidant therapy. Nat. Rev. Drug Discov. 20, 689–709 (2021). https://doi.org/10.1038/s41573-021-00233-1
R.C. Coll, A.A.B. Robertson, J.J. Chae, S.C. Higgins, R. Muñoz-Planillo et al., A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248–255 (2015). https://doi.org/10.1038/nm.3806
K.C. Barnett, S. Li, K. Liang, J.P.-Y. Ting, A 360° view of the inflammasome: mechanisms of activation, cell death, and diseases. Cell 186(11), 2288–2312 (2023). https://doi.org/10.1016/j.cell.2023.04.025
K. Ciazynska, The activated inflammasome. Nat. Struct. Mol. Biol. 30, 125 (2023). https://doi.org/10.1038/s41594-023-00934-8
S.H. Baik, V.K. Ramanujan, C. Becker, S. Fett, D.M. Underhill et al., Hexokinase dissociation from mitochondria promotes oligomerization of VDAC that facilitates NLRP3 inflammasome assembly and activation. Sci. Immunol. 8, eade7652 (2023). https://doi.org/10.1126/sciimmunol.ade7652
S. Li, Z. Lu, Y. Huang, Y. Wang, Q. Jin et al., Anti-oxidative and anti-inflammatory micelles: break the dry eye vicious cycle. Adv. Sci. 9(17), e2200435 (2022). https://doi.org/10.1002/advs.202200435
M.K. Rhee, F.S. Mah, Inflammation in dry eye disease: How do we break the cycle? Ophthalmology 124(11), S14–S19 (2017). https://doi.org/10.1016/j.ophtha.2017.08.029
R. Zhou, A.S. Yazdi, P. Menu, J. Tschopp, A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011). https://doi.org/10.1038/nature09663
J. Tschopp, K. Schroder, NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat. Rev. Immunol. 10, 210–215 (2010). https://doi.org/10.1038/nri2725
L.K. Billingham, J.S. Stoolman, K. Vasan, A.E. Rodriguez, T.A. Poor et al., Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat. Immunol. 23, 692–704 (2022). https://doi.org/10.1038/s41590-022-01185-3
X. Yu, P. Lan, X. Hou, Q. Han, N. Lu et al., HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production. J. Hepatol. 66(4), 693–702 (2017). https://doi.org/10.1016/j.jhep.2016.12.018
Y. Ruan, Y. Xiong, W. Fang, Q. Yu, Y. Mai et al., Highly sensitive curcumin-conjugated nanotheranostic platform for detecting amyloid-beta plaques by magnetic resonance imaging and reversing cognitive deficits of Alzheimer’s disease via NLRP3-inhibition. J. Nanobiotechnology 20, 322 (2022). https://doi.org/10.1186/s12951-022-01524-4
Y. Gan, G. Zhao, Z. Wang, X. Zhang, M.X. Wu et al., Bacterial membrane vesicles: physiological roles, infection immunology, and applications. Adv. Sci. 10(25), e2301357 (2023). https://doi.org/10.1002/advs.202301357
H. Xiang, W. Feng, Y. Chen, Single-atom catalysts in catalytic biomedicine. Adv. Mater. 32(8), e1905994 (2020). https://doi.org/10.1002/adma.201905994
J. Li, S. Song, J. Meng, L. Tan, X. Liu et al., 2D MOF periodontitis photodynamic ion therapy. J. Am. Chem. Soc. 143(37), 15427–15439 (2021). https://doi.org/10.1021/jacs.1c07875
H. Gao, M. Sun, Y. Duan, Y. Cai, H. Dai et al., Controllable synthesis of lignin nanops with antibacterial activity and analysis of its antibacterial mechanism. Int. J. Biol. Macromol. 246, 125596 (2023). https://doi.org/10.1016/j.ijbiomac.2023.125596
Q. Qu, W. Cheng, X. Zhang, A. Zhou, Y. Deng et al., Multicompartmental microcapsules for enzymatic cade reactions prepared through gas shearing and surface gelation. Biomacromol 23(9), 3572–3581 (2022). https://doi.org/10.1021/acs.biomac.2c00324
H. Rashidzadeh, F. Seidi, M. Ghaffarlou, M. Salehiabar, J. Charmi et al., Preparation of alginate coated Pt nanop for radiosensitization of breast cancer tumor. Int. J. Biol. Macromol. 233, 123273 (2023). https://doi.org/10.1016/j.ijbiomac.2023.123273
A. Madni, R. Kousar, N. Naeem, F. Wahid, Recent advancements in applications of chitosan-based biomaterials for skin tissue engineering. J. Bioresour. Bioprod. 6(1), 11–25 (2021). https://doi.org/10.1016/j.jobab.2021.01.002
Q. Qu, J. Zhang, X. Chen, H. Ravanbakhsh, G. Tang et al., Triggered release from cellulose microps inspired by wood degradation by fungi. ACS Sustain. Chem. Eng. 9(1), 387–397 (2021). https://doi.org/10.1021/acssuschemeng.0c07514
Z. Zeng, M. Zhu, L. Chen, Y. Zhang, T. Lu et al., Design the molecule structures to achieve functional advantages of hydrogel wound dressings: advances and strategies. Compos. B Eng. 247, 110313 (2022). https://doi.org/10.1016/j.compositesb.2022.110313
X. Liu, Q. Liu, X. He, G. Yang, X. Chen et al., NIR-II-enhanced single-atom-nanozyme for sustainable accelerating bacteria-infected wound healing. Appl. Surf. Sci. 612, 155866 (2023). https://doi.org/10.1016/j.apsusc.2022.155866
C. Peng, R. Pang, J. Li, E. Wang, Current advances on the single-atom nanozyme and its bioapplications. Adv. Mater. (2023). https://doi.org/10.1002/adma.202211724
T. Hu, Z. Gu, G.R. Williams, M. Strimaite, J. Zha et al., Layered double hydroxide-based nanomaterials for biomedical applications. Chem. Soc. Rev. 51(14), 6126–6176 (2022). https://doi.org/10.1039/d2cs00236a
X. Zhou, S. Zhang, Y. Liu, J. Meng, M. Wang et al., Antibacterial cade catalytic glutathione-depleting MOF nanoreactors. ACS Appl. Mater. Interfaces 14(9), 11104–11115 (2022). https://doi.org/10.1021/acsami.1c24231
R. Zeng, Y. Li, X. Hu, W. Wang, Y. Li et al., Atomically site synergistic effects of dual-atom nanozyme enhances peroxidase-like properties. Nano Lett. 23(13), 6073–6080 (2023). https://doi.org/10.1021/acs.nanolett.3c01454
L. Chen, F. Wu, Y. Pang, D. Yan, S. Zhang et al., Therapeutic nanocoating of ocular surface. Nano Today 41, 101309 (2021). https://doi.org/10.1016/j.nantod.2021.101309
Z. Li, R. Liu, Q. Ma, X. Yu, Z. Xu et al., Eyeliner tattoos disturb ocular surface homeostasis. Ocul. Surf. 23, 216–218 (2022). https://doi.org/10.1016/j.jtos.2021.10.008
H. Ou, Y. Qian, L. Yuan, H. Li, L. Zhang et al., Spatial position regulation of Cu single atom site realizes efficient nanozyme photocatalytic bactericidal activity. Adv. Mater. 35(46), e2305077 (2023). https://doi.org/10.1002/adma.202305077
X. Dai, H. Liu, B. Cai, Y. Liu, K. Song et al., A bioinspired atomically thin nanodot supported single-atom nanozyme for antibacterial textile coating. Small 19(47), e2303901 (2023). https://doi.org/10.1002/smll.202303901
C.-C. Hou, L. Zou, L. Sun, K. Zhang, Z. Liu et al., Single-atom iron catalysts on overhang-eave carbon cages for high-performance oxygen reduction reaction. Angew. Chem. Int. Ed. 59(19), 7384–7389 (2020). https://doi.org/10.1002/anie.202002665
W. Feng, X. Han, H. Hu, M. Chang, L. Ding et al., 2D vanadium carbide MXenzyme to alleviate ROS-mediated inflammatory and neurodegenerative diseases. Nat. Commun. 12, 2203 (2021). https://doi.org/10.1038/s41467-021-22278-x
N.K. Campbell, H.K. Fitzgerald, A. Dunne, Regulation of inflammation by the antioxidant haem oxygenase 1. Nat. Rev. Immunol. 21, 411–425 (2021). https://doi.org/10.1038/s41577-020-00491-x
H. Xian, K. Watari, E. Sanchez-Lopez, J. Offenberger, J. Onyuru et al., Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling. Immunity 55(8), 1370-1385.e8 (2022). https://doi.org/10.1016/j.immuni.2022.06.007
R. Zhang, M. Park, A. Richardson, N. Tedla, E. Pandzic et al., Dose-dependent benzalkonium chloride toxicity imparts ocular surface epithelial changes with features of dry eye disease. Ocul. Surf. 18(1), 158–169 (2020). https://doi.org/10.1016/j.jtos.2019.11.006
L. García-Posadas, R.R. Hodges, D. Li, M.A. Shatos, T. Storr-Paulsen et al., Interaction of IFN-γ with cholinergic agonists to modulate rat and human goblet cell function. Mucosal Immunol. 9(1), 206–217 (2016). https://doi.org/10.1038/mi.2015.53
Y. Dai, J. Zhang, J. Xiang, Y. Li, D. Wu et al., Calcitriol inhibits ROS-NLRP3-IL-1β signaling axis via activation of Nrf2-antioxidant signaling in hyperosmotic stress stimulated human corneal epithelial cells. Redox Biol. 21, 101093 (2019). https://doi.org/10.1016/j.redox.2018.101093