High Fe-Loading Single-Atom Catalyst Boosts ROS Production by Density Effect for Efficient Antibacterial Therapy
Corresponding Author: Jianlin Shi
Nano-Micro Letters,
Vol. 17 (2025), Article Number: 32
Abstract
The current single-atom catalysts (SACs) for medicine still suffer from the limited active site density. Here, we develop a synthetic method capable of increasing both the metal loading and mass-specific activity of SACs by exchanging zinc with iron. The constructed iron SACs (h3-FNC) with a high metal loading of 6.27 wt% and an optimized adjacent Fe distance of ~ 4 Å exhibit excellent oxidase-like catalytic performance without significant activity decay after being stored for six months and promising antibacterial effects. Attractively, a “density effect” has been found at a high-enough metal doping amount, at which individual active sites become close enough to interact with each other and alter the electronic structure, resulting in significantly boosted intrinsic activity of single-atomic iron sites in h3-FNCs by 2.3 times compared to low- and medium-loading SACs. Consequently, the overall catalytic activity of h3-FNC is highly improved, with mass activity and metal mass-specific activity that are, respectively, 66 and 315 times higher than those of commercial Pt/C. In addition, h3-FNCs demonstrate efficiently enhanced capability in catalyzing oxygen reduction into superoxide anion (O2·−) and glutathione (GSH) depletion. Both in vitro and in vivo assays demonstrate the superior antibacterial efficacy of h3-FNCs in promoting wound healing. This work presents an intriguing activity-enhancement effect in catalysts and exhibits impressive therapeutic efficacy in combating bacterial infections.
Highlights:
1 Fe single-atom catalysts (h3-FNCs) with high loading, high catalytic activity and high stability were synthesized via a method capable of increasing both the metal loading and mass-specific activity by exchanging zinc with iron.
2 The “density effect,” derived from the sufficiently high density of active sites, has been discovered for the first time, leading to a significant alteration in the intrinsic activity of single-atom metal sites.
3 The superior oxidase-like catalytic performance of h3-FNCs ensures highly effective bacterial eradication.
Keywords
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- Y. Chao, Z. Liu, Biomaterials tools to modulate the tumour microenvironment in immunotherapy. Nat. Rev. Bioeng. 1, 125–138 (2023). https://doi.org/10.1038/s44222-022-00004-6
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References
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M. Cao, C. Chen, Bioavailability of nanomaterials: bridging the gap between nanostructures and their bioactivity. Natl. Sci. Rev. 9, nwac119 (2022). https://doi.org/10.1093/nsr/nwac119
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B. Yang, Y. Chen, J. Shi, Reactive oxygen species (ROS)-based nanomedicine. Chem. Rev. 119, 4881–4985 (2019). https://doi.org/10.1021/acs.chemrev.8b00626
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F.P. Guengerich, Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem. Res. Toxicol. 14, 611–650 (2001). https://doi.org/10.1021/tx0002583
H. Li, C.S. Raman, P. Martásek, V. Král, B.S. Masters et al., Mapping the active site polarity in structures of endothelial nitric oxide synthase heme domain complexed with isothioureas. J. Inorg. Biochem. 81, 133–139 (2000). https://doi.org/10.1016/s0162-0134(00)00099-4
H. Fei, J. Dong, Y. Feng, C.S. Allen, C. Wan et al., General synthesis and definitive structural identification of MN4C4 single-atom catalysts with tunable electrocatalytic activities. Nat. Catal. 1, 63–72 (2018). https://doi.org/10.1038/s41929-017-0008-y
Z. Xiang, R. Mercado, J.M. Huck, H. Wang, Z. Guo et al., Systematic tuning and multifunctionalization of covalent organic polymers for enhanced carbon capture. J. Am. Chem. Soc. 137, 13301–13307 (2015). https://doi.org/10.1021/jacs.5b06266
J. Li, M.T. Sougrati, A. Zitolo, J.M. Ablett, I.C. Oğuz et al., Identification of durable and non-durable FeNx sites in Fe–N–C materials for proton exchange membrane fuel cells. Nat. Catal. 4, 10–19 (2021). https://doi.org/10.1038/s41929-020-00545-2
N.R. Sahraie, U.I. Kramm, J. Steinberg, Y. Zhang, A. Thomas et al., Quantifying the density and utilization of active sites in non-precious metal oxygen electroreduction catalysts. Nat. Commun. 6, 8618 (2015). https://doi.org/10.1038/ncomms9618
T. Mineva, I. Matanovic, P. Atanassov, M.-T. Sougrati, L. Stievano et al., Understanding active sites in pyrolyzed Fe–N–C catalysts for fuel cell cathodes by bridging density functional theory calculations and 57Fe Mössbauer spectroscopy. ACS Catal. 9, 9359–9371 (2019). https://doi.org/10.1021/acscatal.9b02586
A. Zitolo, V. Goellner, V. Armel, M.-T. Sougrati, T. Mineva et al., Identification of catalytic sites for oxygen reduction in iron- and nitrogen-doped graphene materials. Nat. Mater. 14, 937–942 (2015). https://doi.org/10.1038/nmat4367
Z. Yang, M. Xu, Y. Liu, F. He, F. Gao et al., Nitrogen-doped, carbon-rich, highly photoluminescent carbon dots from ammonium citrate. Nanoscale 6, 1890–1895 (2014). https://doi.org/10.1039/c3nr05380f
X. Wang, W. Chen, L. Zhang, T. Yao, W. Liu et al., Uncoordinated amine groups of metal-organic frameworks to anchor single Ru sites as chemoselective catalysts toward the hydrogenation of quinoline. J. Am. Chem. Soc. 139, 9419–9422 (2017). https://doi.org/10.1021/jacs.7b01686
J. Li, M. Chen, D.A. Cullen, S. Hwang, M. Wang et al., Atomically dispersed manganese catalysts for oxygen reduction in proton-exchange membrane fuel cells. Nat. Catal. 1, 935–945 (2018). https://doi.org/10.1038/s41929-018-0164-8
X. Cui, Z. Pan, L. Zhang, H. Peng, G. Zheng, Selective etching of nitrogen-doped carbon by steam for enhanced electrochemical CO2 reduction. Adv. Energy Mater. 7, 1701456 (2017). https://doi.org/10.1002/aenm.201701456
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G. Fang, F. Wei, J. Lin, Y. Zhou, L. Sun et al., Retrofitting Zr-oxo nodes of UiO-66 by Ru single atoms to boost methane hydroxylation with nearly total selectivity. J. Am. Chem. Soc. 145, 13169–13180 (2023). https://doi.org/10.1021/jacs.3c02121
J. Li, Q. Guan, H. Wu, W. Liu, Y. Lin et al., Highly active and stable metal single-atom catalysts achieved by strong electronic metal-support interactions. J. Am. Chem. Soc. 141, 14515–14519 (2019). https://doi.org/10.1021/jacs.9b06482
F. Gerson, W. Huber, in Electron spin resonance spectroscopy of organic radicals Organic radicals centered on one, two, or three atoms. (Wiley. Chap.7, 2003). https://doi.org/10.1002/3527601627
T. He, Y. Chen, Q. Liu, B. Lu, X. Song et al., Theory-guided regulation of FeN4 spin state by neighboring Cu atoms for enhanced oxygen reduction electrocatalysis in flexible metal-air batteries. Angew. Chem. Int. Ed. 61, e202201007 (2022). https://doi.org/10.1002/anie.202201007
L. Huang, J. Chen, L. Gan, J. Wang, S. Dong, Single-atom nanozymes. Sci. Adv. 5, eaav5490 (2019). https://doi.org/10.1126/sciadv.aav5490
M. Jin, X. Zhang, R. Shi, Q. Lian, S. Niu et al., Hierarchical CoP@Ni2P catalysts for pH-universal hydrogen evolution at high current density. Appl. Catal. B Environ. 296, 120350 (2021). https://doi.org/10.1016/j.apcatb.2021.120350
D.A. Reed, B.K. Keitz, J. Oktawiec, J.A. Mason, T. Runčevski et al., A spin transition mechanism for cooperative adsorption in metal–organic frameworks. Nature 550, 96–100 (2017). https://doi.org/10.1038/nature23674
Y. Xie, X. Chen, K. Sun, J. Zhang, W.-H. Lai et al., Direct oxygen-oxygen cleavage through optimizing interatomic distances in dual single-atom electrocatalysts for efficient oxygen reduction reaction. Angew. Chem. Int. Ed. 62, e202301833 (2023). https://doi.org/10.1002/anie.202301833
A.T. Dharmaraja, Role of reactive oxygen species (ROS) in therapeutics and drug resistance in cancer and bacteria. J. Med. Chem. 60, 3221–3240 (2017). https://doi.org/10.1021/acs.jmedchem.6b01243
S.R. Partridge, S.M. Kwong, N. Firth, S.O. Jensen, Mobile genetic elements associated with antimicrobial resistance. Clin. Microbiol. Rev. 31, e00088 (2018). https://doi.org/10.1128/cmr.00088-17
R. Nussinov, M. Zhang, R. Maloney, C.J. Tsai, B.R. Yavuz et al., Mechanism of activation and the rewired network: New drug design concepts. Med. Res. Rev. 42, 770–799 (2022). https://doi.org/10.1002/med.21863
W. Gao, J. He, L. Chen, X. Meng, Y. Ma et al., Deciphering the catalytic mechanism of superoxide dismutase activity of carbon dot nanozyme. Nat. Commun. 14, 160 (2023). https://doi.org/10.1038/s41467-023-35828-2
M. Chang, Z. Hou, M. Wang, C. Yang, R. Wang et al., Single-atom Pd nanozyme for ferroptosis-boosted mild-temperature photothermal therapy. Angew. Chem. Int. Ed. 60, 12971–12979 (2021). https://doi.org/10.1002/anie.202101924
Z.-H. Zhao, J.-R. Huang, P.-Q. Liao, X.-M. Chen, Highly efficient electroreduction of CO2 to ethanol via asymmetric C–C coupling by a metal-organic framework with heterodimetal dual sites. J. Am. Chem. Soc. 145, 26783–26790 (2023). https://doi.org/10.1021/jacs.3c08974