Efficient nanozyme engineering for antibacterial therapy
doi: 10.1088/2752-5724/ac7068
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Abstract: Antimicrobial resistance (AMR) poses a huge threat to human health. It is urgent to explore efficient ways to suppress the spread of AMR. Antibacterial nanozymes have become one of the powerful weapons to combat AMR due to their enzyme-like catalytic activity with a broad-spectrum antibacterial performance. However, the inherent low catalytic activity of nanozymes limits their expansion into antibacterial applications. In this regard, a variety of advanced chemical design strategies have been developed to improve the antimicrobial activity of nanozymes. In this review, we have summarized the recent progress of advanced strategies to engineer efficient nanozymes for fighting against AMR, which can be mainly classified as catalytic activity improvement, external stimuli, bacterial affinity enhancement, and multifunctional platform construction according to the basic principles of engineering efficient nanocatalysts and the mechanism of nanozyme catalysis. Moreover, the deep insights into the effects of these enhancing strategies on the nanozyme structures and properties are highlighted. Finally, current challenges and future perspectives of antibacterial nanozymes are discussed for their future clinical potential.
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Figure 1. Bioinspired synthesis of SAzymes with enzyme-like active centers. (A) Atomically isolated Fe-N4 sites on nitrogen-doped amorphous carbon (SAF NCs) mimicking the active center of HRP. (i) HRP structure with corresponding active center. (ii) Schematic illustration of SAF NCs model and its catalytic decomposition of H2O2 to ‧OH via the Fe-N4 single sites. (iii) TEM image of SAF NCs. (iv) HAADF-STEM image of SAF NCs. The bright dots as some marked by yellow circles are single iron atoms. Reprinted with permission from [63] John Wiley & Sons [© 2019 Wiley-VCH GmbH]. (B) Monodispersed ZIF-8 derived carbon nanospheres with a zinc-centered porphyrin-like structure (PMCS). (i) Cytochrome c structure with corresponding active center. (ii) PMCS model mimicking the active center of cytochrome c. (iii) TEM image of PMCS. (iv) HAADF-STEM image of Cu SASs/NPC. Reprinted with permission from [66] John Wiley & Sons [© 2019 Wiley-VCH GmbH]. (C) Hollow N-doped carbon sphere doped with a single-atom copper species (Cu-HNCS) mimicking the active center of laccase. (i) Laccase structure with corresponding active center. (ii) Model of Cu-HNCS mimicking the active center of laccase. (iii) TEM image of Cu-HNCS. (iv) HAADF-STEM image of Cu-HNCS. Reprinted with permission from [73] John Wiley & Sons [© 2020 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim].
Figure 2. (A) (i) Catalytic mechanisms of decomposition of H2O2 into ‧OH over Fe-N4-C SAzymes; (ii) energy diagrams of Fe, Co, Zn-N-C SAzymes in proposed reaction process; (iii) EPR signals of ‧OH for different M-N-C SAzymes; (iv) time-dependent absorbance of 3,3-,5,5--Tetramethylbenzidine (TMB) catalyzed by Fe-C-N SAzymes with Fe-atom loading of 1.3 and 13.5 wt %, respectively. Reprinted with permission from [80]. © 2020, American Chemical Society. (B) (i) TEM image of R-CMs; (ii and iii) HRTEM image of RCMs; (iv) time-dependent absorbance changes at 652 nm of TMB for different MoS2; (v) TA signal for different MoS2 nanozymes under different conditions; (vi) proposed catalytic mechanism of decomposition of H2O2 into ‧OH over S-defect MoS2; (vii) energy diagrams of S-defect MoS2 in catalytic process. Reprinted with permission from [43]. John Wiley & Sons [© 2019 Wiley-VCH GmbH].
Figure 3. (A) Schematic illustration of ATP stimulation for enhancing the catalytic decomposition of H2O2 over Fe3O4 NPs for antibacterial application. Reprinted with permission from [38] © 2020 Elsevier. (B) Schematic illustration of glucose stimulation for enhancing the catalytic decomposition of H2O2 over APGH nanozymes. Reprinted with permission from [90] John Wiley and Sons [© 2021 WileyVCH GmbH]. (C) Schematic illustration of visible light stimulation for enhancing the catalytic decomposition of H2O2 over CuO NPs. Reprinted with permission from [39] © 2018, American Chemical Society. (D) Schematic illustration of NIR stimulation for enhancing the catalytic decomposition of H2O2 over N-GDQDs/AuAg NC. Reprinted with permission from [35] © 2022 American Chemical Society. (E) Schematic illustration of AMF stimulation for enhancing the catalytic decomposition of H2O2 over AIron NPs. Reprinted with permission from [92] © 2020 Elsevier B.V.
Figure 4. (A) Scanning electron microscope (SEM) (i) and TEM (ii) images of R-CMs, and SEM images of interaction between R-CMs and bacteria (iii and iv). Reprinted with permission from [43] John Wiley & Sons [© 2019 Wiley-VCH GmbH]. (B) SEM (i) and TEM (ii) images of MoS2/rGO VHS, and SEM images of interaction between MoS2/rGO VHS and bacteria (iii and iv). Reprinted with permission from [81] John Wiley & Sons [© 2020 Wiley-VCH GmbH]. (C) SEM (i) and TEM (ii) images of Fe3O4@MoS2-Ag, and SEM images of interaction between Fe3O4@MoS2-Ag and bacteria (iii and iv). Reprinted with permission from [82] © 2020 Elsevier B.V. (D) SEM (i) and TEM (ii) images of RCF, and SEM images of interaction between RCF and bacteria (iii and iv). Reprinted with permission from [102] © 2021, American Chemical Society.
Figure 5. Pseudopodia-like MOF@COF nanozyme for antibacterial therapy. (A) (i) TEM image of NMCTP-TTA and (ii-vi) corresponding element mappings of O, N, Fe, C, and Merge, respectively. (B) Morphologies of E. coli (i) and S. aureus (iv), and treated with NM-88 + H2O2 (ii and v) and NMCTP-TTA + H2O2 (iii and vi). (C) In vivo catalytic therapy of S. aureus wound-infection. (i) Schematic illustration of treatment strategy; (ii) photographs of wound-healing performance treated by different nanozyme catalysts; (iii) corresponding photographs of bacterial colonies isolated from different treated wound; (iv) H&E staining and immunohistochemical analysis of skin tissues. Reprinted with permission from [58] John Wiley and Sons [© 2020 WileyVCH GmbH].
Table 1. Classification of antibacterial nanozymes based on chemical design strategies for enhancing antibacterial efficiency.
Strategies Enhanced mechanism Chemical approaches Nanomaterials Catalytic activity Km-H2O2 (mM) Vmax-H2O2 (10-8 M s-1) Bacteria Results References Catalytic activity improvement Enzymic active centers mimicking Pyrolysis and acid-etching of MOFs precursors to create metalloenzyme-like atomically dispersed MNx active centers. FeN4-SAF NCs POD-like activity 11.95 22.3 E. coli, S. aureus The Fe-N4-SAF and Fe-N5 SA/CNF with active centers similar to HRP and cytochrome P450 shows much higher Vmax than Fe3O4 and CeO2 NPs, respectively. MOF@COF showed enhanced activity as compare to blank MOFs. [63] ZnN4-PMCSs POD-like activity 40.16 12.15 Pseudomonas aeruginosa [66] CuN4-SASs/NPC POD-like activity E. coli, MRSA [64] FeN5 SA/CNF OXD-like activity 0.148 (TMB) 75.8 (TMB) E. coli, S. aureus [62] Control the growth of COFs to provide spatial microenvironment around active sites (MOFs). NMCTP-TTA POD-like activity 0.458 57 E. coli, S. aureus [58] Downsizing nanoparticles Ultrathin 2D MOFs confine the growth of ultrasmall Au clusters by in-situ reduction. UsAuNPs/MOFs POD-like activity 7.94 E. coli, S. aureus The UsAuNPs/MOFs, SA-Pt/g-C3N4-K, Fe-N-C SAzyme with small-sized metal clusters or single atom sites displayed enhanced catalytic activity compared to their large counterparts. [20] Pyrolysis of atomically dispersed Pt, Fe supported precursors. SA-Pt/g-C3N4-K POD-like activity 0.002 175.0 E. coli [27] Fe-N-C SAzyme POD-like activity 4.84 11.8 E. coli, S. aureus [61] Engineering defects Bare Cu NWs, rGO, and Fe3O4 provided nucleation sites for the nucleation and growth of MoS2 nanosheets with defect-rich edges. R-CMs POD-like activity 0.032 E. coli, S. aureus The defect-rich edges for R-CMs, MoS2/rGO, Fe3O4@MoS2-Ag enhanced their H2O2 affinity as compared to MoS2. [43] MoS2/rGO POD-like activity 0.26 25.6 E. coli, S. aureus [81] Fe3O4@MoS2-Ag POD-like activity 1.0 18.2 E. coli [82] Composition regulation N-doped sponge-like carbon spheres (N-SCSs) were prepared through the pyrolysis of colloidal silica/polyaniline assemblies. Cu-doped phosphate-based glass (Cu-PBG) was prepared by hydrothermal method. N-SCSs Cu-PBG POD-like activity POD-like activity 81.53 23.3 E. coli, S. aureusE. coli, S. aureus N, B, Cu doping endows carbon materials or PBG with multi-enzyme activities. [55] [83] CuCo2S4 can be controllably prepared by hydrothermal method, while Pd-Ir cubes can be synthesized by the wet chemical reduction method. CuCo2S4 POD-like activity 209.9 23.3 E. coli, S. aureus MRSA Bimetallic nanozymes with dual active sites shows remarkably synergistic enhancement in catalytic activity. [84] Ir-Pd cubes POD-like activity 0.034 5.1 [85] Ultrathin 2D MOFs supported ultrasmall Au nanoparticles were prepared by in situ reduction. UsAuNPs/MOFs POD-like activity 7.94 E. coli, S. aureus 2D MOFs significantly improved the catalytic activity of UsAuNPs/MOFs as compared to Au NPs. [20] Different shaped Fe3O4 magnetite nanoparticles (MNPs) were synthesized by solvent-thermal method, while bamboo-like nitrogen-doped carbon nanotubes encapsulating cobalt nanoparticles (N-CNTs@Co) were prepared by pyrolysis of cobalt cyanide cobalt at high temperature. TO-shaped Fe3O4 MNPs Bamboo-like N-CNTs@Co POD-like activity OXD-like activity 0.1 (TMB) 130 (TMB) E. coli, S. aureus Different shapes of Fe3O4 MNPs and N-CNTs@Co displayed different catalytic activity [86] [87] External stimuli pH The addition of ATP or the microenvironment having glucose can be used as a trigger to induce the changes of pH and even H2O2 concentration, thus resulting in enhanced POD-like activities. A hyaluronic acid capsule functionalized with aptamer-Pt NPs and glucose oxidase (APGH) was constructed to break the limitations of pH and H2O2. ATP + Fe3O4 NPs APGH + glucose from bacteria POD-like activity POD-like activity E. coli, Bacillus subtilisS. aureus With ATP, the ‧OH generation for Fe3O4 is about 17 folds higher than that without ATP at neutral pH, resulting in enhanced antibacterial efficiency. When bacteria interacted with APGH, the released glucose oxidase could catalyze glucose into glucose acid and H2O2, providing raw-materials for Pt NPs to catalytic the ‧OH generation. [38] [90] Visible light Introduction of semiconductor to fabricate nanozymes can be used to enhance the catalytic activity of nanozymes under visible light illumination. CuO nanorods + light POD-like activity 3.4 (in light) 14.8 (in dark) 10.9 (in light) 0.6 (in dark) E. coli With visible light irradiation, the nanozyme showed enhanced catalytic activity due to the improved affinity to H2O2. [39] MoS2/rGO + light POD-like activity 0.26 (in dark) 25.6 (in dark) E. coli, S. aureus [81] TiO2 NTs@MoS2 + light POD-like activity 0.085 (in dark) 120.5 (in dark) E. coli, S. aureus [45] NIR The activity of nanozymes with absorption in NIR range can be enhanced by NIR irradiation. Au/CeO2 + NIR POD-like activity 0.006 (with NIR) 0.007 (in dark) 133.4 (with NIR) 82.6 (in dark) E. coli, S. aureus The catalytic activities of nanozymes with strong NIR absorption can be significantly enhanced by NIR generated photothermal effect. Moreover, with semiconductor hybrid, the plasmonic effect can also produce hot carrier to further enhance the catalytic activities. [91] N-GDQDs/AuAg NC + NIR POD-like activity 0.72 (with NIR) 1.24 (in dark) 10.52 (with NIR) 4.75 (in dark) E. coli, S. aureus [35] Au NPTs + NIR POD-like activity MRSA, E. coli [26] AuPt NDs + NIR POD-like activity E. coli, S. aureus [32] NiS2 NPs + NIR POD-like activity MRSA, E. coli [48] WS2 QDs + NIR POD-like activity Mu50, E. coli [126] MoO3-x NDs +NIR POD-like activity 0.26 (in dark) 15.2 (in dark) MRSA, E. coli [127] R-CMs + NIR POD-like activity 0.032 (in dark) E. coli, S. aureus [43] Fe3O4@MoS2-Ag + NIR POD-like activity 1.0 (in dark) 18.2 (in dark) E. coli [82] PEG-MoS2 NFs + NIR POD-like activity E. coli, B. subtilis [106] Cu2MoS4 + NIR POD/OXD-like activity 25.46 (in dark) 42.81 (in dark) E. coli, S. aureus, MRSA [111] CuN4-SASs/NPC + NIR POD-like activity 11.95 (in dark) 22.3 (in dark) E. coli, S. aureus [63] CuN4-SASs/NPC + NIR POD-like activity E. coli, MRSA [64] Mesoporous FeN4-C SAzymes + NIR POD-like activity 4.84 (in dark) 11.8 (in dark) E. coli, S. aureus [61] RFC + NIRII POD-like activity E. coli, S. aureus, MRSA [102] N-SCSs + NIR POD/OXD-like activity 81.53 (in dark) 23.27 (in dark) E. coli, S. aureus [55] PEG@zirconium-ferrocene MOF + NIR POD-like activity E. coli [107] ZIF8-PEG@Zn/Pt-CN + NIR POD-like activity 0.067 (in dark) 5.11 (in dark) E. coli, S. aureus [128] UiO-66-NH-CO-MoS2 + NIR POD-like activity 0.23 (in dark) 15.7 (in dark) MRSA, AREC [129] AMF Amorphous iron nanoparticles (AIronNPs) were prepared by chemical precipitation with PVP, F-127, and ammonium iron (III) citrate as raw materials AIronNPs + AMF POD-like activity 41.36 (with AMF) 117.23 (without AMF) 1.19 (with AMF) 1.45 (without AMF) E. coli, S. aureus The AMF can significantly improve the catalytic activity of AIronNPs due to the enhanced release of iron ions. [92] Bacterial affinity enhancement Rough surface engineering Bare Cu NWs, rGO, and Fe3O4 provided nucleation sites for the nucleation and growth of MoS2 nanosheets with defect-rich edges, while RFC was synthesized by a three-step template-carbonization corrosion method. R-CMs POD-like activity 0.032 E. coli, S. aureus Nanozymes with strong bacterial capture ability due to the rough surfaces can localize the ROS-mediated damages around the bacteria, thus resulting in the enhanced catalytic therapeutic efficiency. [43] MoS2/rGO POD-like activity 0.26 25.6 E. coli, S. aureus [81] Fe3O4@MoS2-Ag POD-like activity 1.0 18.2 E. coli [82] RFC POD-like activity E. coli, S. aureus, MRSA [102] Pseudopodia mimicking The growth of COFs on MOFs form pseudopodia-like shapes, allowing the bacterial capture. NMCTP-TTA POD-like activity 0.458 57 E. coli, S. aureus [58] Multifunctional nanozyme-based platforms PTT Nanozymes with NIR absorption can be used for CDT and PTT combined nanoplatforms. Listed in the part of NIR stimuli CDT + PTT E. coli, S. aureus, MRSA, Mu50, AREC Nanozymes with strong NIR absorption can be a benign nanoplatform for combining CDT and PTT for synergistic enhanced antibacterial applications. As listed above Drug release Using MOF-based nanozymes as nanocarriers to load metal ions or drugs due to the porosity and large surface area of MOFs. Pd-MOF@PAzo@SNP CDT + NO E. coli, S. aureus, Biofilm The MOF-nanozyme based nanoplatforms can be used as a good synergistic germicidal system for chronic wound disinfection. [113] ZIF8/Au-GOx NPs CDT + Zn2+ E. coli, S. aureus [114] NH2-MIL-88B(Fe)-Ag CDT + Ag+ E. coli, S. aureus [112] Fe3O4@MoS2-Ag CDT + Ag+ E. coli [82] Cascaded reactions The cascaded nanozymes are generally composed of POD-like nanozymes and GOx, which can be easily loaded on nanomaterials by the electrostatic interaction. APGH Glucose oxidation + POD catalysis S. aureus Owing to cascaded reactions, the nanozymes can act even at neutral conditions without H2O2 addition Since GOx catalyze the conversion of glucose into gluconic acid and H2O2. [90] Fe3O4-GOx Glucose oxidation + POD catalysis E. coli, MRSA [116] GOX-on-Fe-iCOF Glucose oxidation + POD catalysis E. coli, S. aureus [117] Fe2(MoO4)3@GOx Glucose oxidation + POD catalysis E. coli, MRSA [118] Pro-inflammatory CuFe5O8 nanocubes can be synthesized by the solvent-thermal method. CuFe5O8 nanocubes CDT + Pro-inflammatory E. coli, S. aureus, Biofilm CuFe5O8 nanocubes exhibit space-selective CDT and induce pro-inflammatory macrophage polarization for curing implant-related infection due to the different pH and H2O2 concentration inside and outside the biofilm. [119] Hydrogel Hydrogel can provide a versatile and porous framework of loading different kinds of nanomaterials for constructing a multifunctional platform for antibacterial therapy. MoS2-hydrogel POD-like catalysis + bacterial capture E. coli Owing to the multiple functions of the hydrogel, the antibacterial therapeutic effect and wound healing efficacy can be significantly enhanced. [70] MoS2@TA/Fe-PVA/Dex hydrogels POD/CAT like catalysis + PTT + tannic acid anti-inflammatory E. coli, S. aureus [122] Tannic acid chelated-Ag hydrogel POD-like catalysis + Ag + tannic acid anti-inflammatory Staphylococcus epidermidis, E. coli. [124] CNT@MoS2 hydrogels POD/SOD/CAT-like catalysis + PTT E. coli, S. aureus [125] Nanozymes without enhancements HRP POD-like activity 11.63 2.758 [66] Fe3O4 NPs POD-like activity 150.5 0.292 [63] Nano-CeO2 OXD-like activity 0.420 (TMB) 0.100 (TMB) [130] NM-88 POD-like activity 0.913 21.3 [58] MSN-AuNPs POD-like activity 15.81 17.30 [78] Pt-PCN POD-like activity 7.362 0.252 [131] MoS2 POD-like activity 60.87 [43] CuS POD-like activity 264.1 12.6 [84] CoS POD-like activity 114.5 5.9 [84] Pd cubes POD-like activity 0.07 6.5 [85] -
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