5-Fluorouracil-containing inorganic iron oxide/platinum nanozymes with dual drug delivery and enzyme-like activity for the treatment of breast cancer

Intrinsic enzyme-mimic activity of inorganic nanoparticles has been widely used for nanozymatic anticancer and antibacterial treatment. However, the relatively low peroxidase-mimic activity (PMA) and catalse-mimic activity (CMA) of nanozymes in tumor microenvironment has hampered their potential application in the cancer therapy. Therefore, in this study, we aimed to fabricate platinum (Pt) nanozymes dispersed on the surface of iron oxide (Fe₃O₄) nanosphere that, in addition to boosting the PMA and CMA, resulted in the formation of a pH-sensitive nano-platform for drug delivery in breast cancer therapy. After development of Fe₃O₄ nanospheres containing Pt nanozymes and loading 5-fluorouracil (abbreviated as: Fe₃O₄/Pt-FLU@PEG nanospheres), the physicochemical properties of the nanospheres were examined by electron microscopy, dynamic light scattering, zeta potential, X-ray diffraction, thermogravimetric, BET surface, and PMA/CMA analyses. Then, the cytotoxicity of the Fe₃O₄/Pt-FLU@PEG nanospheres against 4T1 cells was investigated by the cell counting kit-8 assay and flow cytometry. Also, the anticancer effect of fabricated nanoplatform was assessed in mouse bearing 4T1 cancer tumors, in vivo. The results showed that the Fe₃O₄/Pt-FLU@PEG nanospheres provide a platform for optimal FLU loading, continuous pH-sensitive drug release, and potential PMA and CMA to increase the level of ROS and O₂, respectively. Cytotoxicity outputs showed that the Fe₃O₄/Pt-FLU@PEG nanospheres mitigate the proliferation of 4T1 cancer cells mediated by apoptosis and intracellular generation of reactive oxygen species (ROS). Furthermore, in vivo assays indicated a significant reduction in tumor size and overcoming tumor hypoxia. Overall, we believe that the developed nanospheres with dual enzyme-mimic activity and pH-sensitive drug delivery can be used for ROS/chemotherapy double-modality antitumor therapy.     

Rhodium-Based Nanozymes: Recent Advances and Challenges

Rhodium (Rh) is a non-toxic transition metal used as various nanomaterials with unique structures and properties. Rh-based nanozymes can mimic the activities of natural enzymes, overcome the limitation of the application scope of natural enzymes, and interact with various biological microenvironments to play a variety of functions. Rh-based nanozymes can be synthesized in various ways, and different modification and regulation methods can also enable users to control catalytic performance by adjusting enzyme active sites. The construction of Rh-based nanozymes has attracted great interest in the biomedical field and impacted the industry and other areas. This paper reviews the typical synthesis and modification strategies, unique properties, applications, challenges, and prospects of Rh-based nanozymes. Next, the unique features of Rh-based nanozymes are emphasized, including adjustable enzyme-like activity, stability, and biocompatibility. In addition, we discuss Rh-based nanozymes biosensors and detection, biomedical therapy, and industrial and other applications. Finally, the future challenges and prospects of Rh-based nanozymes are proposed.     

Carbon Nanozymes: Enzymatic Properties,Catalytic Mechanism,and Applications

Nanozymes have advantages over natural enzymes, such as facile production on large scale, long storage time, low costs, and high stability in harsh environments. Carbon nanomaterials (CNMs), including fullerenes, carbon nanotubes, graphene, carbon quantum dots, and graphene quantum dots, have become a star family in materials science. As a new class of nanozymes, the catalytic activity of CNMs and their hybrids has been extensively reported. In this Minireview, recent progress of CNMs based artificial enzymes, focusing on those with peroxidase‐like activity, has been summarized. The enzymatic properties, catalytic mechanisms, and novel applications of CNM nanozymes in sensing, therapy, and environmental engineering are discussed in detail. Additionally, we also highlight the remaining challenges and unsolved problems. With the fast development of bionanotechnology, the unique enzymatic properties and advantages of CNM nanozymes have received much attention and will continue to be an active and challenging field for the years to come.     

Enhanced macrophage polarization induced by COX-2 inhibitor-loaded Pd octahedral nanozymes for treatment of atherosclerosis

Inhibition of foam cell formation is considered a promising treatment method for atherosclerosis, the leading cause of cardiovascular diseases worldwide. However, currently available therapeutic strategies have shown unsatisfactory clinical outcomes. Thus, herein, we design aloperine (ALO)-loaded and hyaluronic acid (HA)-modified palladium (Pd) octahedral nanozymes (Pd@HA/ALO) that can synergistically scavenge reactive oxygen species (ROS) and downregulate cyclooxygenase-2 (COX-2) expression to induce macrophage polarization, thus inhibiting foam cell formation to attenuate atherosclerosis. Due to the targeted effect of HA on stabilin-2 and CD44, which are overexpressed in atherosclerotic plaques, Pd@HA/ALO can actively accumulate in atherosclerotic plaques. Subsequently, the antioxidative effects of Pd octahedral nanozymes are mediated by their intrinsic superoxide dismutase- and catalase-like activities capable of effective scavenging of ROS. In addition, anti-inflammatory effects are mediated by controlled, on-demand near-infrared-triggered ALO release leading to inhibition of COX-2 expression. Importantly, the combined therapy can promote the polarization of macrophages to the M2 subtype by upregulating Arg-1 and CD206 expression and downregulating expression of TNF-α, IL-1β and IL-6, thereby inhibiting atherosclerosis-related foam cell formation. In conclusion, the presented in vitro and in vivo data demonstrate that Pd@HA/ALO enhanced macrophage polarization to reduce plaque formation, identifying an attractive treatment strategy for cardiovascular disease.     

A Nanozyme with Photo‐Enhanced Dual Enzyme‐Like Activities for Deep Pancreatic Cancer Therapy

Nanozymes have attracted extensive interest owing to their high stability, low cost and easy preparation, especially in the field of cancer therapy. However, the relatively low catalytic activity of nanozymes in the tumor microenvironment (TME) has limited their applications. Herein, we report a novel nanozyme (PtFe@Fe₃O₄) with dual enzyme‐like activities for highly efficient tumor catalytic therapy. PtFe@Fe₃O₄ shows the intrinsic photothermal effect as well as photo‐enhanced peroxidase‐like and catalase‐like activities in the acidic TME, thereby effectively killing tumor cells and overcoming the tumor hypoxia. Importantly, a possible photo‐enhanced synergistic catalytic mechanism of PtFe@Fe₃O₄ was first disclosed. We believe that this work will advance the development of nanozymes in tumor catalytic therapy.     

Mechanistic and kinetic insights into size-dependent activity in ultra-small Pt/CNTs nanozymes during antibacterial process

In enzyme-like catalytic reactions, the size effect of nanoparticles has been an essential yet unclear factor for the catalytic activity of nanozymes. Moreover, the synthesis of nanozymes with controllable size and electronic structures represents a grand challenge, which limits the systemic exploration the underlying nature of their structure–property relations and practical application. In this work, we proposed a novel strategy to regulate the size of Pt (0.55 ～ 2.81 nm) by atomic layer deposition for precisely tailoring Pt-based nanozymes. The size-dependent electronic and kinetic effects have been observed for the peroxidase-like reaction and antibacterial process, revealing a volcano-type dependence of intrinsic activity on Pt nanoparticle sizes, and the optimum Pt nanoparticle size was found to be ca. 1.69 nm. A combination of kinetic study and XPS analyses, as well as multiple nanozyme characterizations, demonstrates that Pt nanoparticles with an appropriate size contribute to proper affinity to the substrates, relating to a high ratio of Pt⁰/Pt²⁺ on the surface of Pt nanoparticles, which is beneficial to obtain the excellent catalytic performance and antibacterial activity. Our work provides insights for an in-depth understanding size-dependent catalytic mechanism of nanozymes during antibacterial processes.     

Carbon Dot Nanozymes: How to Be Close to Natural Enzymes

The design, catalytic process, and property study of nanozymes are of importance for both fundamental research and application demand. Here, the peroxidase-mimicking properties of a series of carbon dots (C-dots) was systematically investigated and they were found to be probably closer to their natural counterparts, as compared to the known corresponding nanozymes. Firstly, four kinds of metal-free and surface-modulated C-dots were bottom-up fabricated using glucose, α-cyclodextrin (CD), β-CD, and γ-CD as precursors, respectively, and their formation processes, structures, as well as surface chemistry were investigated. Secondly, in the peroxidase-mimicking catalytic system, no hydroxyl radicals were produced, which indicates a different and special catalytic mode. By employing a joint experimental–theoretical study, a probable catalytic mechanism is proposed. Thirdly, the present C-dots maintained well their catalytic activity even in complicated serum matrices because their catalytic performances are completely irrelevant of any cation-related binding sites. Finally, the catalytic performances of the as-prepared C-dots were modulated by either pre-engineering NP surface structures or subsequently introducing photo-regulated host–guest reactions.     

Recent advances in the development of colorimetric analysis and testing based on aggregation-induced nanozymes

Colorimetric sensing strategies as a powerful point-of-care testing(POCT) tool have attracted significant interest in various chem/biosensing applications.Taking the excellent bare-eye-detectable signaling feature,nanozymes-based colorimetric sensors enable more potential applications and have been a new forefront in the colorimetric POCT analysis toward different target analytes.However,the low catalytic activity of nanozymes in most cases limits their practical application.Recent efforts demonstrate that the aggregation-induced nanozymes provide a general means to modulate nanozymes activity and enhance colorimetric sensing performances of some nanozymes-based colorimetric sensors.But there are few reports are explored to discuss and review such aggregation-induced nanozymes and their colorimetric sensing applications.To highlight the advances and progress in aggregation-induced nanozymes based colorimetric assays,we herein summary the fundamentals,classify and applications of this newlydeveloping field,focusing on the aggregation-induced activity enhancement of nanozymes(AIAEnanozymes) with a significant "signal-on" feature and aggregation-induced activity inhibition of nanozymes(AIAI-nanozymes) with a dramatical "signal-of" characteristics.Finally,we also propose the current challenges and the future prospects on both AIAE-nanozymes and AIAI-nanozymes.     

MicroRNA-Triggered Nanozymes Cascade Reaction for Tumor-Specific Chemodynamic Therapy

Off-target toxicity and insufficient hydroxyl radicals (^.OH) generation limit the further clinical application of nanozymes in chemodynamic therapy (CDT). Herein, we designed and constructed a microRNA-triggered nanozyme cascade platform for enhanced tumor-specific chemodynamic therapy. The nanozyme-based cascade reaction could be triggered successfully by the high expression of microRNA in cancer cells to generate more ^.OH, thus exhibiting excellent tumor-specific therapeutic performance. Our work provides a new dimension for tumor-specific chemodynamic therapy.     

Natural Polyphenol–Vanadium Oxide Nanozymes for Synergistic Chemodynamic/Photothermal Therapy

The selection of suitable nanozymes with easy synthesis, tumor specificity, multifunction, and high therapeutics is meaningful for tumor therapy. Herein, a facile one-step assembly approach was employed to successfully prepare a novel kind of natural polyphenol tannic acid (TA) hybrid with mixed valence vanadium oxide nanosheets (TA@VO_x NSs). In this system, VO_x is assembled with TA through metal–phenolic coordination interaction to both introduce superior peroxidase-like activity and high near infrared (NIR) absorption owing to partial reduction of vanadium from V⁵⁺ to V⁴⁺. The presence of mixed valence vanadium oxide in TA@VO_x NSs is proved to be the key for the catalytic reaction of hydrogen peroxide (H₂O₂) to ^. OH, and the corresponding catalytic mechanism of H₂O₂ by TA@VO_x NSs is proposed. Benefitting from such peroxidase-like activity of TA@VO_x NSs, the overproduced H₂O₂ of the tumor microenvironment allows the realization of tumor-specific chemodynamic therapy (CDT). As a valid supplement to CDT, the NIR absorption enables TA@VO_x NSs to have NIR light-mediated conversion ability for photothermal therapy (PTT) of cancers. Furthermore, in vitro and in vivo experiments confirmed that TA@VO_x NSs can effectively inhibit the growth of tumors by synergistic CDT/PTT. These results offer a promising way to develop novel vanadium oxide-based nanozymes for enhanced synergistic tumor-specific treatment.     

单原子催化剂的生物医学应用

单原子催化剂(SACs)具有100%的原子利用率及充分暴露的原子金属活性位点, 其催化活性和选择性更具优势, 已广泛应用在化学、 能源及环境等领域. 近年来, SACs在生物医学领域也引起了广泛关注. 本文综述了SACs在肿瘤治疗、 抗菌、 抗氧化和生物传感等生物医学领域的应用及研究进展, 并简要总结了SACs未来应用的挑战和机遇, 为合理设计多性能的SACs提供了可行策略.     

Atomic engineering of single-atom nanozymes for enzyme-like catalysis

Enzyme mimics, especially nanozymes, play a crucial role in replacing natural enzymes for diverse applications related to bioanalysis, therapeutics and other enzyme-like catalysis. Nanozymes are catalytic nanomaterials with enzyme-like properties, which currently face formidable challenges with respect to their intricate structure, properties and mechanism in comparison with enzymes. The latest emergence of single-atom nanozymes (SAzymes) undoubtedly promoted the nanozyme technologies to the atomic level and provided new opportunities to break through their inherent limitations. In this perspective, we discuss key aspects of SAzymes, including the advantages of the single-site structure, and the derived synergetic enhancements of enzyme-like activity, catalytic selectivity and the mechanism, as well as the superiority in biological and catalytic applications, and then highlight challenges that SAzymes face and provide relevant guidelines from our point of view for the rational design and extensive applications of SAzymes, so that SAzyme may achieve its full potential as the next-generation nanozyme.

Single-atom nanozymes with definite active centers, high catalytic activities and enzyme-like selectivities promote the nanozyme research entering a new period of atomic level.     

Recent progress in carbon-dots-based nanozymes for chemosensing and biomedical applications

Nanozymes are nanomaterials with enzyme-like activities that efficiently overcome the drawbacks of natural enzymes in biosensing, detection, and biomedical fields, and they are the most widely used artificial enzymes. Owing to their excellent catalytic characteristics, biocompatibility, and environmental favorability, carbon-dots-based (CDs) nanozymes have inspired a research upsurge. However, no review focusing on CDs nanozymes has been published, even though substantial advances have been achieved. Herein, the advances, catalytic activities, and applications of CDs nanozymes are highlighted and summarized. In addition, the critical issues and challenges of researching nanozymes are discussed. We hope that this review will broaden the horizons of nanozymes and CDs nanozymes, as well as promote their development.     

Emerging nanozymes for potentiating radiotherapy and radiation protection

While radiotherapy is a mainstay therapeutic modality for malignant tumor, the intrinsic tumor resistance to radiotherapy, as well as the concomitant radiation injury to adjacent healthy tissues, greatly limits the efficacy of cancer radiotherapy. As a result, the development of novel radioenhancers and radioprotectants is highly desired for clinical radiotherapy. In recent years, nanozymes have inspired ever-growing research interest because of their multi-enzyme activities and microenvironment-responsive feature. In view of the significant progress of nanozymes in radiation medicine, we, in this review, systematically illustrate the impressive progress of nanozymes for potentiating radiotherapy and radiation protection. First, the types of nanozymes used in tumor radiotherapy are briefly discussed. Subsequently, the main strategies of nanozymes to enhance the radiotherapy efficiency, including promoting the generation of reactive oxygen species (ROS), relieving hypoxia in tumor microenvironment and combining with other cancer therapeutic regimens, are summarized. Finally, the advances of typical nanozymes for preventing radiation-induced hematopoietic damage and gastrointestinal damage are highlighted.     

Chirality-Dependent Reprogramming of Macrophages by Chiral Nanozymes

It is known that extracellular free radical reactive oxygen species (ROS) rather than intracellular ROS plays a non-substitutable role in regulation of tumor-suppressing (M1) tumor-associated macrophages (TAMs) polarization. However, most therapeutic nanoplatforms mainly provide intracellular ROS and exhibit insufficient accumulation near TAMs, which strongly limits the macrophage-based immunotherapeutic effects. Here we design and synthesize chiral MoS₂/CoS₂ nanozymes with peroxidase (POD)-like and catalase (CAT)-like activities to efficiently modulate TAMs polarization and reverse tumor immunosuppression by harnessing their chirality-specific interactions with biological systems. MoS₂/CoS₂ nanoparticles coordinated with d -chirality (d -NPs, right-handed) show improved pharmacokinetics with longer circulating half-life and higher tumor accumulation compared with their l ( left-handed)- and dl ( racemate)-counterparts. Further, d -NPs can escape from macrophage uptake in the tumor microenvironment (TME) with the aid of cell-unpreferred opposite chirality and act as extracellular hydroxyl radicals (⋅OH) and oxygen (O₂) generators to efficiently repolarize TAMs into M1 phenotype. On the contrary, l -NPs showed high cellular uptake due to chirality-driven homologous adhesion between l -NPs and macrophage membrane, leading to limited M1 polarization performance. As the first example for developing chiral nanozymes as extracellular-localized ROS generators to reprogram TAMs for cancer immunotherapy, this study opens an avenue for applications of chiral nanozymes in immunomodulation.     

Unveiling the Intrinsic Catalytic Activities of Single‐Gold‐Nanoparticle‐Based Enzyme Mimetics

Gold nanoparticles (AuNPs) have been demonstrated to serve as effective nanomaterial‐based enzyme mimetics (nanozymes) for a number of enzymatic reactions under mild conditions. The intrinsic glucose oxidase and peroxidase activities of single AuNPs and Ag–Au nanohybrids, respectively, were investigated by single NP collision electrochemical measurements. A significantly high turnover number of nanozymes was obtained from individual catalytic events compared with the results from the classical, ensemble‐averaged measurements. The unusual enhancement of catalytic activity of single nanozymes is believed to originate from the high accessible surface area of monodispersed NPs and the high activities of carbon‐supported NPs during single‐particle collision at a carbon ultramicroelectrode. This work introduces a new method for the precise characterization of the intrinsic catalytic activities of nanozymes, giving further insights to the design of high‐efficiency nanomaterial catalysts.     

Recent Progress in the Biological Applications of Reactive Oxygen Species-Responsive Polymers

Abstract

Responsive polymeric materials that are sensitive to biological stimuli including temperature, pH, enzymes, or redox conditions have attracted research interest in recent years. Among these, reactive oxygen species (ROS)-responsive polymers are particularly appealing because of the special role of ROS in living organisms. ROS are the indicator and cause of certain diseases, and they are also important signaling molecules. ROS-responsive polymers could possess the following functions: drug carriers, ROS probes, or medications for certain ROS-related diseases. In this review, we analyze the progress about ROS-responsive polymers made in recent years and predict the future trends of ROS-responsive polymers from the above mentioned perspectives. Due to the limited scope of this review, some older articles are not covered here and are left for more comprehensive reviews.     

In vivo therapeutic response monitoring by a self-reporting upconverting covalent organic framework nanoplatform

The real-time and in situ monitoring of reactive oxygen species (ROS) generation is critical for minimizing the nonspecific damage derived from the high doses of ROS required during the photodynamic therapy (PDT) process. However, phototherapeutic agents that can generate ROS-related imaging signals during PDT are rare, hampering the facile prediction of the future therapeutic outcome. Herein, we develop an upconverting covalent organic framework (COF) nanoplatform via a core-mediated strategy and further functionalized it with a singlet oxygen reporter for the efficient near-infrared activated and in situ self-reporting of PDT. In this work, the COF photodynamic efficacy is greatly improved (12.5 times that of irregular COFs) via tailoring the size. Furthermore, this nanoplatform is able to not only produce singlet oxygen for PDT, but it can also emit singlet oxygen-correlated luminescence, allowing the real-time and in situ monitoring of the therapeutic process for cancer cells or solid tumors in vivo via near-infrared luminescence imaging. Thus, our core-mediated synthetic and size-tailored strategy endows the upconverting COF nanoplatform with promising abilities for high-efficacy, deep-tissue, precise photodynamic treatment.

An upconverting covalent organic framework nanoplatform is designed for the first time for the near-infrared activated in situ self-reporting of photodynamic therapy in vivo.     

Advances in Single‐Atom Nanozymes Research†

Nanozymes with intrinsic enzyme‐like properties have attracted significant interest owing to their capability to address the limitations of traditional enzymes such as fragility, high cost and difficult mass production. However, the currently reported nanozymes are generally less active than natural enzymes. In recent years, with the rapid development of nanoscience and nanotechnology, single‐atom nanozymes (SAzymes) with well‐defined electronic and geometric structures have shown a promise to serve as direct surrogates of traditional enzymes by mimicking the highly evolved catalytic center of natural enzymes. In this review, we will introduce the enzymatic characteristics and recent advances of SAzymes, and summarize their significant applications from in vitro detection to in vivo monitoring and therapy.     

超分子手性聚苯胺-金复合纳米酶的构建及其对映选择性催化

对映选择性催化是生物体内普遍存在的反应,与生命的产生代谢有着非常紧密的联系。设计研发具有高对映选择性催化效果的纳米酶在各类生物医药相关领域都至关重要。目前,关于纳米酶的研究大都集中在提高其催化活性,而涉及纳米酶对映选择性的研究相对较少。已有对映选择性酶催化报道表明,手性纳米酶主要通过手性分子修饰纳米颗粒来构建。考虑到天然酶的选择性不仅仅取决于氨基酸等手性分子的手性,而且与蛋白质空间排列和折叠所产生的超分子手性微环境密切相关,因此构建具有超分子手性微环境的纳米酶也成为设计具有优异对映选择性纳米酶的有效途径。此外,为了进一步提高手性纳米酶的对映选择性,深入理解手性纳米酶选择性因子的影响因素也成为一个重要研究方向。基于此,本文构建了一种由不含任何手性分子的M-聚苯胺(M-PANI)扭曲纳米带和三种不同尺寸(3、10和16 nm)的金纳米颗粒(AuNPs)组成的超分子纳米复合材料。扫描电子显微镜、透射电子显微镜、紫外-可见吸收光谱和X射线光电子能谱结果证实了M-PANI-Au超分子纳米复合材料的成功制备。同时,圆二色光谱显示M-PANI-Au超分子复合材料具有清晰的手性信号,表明它们在手性纳米催化方面具有潜在应用。以手性R-/S-3, 4-二羟基苯丙氨酸(R-/S-DOPA)对映体的催化氧化为模型反应,该类纳米酶对R-DOPA的催化选择性均高于对S-DOPA。进一步研究表明,得益于超分子手性聚苯胺载体和3 nm AuNPs之间的强手性传递作用,3 nm Au NPs(2.59)负载的M-PANI比10 nm Au NPs(1.46)和16 nm NPs(1.58)负载的M-PANI具有更高的选择因子。这一发现阐明了手性转移是调控对映选择性催化的关键影响因素,为负载型超分子手性纳米酶的构建和设计提供了方向和指导。