Nanomaterials for refining tumor microenvironment and enhancing therapy in head and neck squamous cell carcinoma: a review

Head and neck squamous cell carcinoma (HNSCC) is a prevalent and lethal solid tumor with a high mortality rate. Conventional cancertreatments, including surgery, radiotherapy, and chemotherapy, primarily target cancer cell eradication. However, uncontrolled proliferation and metabolic activities of these cells result in abnormalities in nutrient levels, hypoxia, and immunosuppression within the tumor microenvironment (TME). These factors constrain the efficacy of traditional treatments by promoting drug resistance, recurrence, and metastasis. Nanomaterials (NMs), such as nanozymes, can exhibit enzymatic activity similar to that of natural enzymes and offer a promising avenuefor the direct modification of the TME through catalytic oxidation-reduction processes. Moreover, they can serve as sensitizers or drug deliverycarriers, enhancing the efficacy of traditional treatment methods. Recently, NMs have garnered significant attention from oncologists. Thisreview begins with an overview of the composition and unique characteristics of the TME. Subsequently, we comprehensively exploredthe application of NMs in the treatment of HNSCC. Finally, we discuss the potential prospects and challenges associated with usingNMs in biomedical research.

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

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.

Peptide nanozymes:An emerging direction for functional enzyme mimics

The abundance of molecules on early Earth likely enabled a wide range of prebiotic chemistry,with peptides playing a key role in the development of early life forms and the evolution of metabolic pathways.Among peptides,those with enzyme-like activities occupy a unique position between peptides and enzymes,combining both structural flexibility and catalytic functionality.However,their full potential remains largely untapped.Further exploration of these enzyme-like peptides at the nanoscale could provide valuable insights into modern nanotechnology,biomedicine,and even the origins of life.Hence,this review introduces the groundbreaking concept of“peptide nanozymes(PepNzymes)”,which includes single peptides exhibiting enzyme-like activities,peptide-based nanostructures with enzyme-like activities,and peptide-based nanozymes,thus enabling the investigation of biological phenomena at nanoscale dimensions.Through the rational design of enzyme-like peptides or their assembly with nanostructures and nanozymes,researchers have found or created PepNzymes capable of catalyzing a wide range of reactions.By scrutinizing the interactions between the structures and enzyme-like activities of PepNzymes,we have gained valuable insights into the underlying mechanisms governing enzyme-like activities.Generally,PepNzymes play a crucial role in biological processes by facilitating small-scale enzyme-like reactions,speeding up molecular oxidation-reduction,cleavage,and synthesis reactions,leveraging the functional properties of peptides,and creating a stable microenvironment,among other functions.These discoveries make PepNzymes useful for diagnostics,cellular imaging,antimicrobial therapy,tissue engineering,anti-tumor treatments,and more while pointing out opportunities.Overall,this research provides a significant journey of PepNzymes’potential in various biomedical applications,pushing them towards new advancements.

纳米酶

纳米酶(Nanozymes)是由我国科学家首次提出的新概念,它是一类具有生物催化功能的纳米材料,能够基于特定的纳米结构催化天然酶的底物并作为酶的代替品。自2007年首次报道以来,全球已有来自于55个国家的420多个研究机构证实了纳米酶的普遍规律。纳米酶的发现第一次揭示纳米材料蕴含一种独特的纳米效应———类酶催化效应。纳米酶作为一种新材料,既有纳米材料本身的理化性质,又有类似酶的催化功能,兼具天然酶与人工酶的优势于一身。其中,纳米结构不仅赋予纳米酶高效催化功能,而且使纳米酶比天然酶稳定,易于规模化生产。另外,纳米酶独特的多酶活性将为设计廉价、稳定、各种各样全新的催化级联反应提供功能分子。纳米酶是多学科交叉融合的典范,2022年被IUPAC评为十大化学新兴技术。在全球从事化学、酶学、材料学、生物学、医学、理论计算等多领域科学家的共同推进下,如今纳米酶已经成为新的研究热点。我国科学家在这一新兴领域一直发挥着引领作用,解析了纳米酶的构⁃效关系,将其催化活性提高了约1万倍,实现了超越天然酶的理性设计,创造了全球首个纳米酶产品,出版了纳米酶学英文专著,发布纳米酶术语及中国/国际标准化。更可喜的是,纳米酶新领域汇集了一大批多学科交叉融合的优秀青年科学家,推动纳米酶进入高速发展阶段,纳米酶的种类已经超过1200多种,其催化机制研究也更加深入,应用研究也从当初的检测逐步拓展到纳米酶催化医学、传感检测、绿色合成、新能源、环境治理等多个领域。本文向读者介绍纳米酶自发现以来的主要进展,包括最近发现的天然纳米酶,期待纳米酶从新概念、新材料衍生出新技术、新产品、新商品,服务人类健康,并带动新学科发展。

Erratum to:Black phosphorus quantum dots as multifunctional nanozymes for tumor photothermal/catalytic synergistic therapy

Erratum to Nano Research 2022,15(2):1554–1563 https://doi.org/10.1007/s12274-021-3701-8 Figure 3(d)in the original paper contained duplicated micrographs(BPQDs+NIR)for different xenografts(B16 vs.CNE-2).This error did not affect any of the conclusions from the published paper.

Corrigendum to“Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics”[Bioact.Mater.6(2021)2676-2687/452]

The authors regret<that the published version of the above article contained an error in Figure 5d,which was not identified during the proofing stage.The Figure 5d has been revised as follow.The authors would like to apologise for any inconvenience caused and state that the correction does not change the scientific conclusions of the article in any way.

纳米酶的发展态势与优先领域分析

纳米酶作为中国科学家的原创科研成果之一,是多学科交叉融合的产物.本文简要综述了纳米酶的发展现状,并基于文献计量学的视角,重点关注自2007年以来纳米酶领域的论文发表数量和被引用情况、研究机构和国家/地区情况、研究主题及其演变规律、国际发展态势比较分析等方面,系统梳理了纳米酶的发展历程,呈现了纳米酶可视化的知识图谱;并结合专家研判,展望了纳米酶领域未来的发展方向.

Nanozymes: created by learning from nature

Nanozymes,a type of nanomaterials with enzyme-like activity,have shown great potential to replace natural enzymes in many fields such as biochemical detection,environmental management and disease treatment.However,the catalytic efficiency and substrate specificity of nanozymes still need improvement.To further optimize the enzymatic properties of nanozymes,recent studies have introduced the structural characteristics of natural enzymes into the rational design of nanozymes,either by employing small molecules to mimic the cofactors of natural enzymes to boost nanozymes’catalytic potential,or by simulating the active center of natural enzymes to construct the nanostructure of nanozymes.This review introduces the commonly used bio-inspired strategies to create nanozymes,aiming at clarifying the current progress and bottlenecks.Advances and challenges focusing on the research of bio-inspired nanozymes are outlined to provide ideas for the de novo design of ideal nanozymes.

Mussel-inspired nanozyme catalyzed conductive and self-setting hydrogel for adhesive and antibacterial bioelectronics

Adhesive hydrogels have broad applications ranging from tissue engineering to bioelectronics;however,fabricating adhesive hydrogels with multiple functions remains a challenge.In this study,a mussel-inspired tannic acid chelated-Ag(TA-Ag)nanozyme with peroxidase(POD)-like activity was designed by the in situ reduction of ultrasmall Ag nanoparticles(NPs)with TA.The ultrasmall TA-Ag nanozyme exhibited high catalytic activity to induce hydrogel self-setting without external aid.The nanozyme retained abundant phenolic hydroxyl groups and maintained the dynamic redox balance of phenol-quinone,providing the hydrogels with long-term and repeatable adhesiveness,similar to the adhesion of mussels.The phenolic hydroxyl groups also afforded uniform distribution of the nanozyme in the hydrogel network,thereby improving its mechanical properties and conductivity.Furthermore,the nanozyme endowed the hydrogel with antibacterial activity through synergistic effects of the reactive oxygen species generated via POD-like catalytic reactions and the intrinsic bactericidal activity of Ag.Owing to these advantages,the ultrasmall TA-Ag nanozyme-catalyzed hydrogel could be effectively used as an adhesive,antibacterial,and implantable bioelectrode to detect bio-signals,and as a wound dressing to accelerate tissue regeneration while preventing infection.Therefore,this study provides a promising approach for the fabrication of adhesive hydrogel bioelectronics with multiple functions via mussel-inspired nanozyme catalysis.

Nanozymes: an emerging field bridging nanotechnology and enzymology

Nanozyme,a class of nanomaterials with intrinsic enzymelike properties,is a new concept which has been included in the Encyclopedia of China and the textbook of enzyme engineering.Since the first evidence published in 2007(Gao et al.,2007),great progress has been achieved in the study of nanozyme from new concept,new material to its new application,and it becomes an emerging field bridging nanotechnology and biology(Gao and Yan,2016).

Nanozyme:A promising tool from clinical diagnosis and environmental monitoring to wastewater treatment

Natural enzymes,owing to their outstanding catalytic efficiency and substrate specificity,have been used in a variety of applications including clinical diagnosis,environmental monitoring and wastewater treatment.However,they face inevitable problems such as relatively high cost and lack of stability,dramatically hindering their practical applications in the industry.Recently,a class of nanomaterial that possesses intrinsic enzyme-like properties,nanozyme,has emerged exhibiting numerous advantages over its natural counterpart and has been used as a viable enzyme alternative.In the past decade there are many reviews on nanozyme.The previous discussions tend to view nanozyme as a type of nanomaterial rather than an enzyme.However,it is the enzyme-like activity of nanozymes that provides foundation for their application and nanozymes with the same enzymatic activity usually have some regularity in application.Herein,in this review,we attempt to classify nanozymes by their enzyme-like activity to explain the application principle and relevant cases of nanozymes in clinical diagnosis,environmental monitoring and wastewater treatment,expecting to promote deeper thinking of nanozymes as enzyme mimics and provide useful guidance for future research.

Nanozymes Inspired by Natural Enzymes

CONSPECTUS:Nanozymes,nanomaterials with enzyme-like activities with high structural stability,adjustable catalytic activity,functional diversity,recyclability,and feasibility in large-scale preparation,have become a hot spot in the field of artificial enzymes in recent years and are expected to become potential surrogates and competitors for natural enzymes in practical applications.With the development of in-depth research and a wide range of application requirements,creating nanozymes with catalytic performance comparable to or even surpassing that of natural enzymes has been the key research topic in this field.Most of the nanozymes reported in the past were obtained based on random synthesis and screening,for which the catalytic efficiency is far inferior to that of natural enzymes.Natural enzymes that have evolved over hundreds of millions of years have developed a lot of high-efficiency catalysis know-how hidden in their structural features.To create highly active nanozymes,we assumed that there is a general structure−activity relationship between nanozymes and natural enzymes and proposed the nanozyme optimization strategy by grafting the catalytic principles of natural enzymes into the rational design of nanozymes.On the basis of this bioinspired strategy,a series of nanozymes that exhibit similar catalytic activities that are closer to or even beyond those of natural enzymes have been successfully synthesized.By now,rationally designed high-activity bioinspired nanozymes have become a hot topic in the current research on nanozymes.In this Account,we focus on recent representative research progress in the systemic design and construction of bioinspired nanozymes and are devoted to introducing strategic concepts in the bioinspired optimization of nanozymes.We show that the de novo design of nanozymes by simulating the amino acid microenvironment and using metal-free architecture and the coordination structure of metal active sites in natural enzymes is an effective strategy for significantly improving the catalytic performance of nanozymes.A future perspective of the challenges and countermeasures of bioinspired nanozymes is proposed on the basis of these achievements.We hope that the biologically inspired perception will arouse widespread interest in fundamental research and practical applications as well as provide inspiration for the rational design of nanozymes.

Questions about horse the blood brain barrier receptor 1 spleen ferritin crossing via mouse transferrin

Ferritin, an iron storage protein naturally occurring in the body, has emerged as a promising nanocarrier thanks to its unique architecture, excellent biocompatibility, and ability to self-assemble/disassemble （Fan et al., 2013）. More specifically, the finding that human H-ferritin intrinsically targets tumor cells via binding to its receptor transferrin receptor 1 （TfR1） （Li et al., 2010; Fan et al., 2012; Liang et al., 2014; Zhao et al., 2016） inspired research into using ferritins for tumor target therapy.

Black phosphorus quantum dots as multifunctional nanozymes for tumor photothermal/catalytic synergistic therapy

Nanozymes are nanomaterials with enzyme-like properties that have attracted significant interest owing to their high stability,easy preparation,and tunable catalytic properties,especially in the field of cancer therapy.However,the unfavorable catalytic effects of nanozymes in the acidic tumor microenvironment have limited their applications.Herein,we developed a biomimetic erythrocyte membrane-camouflaged ultrasmall black phosphorus quantum dots(BPQDs)nanozymes that simultaneously exhibited an exceptional near-infrared(NIR)photothermal property and dramatically photothermal-enhanced glucose oxidase(GOx)-like activity in the acidic tumor microenvironment.We demonstrated the engineered BPQDs gave a photothermal conversion efficiency of 28.9%that could rapidly heat the tumor up to 50℃ while effectively localized into tumors via homing peptide iRGD leading after intravenously injection.Meanwhile,the significantly enhanced GOx-like activity of BPQDs under NIR irradiation was capable of catalytical generating massive toxic reactive oxygen species via using cellular glucose.By combining the intrinsic photothermal property and the unique photothermal-enhanced GOx-like catalytic activity,the developed BPQDs were demonstrated to be an effective therapeutic strategy for inhibiting tumor growth in vivo.We believe that this work will provide a novel perspective for the development of nanozymes in tumor catalytic therapy.

Bioengineered magnetoferritin nanozymes for pathological identification of high-risk and ruptured atherosclerotic plaques in humans

Atherosclerotic plaque rupture results in thrombus formation and vessel occlusion, and is the leading cause of death worldwide. There is a pressi ng need to identify plaque vuln erability for the treatment of carotid and coronary artery diseases. Nano materials with en zyme-like properties have attracted significant interest by providing biological, diagnostic and prognostic information about the diseases. Here we showed that bioe ngin eered mag netoferritin nan oparticles (M-HFn NPs) functionally mimic peroxidase en zyme and can intrin sically recog nize plaque-infiltrated active macrophages, which drive atherosclerotic plaque progression and rupture and are significantly associated with the plaque vulnerability. The M-HFn nanozymes catalyze the oxidation of colorimetric substrates to give a color reaction that visualizes the recognized active macrophages for one-step pathological identification of plaque vulnerability. We examined 50 carotid endarterectomy specimens from patients with symptomatic carotid disease and demonstrated that the M-HFn nanozymes could distinguish active macrophage infiltration in ruptured and high-risk plaque tissues, and M-HFn staining displayed a significant correlation with plaque vulnerability (r= 0.89, P< 0.0001).

Ferritin nanocages for early theranostics of tumors via inflammation-enhanced active targeting

Engineered nanocarriers have been widely developed for tumor theranostics.However,the delivery of imaging probes or therapeutic drugs to the tumor pre-formation site for early and accurate detection and therapy remains a major challenge.Here,by using tailor-functionalized human H-ferritin(HFn),we developed a triple-modality nanoprobe IRdye800-M-HFn and achieved the early imaging of tumor cells before the formation of solid tumor tissues.Then,we developed an HFn-doxorubicin(Dox)drug delivery system by loading Dox into the HFn protein cage and achieved early-stage tumor therapy.The intravenous injection of HFn nanoprobes enabled the imaging of tumor cells as early as two days after tumor implantation,and the triple-modality imaging techniques,namely,near-infrared fluorescence molecular imaging(NIR-FMI),magnetic resonance imaging(MRI),and photoacoustic imaging(PAI),ensured the accuracy of detection.Further exploration indicated that HFn could specifically penetrate into pre-solid tumor sites by tumor-associated inflammation-mediated blood vessel leakage,followed by effective accumulation in tumor cells by the specific targeting property of HFn to transferrin receptor 1.Thus,the HFn-Dox drug delivery system delivered Dox into the tumor pre-formation site and effectively killed tumor cells at early stage.IRDye800-M-HFn nanoprobes and HFn-Dox provide promising strategies for early-stage tumor diagnosis and constructive implications for early-stage tumor treatment.