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.

Highly sensitive nanozyme strip:An effective tool for forensic material evidence identification

During criminal case investigations,blood evidence tracing is critical for criminal investigation.However,the blood stains are often cleaned or covered up after the crime,resulting in trace residue and difficult tracking.Therefore,a highly sensitive and specific method for the rapid detection of human blood stains remains urgent.To solve this problem,we established a nanozyme-based strip for rapid detection of blood evidence with high sensitivity and specificity.To construct reliable nanozyme strips,we synthesized CoFe_(2)O_(4) nanozymes with high peroxidase-like activity by scaling up to gram level,which can be supplied for six million tests,and conjugated antibody as a detection probe in nanozyme strip.The developed CoFe_(2)O_(4) nanozyme strip can detect human hemoglobin(HGB)at a concentration as low as 1 ng/mL,which is 100 times lower than the commercially available colloidal gold strips(100 ng/mL).Moreover,this CoFe_(2)O_(4) nanozyme strip showed high generality on 12 substrates and high specificity to human HGB among 13 animal blood samples.Finally,we applied the developed CoFe_(2)O_(4) nanozyme strip to successfully detect blood stains in three real cases,where the current commercial colloidal gold strip failed to do.The results suggest that the CoFe_(2)O_(4) nanozyme strip can be used as an effective on-scene detection method for human blood stains,and can further be used as a long-term preserved material evidence for traceability inquiry.

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.

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.

Rapid and sensitive detection of Epstein-Barr virus antibodies in nasopharyngeal carcinoma by chemiluminescence strips based on iron-porphyrin single atom nanozyme

The correlation between Epstein-Barr virus(EBV)infection and nasopharyngeal carcinoma(NPC)risk has been extensively researched.The continual monitoring of EBV-IgAs provides a promising approach of NPC screening in its early stage.In this study,we successfully synthesized a single-atom nanozyme(SANzyme)through the application of iron-porphyrin based metal organic framework(MOF-FeP).The MOF-FeP possesses precisely-defined electronic and geometric structures that accurately mimic highly-evolved catalytic site of natural peroxidase.The peroxidase-like activity of MOF-FeP enables it to catalyze the chemiluminescence of luminol substrate.By integrating MOF-FeP into a traditional strip,we created a rapid and highly-sensitive evaluation tool for detecting EBV-IgAs.Importantly,the MOF-FeP strip enables the simultaneous detection of three EBV-IgAs,greatly improving the accuracy of EBV-associated NPC screening.The sensitivities of the MOF-FeP strip(75.56%–93.30%)surpass those of current enzyme-linked immunosorbent assay(ELISA)methods(64.44%–82.22%).This test takes only 16 min to perform as opposed to the customary 1–2 h required for standard ELISA.Additionally,the MOF-FeP strip is suitable for whole blood samples,thereby significantly simplifying the sample preparation and detection process.In conclusion,the MOF-FeP strip combines the simplicity of traditional strip with the high catalytic activity of SANzyme.Our innovative MOF-FeP strip offers a new point-of-care strategy for EBV-IgAs detection,which is expected to markedly facilitate early screening for EBV-associated diseases.

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.

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.

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.

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.

A natural nanozyme in life is found:the iron core within ferritin shows superoxide dismutase catalytic activity

Nanozymes are nanomaterials exhibiting intrinsic enzymatic properties,which suggests that inorganic nanoparticles could be bioactive.It’s in 2007,when we introduced the biological methodologies for natural enzymes to systematically study the enzymatic properties of iron oxide nanoparticles,we discovered nanozymes.We found that nanozymes,just as natural enzymes,are able to catalyze biochemical reactions under the physiological conditions,following the similar enzymatic kinetics and catalytic mechanisms(Gao et al.,2007).Since then,the developments of nanozymes bloomed,and lots of nanomaterials were found exhibiting various enzymatic activities(Huang et ah,2019).

CD146,a therapeutic target involved in cell plasticity

Since its identification as a marker for advanced melanoma in the 1980s,CD146 has been found to have multiple functions in both physiological and pathological processes,including embryonic development,tissue repair and regeneration,tumor progression,fibrosis disease,and inflammations.Subsequent research has revealed that CD146 is involved in various signaling pathways as a receptor or coreceptor in these processes.This correlation between CD146 and multiple diseases has sparked interest in its potential applications in diagnosis,prognosis,and targeted therapy.To better comprehend the versatile roles of CD146,we have summarized its research history and synthesized findings from numerous reports,proposing that cell plasticity serves as the underlying mechanism through which CD146 contributes to development,regeneration,and various diseases.Targeting CD146 would consequently halt cell state shifting during the onset and progression of these related diseases.Therefore,the development of therapy targeting CD146 holds significant practical value.

Biochemistry of mammalian ferritins in the regulation of cellular iron homeostasis and oxidative responses

Ferritin,an iron-storage protein,regulates cellular iron metabolism and oxidative stress.The ferritin structure is characterized as a spherical cage,inside which large amounts of iron are deposited in a safe,compact and bioavailable form.All ferritins readily catalyze Fe(II)oxidation by peroxides at the ferroxidase center to prevent free Fe(II)from participating in oxygen free radical formation via Fenton chemistry.Thus,ferritin is generally recognized as a cytoprotective stratagem against intracellular oxidative damage.The expression of cytosolic ferritins is usually regulated by iron status and oxidative stress at both the transcriptional and post-transcriptional levels.The mechanism of ferritin-mediated iron recycling is far from clarified,though nuclear receptor co-activator 4(NCOA4)was recently identified as a cargo receptor for ferritin-based lysosomal degradation.Cytosolic ferritins are heteropolymers assembled by H-and L-chains in different proportions.The mitochondrial ferritins are homopolymers and distributed in restricted tissues.They play protective roles in mitochondria where heme-and Fe/S-enzymes are synthesized and high levels of ROS are produced.Genetic ferritin disorders are mainly related to the L-chain mutations,which generally cause severe movement diseases.This review is focused on the biochemistry and function of mammalian intracellular ferritin as the major iron-storage and anti-oxidation protein.

Metastable Iron Sulfides: A Versatile Antibacterial Candidate with Multiple Mechanisms against Bacterial Resistance

Bacterial infections pose an ongoing threat to global human health,an issue of growing urgency due to the emergence of resistance against many currently available antibiotics.Recently,the World Health Organization(WHO)launched a global appeal for the development of novel antibiotics to combat this issue.Ideal antibiotics should possess specific antibacterial effects,without causing resistance.However,the discovery of different antibiotics is lagging the development of drug-resistant bacteria.Many newly developed antibiotics not only are rapidly resisted by bacteria but also are ineffective against persistent bacteria embedded in biofilms and host cells.To tackle these challenges,innovative concepts and approaches are required for the discovery of novel antibacterial candidates.Agents for use against pathogenic bacteria were developed long before the discovery of antibiotics.For 3000 years,garlic has been considered an efficient antibacterial compound,utilized to prevent and treat bacterial infection worldwide,although the specific mechanisms remain unclear.Modern research shows that sulfur-containing chemicals are the primary active constituents of garlic and play key roles in its inherent antimicrobial activity,such as diallyl disulfide(DADS)and diallyl trisulfide(DATS).In contrast,inorganic sulfides for antibacterial use have not been deeply studied.It has been well-known that iron sulfides are an essential part of the geochemical and biological sulfur cycles.Both stable and metastable iron sulfides can be formed under abiotic sediment conditions and biotic process.In particular,certain bacteria species growth need iron sulfide as nutrient source or produce iron sulfide.In addition,iron sulfur clusters as special metastable iron sulfide take part in many important metabolic pathways in most organisms.These physicochemical and biological properties inspire us that iron sulfides are a type of valuable material for investigation and utilization.Below we will introduce a new antibacterial candidate based on iron sulfides,which kill bacteria via multiple mechanisms of action(MoAs).We will first discuss the types of iron sulfides with inherent antibacterial activity,i.e.,metastable species that can release iron ions and polysulfides in aqua.The intrinsic properties of iron sulfides and released iron and polysulfides are analyzed in regard to antibacterial effects under different physiological conditions.In particular,ferrous ion−polysulfide synergized ferroptosis-like death is proposed to kill bacteria with broad spectrum and selectivity.In addition,the versatile MoAs enable metastable iron sulfides(mFeSs)to kill resistant bacteria,eradicate biofilms,and suppress intracellular persistent species without causing new drug resistance.Importantly,the efficient antibacterial properties have been validated in animal models bearing infections including wounds,pneumonia,caries,and bacterial vaginosis,demonstrating great translational potential.Lastly,we will summarize the challenges of iron sulfides,proposing a possible development direction in the future.Our studies on iron sulfides can serve as a paradigm for the design and discovery of antibacterial nanomaterials,which may contribute for the war against drug-resistant pathogenic bacteria.