Single-Atom Nanozymes for Tumor Diagnosis and Therapy

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Junqiu Liu	--	7200	2023-11-23 06:40:53	\|
2	Reference format revised.	Lindsay Dong	-2 word(s)	7198	2023-11-24 07:04:29	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms242115712

Nanozymes, which combine enzyme-like catalytic activity and the biological properties of nanomaterials, have been widely used in biomedical fields. Single-atom nanozymes (SANs) with atomically dispersed metal centers exhibit excellent biological catalytic activity due to the maximization of atomic utilization efficiency, unique metal coordination structures, and metal–support interaction, and their structure–activity relationship can also be clearly investigated. Therefore, they have become an emerging alternative to natural enzymes.

single-atom nanozymes nanocatalytic therapy cancer diagnosis and therapy

1. Introduction

Cancer is recognized as one of the deadliest diseases threatening human health. Malignant tumors are the second leading cause of human death ^[1]. Cancer incidence and mortality continue to rise despite rapid advances in medicine and biology. Traditional strategies for clinical oncology treatment, including surgery, radiotherapy, and chemotherapy, still have unavoidable side effects despite their technological maturity and great success ^[2]^[3]^[4]^[5]^[6]^[7]^[8]. For example, surgery cannot completely cut the tumor tissue, easily leading to cancer recurrence and metastasis. The long-term use of chemotherapeutic drugs will lead to drug resistance in tumor cells, weakening the therapeutic effect. High radiation will cause severe damage to normal tissues and cause great pain to patients ^[9]^[10]^[11]. Therefore, developing new tumor treatment strategies and accurate early cancer diagnosis are significant to cancer prevention and treatment.

With the rapid development of nanotechnology, non-invasive nanocatalytic therapy based on nanozymes is widely used in diagnosing and treating tumors. Nanozymes are based on a nanomaterial with enzyme-like activity and have a kinetic catalytic reaction process similar to that of natural enzymes ^[12]. Nanozymes have the biological effects of nanomaterials and can also induce apoptosis or ferroptosis of cancer cells by utilizing the particular tumor microenvironment (TME) to generate ROS ^[13]^[14]^[15]^[16]^[17]. However, the leakage of metal ions in nanozymes is potentially toxic to normal organs and tissues, limiting their clinical applications ^[18]. Therefore, maximizing the utilization of metal atoms and improving the catalytic activity of the active site are effective ways to address the toxicity of nanozymes.

With the progress of single atomization and characterization techniques, single-atom nanozymes (SANs) with atomically dispersed active sites, well-defined electronic and geometrical structures, tunable coordination environments, and maximal metal–atom utilization have been developed and exploited ^[19]. In 2011, Zhang et al. synthesized Pt₁/FeO_X catalysts, and the innovative concept of single-atom catalysis was proposed for the first time, which set off an international research frenzy for single-atom catalysts (SAC) ^[20]. Subsequently, Dong et al. proposed the concept of SANs and prepared high-performance single-atom catalysts with Fe-N₅ structure by mimicking the active center of cytochrome P450, whose catalytic rate constant of oxidase-like activity is more than 70 times that of platinum ^[21]. Since then, various SANs with different mimetic enzyme activities have been developed, including catalase-like (CAT-like), peroxidase-like (POD-like), oxidase-like (OXD-like), and glutathione oxidase-like (GSHOx-like) ^[22]^[23]^[24]^[25]. The activities of some SANs are even comparable to natural enzymes. SANs with atomically dispersed bimetallic catalytic sites have also been developed. The parallel catalytic effect of the isolated bis-monatomic sites ^[26]^[27] and the synergistic effect of the neighboring diatomic pairs ^[28]^[29] can further enhance the catalytic performance of the SANs.

The excellent catalytic properties and the structural stability of SANs ensure that they can achieve satisfactory cancer therapeutic effects at relatively low metal concentrations ^[30]. In addition, a clear structure of the active site is conducive to revealing the conformational relationship and catalytic mechanism to rationally design more suitable SANs ^[31]^[32]. SANs can respond to the weak acidity and high levels of hydrogen peroxide (H₂O₂) of TME by converting hydrogen peroxide and oxygen into toxic ROS (hydroxyl radicals (•OH), superoxide radicals (

O_{2}^{• -}

), singlet oxygen (¹O₂)) while consuming reduced glutathione (GSH) in the tumor cells, thus coming to kill cancer cells ^[33].

2. Classification of SANs for Cancer Treatment

2.1. SANs Classified According to Metal Active Centers

2.1.1. Single-Atom Site Nanozymes

Mn SANs

Manganese (Mn) is an essential element for living organisms. Due to its multivalency and high spin, Mn is a crucial cofactor for many metalloenzymes such as Mn superoxide dismutase (Mn SOD), glutamine synthetase (GS), pyruvate carboxylase and arginase ^[34]^[35]^[36]^[37]. Different Mn-based nanozymes exhibit CAT-like, SOD-like, and POD-like activities. Manganese-based nanozymes with multi-enzyme activities have been used to regulate nitric oxide levels and ROS levels in mammalian cells ^[38].

Cu SANs

In recent years, scientists have found that bacteria exist in almost all tumor sites, and this pathogen–tumor symbiosis system facilitates tumor development, including escaping immune recognition, inhibiting apoptosis, enhancing drug resistance, and inducing distal metastasis ^[39]. In particular, in treating colorectal cancer, the abundant Fusobacterium (F.) nucleatum will continuously affect the incidence, progression, metastasis, and prognosis of colorectal cancer.

Ir SANs

Iridium (Ir) is a noble metal belonging to the platinum group of elements, chemically stable and highly resistant to corrosion ^[40]. Ir exhibits excellent catalytic properties due to its multivalency and adsorption capacity for organic substances. Ir (III) complexes have been widely used in tumor therapy in recent years due to their potential chemotherapeutic properties ^[41]^[42]^[43]. Also, due to the ligand and charge transfer potentials favoring the catalytic properties of Ir atoms, scientists have delved into exploring the biomedical significance of Ir-based nanocatalysts ^[44].

Fe SANs

Qin et al. used an interfacial domain-confined coordination strategy to construct Fe single-atom anchored defective carbon dots in poly (ethylene glycol)-modified porous silica nanoreactors (Fe/CDs@PPSNs) ^[45]. This strategy involves in situ high-temperature carbonization of polymer/nitrogen-containing molecules into nitrogen-doped carbon dots and confinement of interfacial coordination of N and Fe atoms at the interface between the carbon dots and the iron oxide nanoparticles, followed by acid etching in biocompatible porous nanoreactors to remove the excess iron-based nanoparticles. The Fe- N-C single atoms are formed by strong formation coordination interactions that occur in uniform and connected hierarchical mesopores. The interconnected porous skeleton also facilitates substance transport to expose more active sites, increasing the local reactant concentration and generating ROS more efficiently. Meanwhile, the excellent photothermal conversion efficiency of Fe/CDs@PPSNs further amplifies the effect of the tumor therapy under 808 nm laser irradiation. Moreover, the compositional tunability within the mesoporous pores offers the possibility of encapsulating different metal-based cores to prepare multiple nitrogen-coordinated metal single-atom nanotherapeutics.

Co SANs

Cobalt (Co) is a biologically essential trace element, generally found in vitamin B12, whose central CoIII ion is coordinated to the four nitrogen atoms in the Corin ^[46]. Various cobalt-based nanozymes show different enzyme-like activities, such as such as CAT-like, SOD-like, OXD-like, and POD-like. Co-N₄ centers anchored on graphene with N-doped graphene exhibit prominent Fenton-like activity that can produce •OH ^[47]. Co single atoms on MoS₂ nanosheets also exhibit remarkable POD-like activity, where Co follows an electron transfer mechanism ^[48].

2.1.2. Isolated Double Monoatomic Nanozymes

Fe/Co Bimetallic SANs

Zhao et al. prepared bimetallic SANs consisting of single-atom Fe and single-atom Co to form non-alloyed isolated atoms (DIA) anchored in N-doped carbon carriers ^[27]. Briefly, Fe ions and Co ions were isolated within the cavities of ZIF-8, and then the surface of ZIF-8 was covered with a Si shell to prevent irreversible fusion and aggregation during high-temperature pyrolysis. Finally, the SiOx shell layer and metal nanoparticles were then etched away using 12% hydrofluoric acid and 1 M hydrochloric acid, respectively, to form FeCo-DIA/NC. Hyaluronic acid (HA) was modified on the surface of FeCo-DIA/NC (FeCo-DIA/NC@HA) to improve its tumor-targeting properties. The Fe-N₄ active sites in FeCo-DIA/NC mainly exhibit POD-like and OXD-like activities, catalyzing in parallel the formation of •OH and

O_{2}^{• -}

from H₂O₂ and O₂, respectively. The Co-N₅ active sites in FeCo-DIA/NC can catalyze in parallel the formation of ¹O₂ and

O_{2}^{• -}

from H₂O₂ and O₂, respectively. The synergistic and “division of labor” bimetallic dual active sites exhibit much higher catalytic activity than single metal sites. The results of in vitro and in vivo experiments showed that FeCo-DIA/NC@HA could significantly reduce cell survival and inhibit tumor growth ^[27].

Cu/Zn Bimetallic SANs

In addition, the catalytic activity of enzyme-like enzymes can be further improved by exploiting the localized surface-isolated exciton resonance (LSPR) effect of metal doping. Liu et al. designed a Cu/Zn bimetallic two-single-atom nanozyme (Cu/PMCS) for treating skin melanoma ^[49]. The doping of Cu enhanced the photothermal properties, catalytic activity, and GSH depletion capacity of PMCS, and improved the elimination of skin melanoma ^[49]. According to DFT theoretical calculations, Cu doping significantly improves the photothermal performance of PMCS, which is attributed to the introduction of impurity energy levels by Cu ion doping, resulting in a new d-orbital transition with strong spin–orbit coupling.

These isolated bimetallic two-single-atom nanozymes, possessing higher catalytic activity than monometallic SANs, could significantly increase the ROS level of tumor cells and enhance the anti-tumor effect. However, this is only a superposition of the two metals’ catalytic effect; if more metals are encapsulated in the MOF cavity, it should show better catalytic activity. Pull in the distance between the two metals to construct a diatomic pair of SANs, which can produce the effect of “1 + 1 > 2” by utilizing the synergistic effect between the metals.

2.1.3. Diatomic Pair Nanozymes

Isolated single metal sites usually exhibit end-on conformation for H₂O₂ adsorption, making the energy barrier for O-O bond cleavage is higher and unfavorable for forming active intermediates ^[50]. In nature, some enzymes with binuclear metal sites can accelerate O-O breaking due to their unique geometries and electronic structures, such as cytochrome c oxidase (Fe-Cu hetero-dinuclear active center), methane monooxygenase (Fe-Fe dinuclear active center), and polyphenol oxidase (Cu-Cu dinuclear active center) ^[51]^[52]^[53]. Two adjacent metal atoms as active sites can bind O atoms through double-site adsorption, which facilitates the modulation of D-band centers through electron orbital interactions and further optimizes the adsorption/desorption of oxygen intermediates, accelerating the rate of catalytic reactions ^[54].

2.2. SANs Classified According to Carrier

2.2.1. Nitrogen-Doped Carbon-Based SANs

Nitrogen-doped carbon nanomaterials are a highly desirable carrier for constructing SANs because of their high carrier density, high catalytic activity, and high chemical affinity. The coordination of nitrogen with various metals (noble and non-noble) forms a unique electronic structure, and the synthesis process is often accompanied by the generation of topological defects, which makes the constructed SANs exhibit superior catalytic activity. In addition, nitrogen-doped carbon nanomaterials have tunable morphology and ordered porosity properties, allowing them to function as platforms for integrating other therapeutic modalities to facilitate tumor therapy.

2.2.2. MOF-Based SANs

Artificially creating specific coordination sites within the framework of MOFs for anchoring heterogeneous metal atoms without loss of crystallinity and porosity is also a viable strategy for constructing SANs. For example, Yaghi et al. reported a single-atom catalyst in which a single Cu atom anchored to an oxygen atom of the -OH/-OH₂ species covering the defective sites of the Zr oxide cluster of MOF UiO-66, achieving 100% selective CO oxidation ^[55].

Wang et al. anchored Pt nanoparticles and single Pt atoms to the skeleton of the Prussian blue analog Mn[Co(CN)₆] _2/3 _1/3 MOF (MC_2/3, represents one-third of the internal missing linker) through the “missing-linker-confined coordination” strategy, and prepared traditional nanozymes (MC_2/3CpNE) and single-atom nanozymes (MC_2/3Cp-SAN) ^[56]. Specifically, the biocompatible polyvinylpyrrolidone polymer (PVP) and Mn ions were mixed to form a homogeneous solution, and the K₃[Co(CN)₆] solution was added to form a milky white colloidal suspension, which was the self-assembled MC_2/3. MC_2/3 loaded with Ce6 and anchored single Pt atoms (MC_2/3Cp-SAN) can be obtained by adding the photosensitizer Ce6 and PtCl₂ during the formation of MC_2/3, with loadings of 27.8 wt% and 8.48 wt%, respectively. MC_2/3Cp-SAN exhibited stronger CAT-like activity together with cyclic catalytic stability than MC_2/3CpNE. The in vitro and in vivo results demonstrated that MC_2/3Cp-SAN could efficiently catalyze the conversion of excess H₂O₂ to O₂ in tumor cells, thereby enhancing the photodynamic therapy (PDT) efficiency for cancer cells. This work not only proves the superiority of SANs over traditional nanozymes but also broadens the strategy for synthesizing SANs based on MOFs.

2.2.3. Carbon Dots-Based SANs

Carbon dots (CDs), as graphene derivatives, have uniform and ultra-small sizes (<10 nm) ^[57]^[58]^[59]. The CD surface is rich in coordination unsaturated chemical groups (-OH, -CO, and -NH₂), which can anchor the active metal sites and catalyze various biochemical reactions ^[60]. The high specific surface area of the CDs ensures complete contact between the active sites and the substrates, which enhances the catalytic activity.

Wang et al. used biocompatible carbon dots as carrier materials loaded with Ru single-atoms to prepare Ru SANs with multiple enzyme-like activities and stability ^[61]. The OXD-like, POD-like, and GSHOx-like activities of Ru SANs can synchronously catalyze the production of ROS and the depletion of GSH, which can amplify the ROS damage and ultimately lead to the death of the cancer cells. The specific activity of the POD-like activity of the Ru SAEs (7.5 U/mg) is 20 times higher than that of Ru/C. The theoretical results suggest that the electron transfer from the 4D orbital of the Ru single atom to the O atom in H₂O₂ effectively activates H₂O₂ to produce •OH, thus exhibiting excellent catalytic activity.

2.2.4. Metal Oxides-Based SANs

Titanium dioxide (TiO₂) nanoparticles are a typical class of inorganic sonosensitizers that produce ROS by separating electrons (e⁻) and holes (h⁺) from the energy band structure through ultrasonic excitation. Transition metal ion-doped sonosensitizer can significantly increase the separation of e⁻ and h⁺ and inhibit their complexation, enhancing ROS production efficiency ^[62]. In addition, the Fenton reaction is also an efficient way to generate ROS. However, the optimum pH of the Fe²⁺-mediated Fenton reaction is 2–4, whereas copper-based Fenton nanocatalysts are more efficient in weakly acidic TME. Breast cancer, the most common cancer worldwide, is one of the major public health problems threatening women’s health, and CT is currently the mainstream strategy to inhibit the progression of TNBC, but it is limited by poor efficacy and serious side effects ^[63]^[64]. SDT is an effective treatment for breast cancer, which uses the massive production of ROS to induce oxidative stress damage and trigger apoptosis and necrosis of tumor cells. However, mutant breast cancers, especially TNBC, have evolved specific antioxidant defenses that limit the killing efficiency of SDT ^[65]^[66].

Compositionally tunable two-dimensional (2D) MoS₂ nanosheets, as an inorganic co-catalyst, are ideally suited to act as SAC nanocarriers due to their large specific surface area, unique planar structure, and abundant active sites ^[67]. Yang et al. dispersed single-atom Fe sites on MoS₂ nanosheets sulfur-rich vacancies and active Mo⁴⁺ sites to construct a 2D composite nanocatalyst for achieving co-catalytic synergistic therapy of tumors ^[68]. The therapy S vacancies can increase the surface electron density and promote the electron capture by H₂O₂ to generate •OH. The reductive Mo⁴⁺ sites can accelerate the conversion of Fe³⁺ to Fe²⁺. Meanwhile, the 2D lamellar structure can more fully expose Fe atoms, sulfur vacancies, and Mo⁴⁺ active sites, which facilitates the synergistic overall reaction process and improves the POD-like activity (V_max = 4.37 × 10⁻⁸ M s⁻¹, Km = 15.06 μM). In addition, in vitro and in vivo experiments demonstrated that the constructed nanocatalysts have promising therapeutic efficacy and biosafety, and the concept of co-catalysis will be beneficial for developing nanocatalysis in tumor therapy.

3. Modulation of Activity of SANs for Cancer Therapy

SANs can generate large amounts of ROS to kill tumor cells in response to the weak acidity and high H₂O₂ levels of the TME. Different types of SANs achieve the regulation of intracellular ROS levels mainly through POD-like, OXD-like, CAT-like, and GSHOx-like activities to kill cancer cells. Among them, the POD-like activities of SANs catalyze the generation of •OH with H₂O₂ as the electron acceptor when functioning. Due to the high reactivity of •OH, which can use various small molecules and macromolecules such as nucleic acids, lipids, and proteins as electron donors, causing severe oxidative damage to cancer cells. The CAT-like activity of SANs can decompose the endogenous H₂O₂ of the cancer cells into O₂, which alleviates the anoxic environment of the tumor, thus increasing the efficiency of the generation of ¹O₂ in RT, PDT, and SDT. The OXD-like activity of SANs can catalyze the generation of H₂O₂ and $O_{2}^{• -}$ , whose cancer cell-killing ability is weaker than that of •OH and needs to be combined with other enzyme-like activities to kill tumors. The GSHOx-like activity of SANs can consume excessive intracellular GSH, thus weakening the antioxidant ability of cancer cells and playing a very auxiliary therapeutic effect.

3.1. Regulation of Intrinsic Enzyme-like Activities of SANs

3.1.1. Defect Engineering

Defect engineering can effectively regulate the geometry and electronic structure of single-atom catalysts and endow the catalysts with unique physicochemical properties, which is an effective strategy to modulate the catalytic activity. Common approaches include heteroatom doping, modulation of vacancies, and introduction of topological defects ^[69]. The properties of metal catalytic sites in intrinsic defects (e.g., edges) are different from that of the basal plane, which can profoundly affect the catalytic activity of SANs due to their unique geometrical and electronic structures that generate different local electronic environments ^[70]. In addition, edge sites allow substrates to fully contact the active center, speeding up mass transfer and accelerating reaction kinetics.

Despite the excellent performance of FeNC-edge, another issue to be considered is that the introduction of the edge structure also increases the Fe content of the material from 0.45 wt% to 0.72 wt%, so whether the increase in activity is due to the increase in the number of active sites or to the edge structure needs to be further considered. As can be seen in the preparation of the materials section of the article, the preparation of FeNC was only completed with less H₂O₂ etching than the preparation of FeNC-edge, which means that the authors did not deliberately control the consistency of the Fe content in the two materials when comparing the activities. Therefore, to more fully illustrate the effectiveness of the edge structure, it is necessary to compare the effect of the edge structure’s presence or absence on the materials’ catalytic activity in the presence of a consistent Fe content. Revealing the relationship between enzyme activity and structural properties is essential for guiding the synthesis of SANs and developing high-performance artificial enzymes for tumor therapy.

3.1.2. Regulation of the Coordination Environment

Nanozymes are a class of nanomaterials with intrinsic mimetic enzyme activity, which have excellent catalytic activity and physicochemical properties. Meanwhile, compared with similar materials, nanozymes have the advantages of low cost, excellent stability, and adjustable catalytic activity, and they are widely used in the treatment and diagnosis of tumors. However, the catalytic activity of nanozymes is still far from that of natural enzymes, while the disadvantages of poor substrate selectivity, low atom utilization efficiency, and intrinsic biotoxicity have hindered their further application. Due to their well-defined electronic structure, excellent substrate selectivity, and maximum atomic utilization efficiency, the new generation of SAN has been explored for biomedical applications

Regulating the Number of Coordination N

The MN₄-type SANs with non-polar coordination structures have a symmetrical electron distribution that limits their adsorption capacity and catalytic activity. Therefore, changing the electron distribution of SANs by adjusting the number of coordinated N atoms is an effective strategy to improve its catalytic activity. By theoretical calculations, Wang et al. have designed a series of non-homogeneous molybdenum single-atom nanozymes (MoSA-Nx-C, x = 2, 3, 4) ^[71]. The molybdenum site coordination number has a strong correlation with the POD-like specificity. MoSA-N₃-C exhibits a dedicated POD-like activity and achieves this behavior through a homocleavage pathway, whereas the MoSA-N₂-C and MoSA-N₄-C catalysts have different heterocleavage pathways. This coordination number-dependent enzyme specificity is attributed to the geometrical differences and the orientation of the front molecular orbitals of MoSA-Nx-C.

HRP has a heme moiety centered on active iron and the imidazole nitrogen of histidine as the fifth axial ligand ^[72]. The axial nitrogen ligand plays a crucial role in stabilizing the active structure and enhancing enzyme activity. In chemical catalysis, the axially coordinated MN₅ structure is capable of downgrading the reaction activation energy and increasing the catalytic rate.

Heteroatom Doping

Ferroptosis is a cell death pathway that accumulates lipid peroxides in an iron-dependent manner. Scientists have employed different iron-based nanozymes to induce ferroptosis by oxidizing polyunsaturated fatty acids (PUFAs) and LPO ^[73]. However, the efficiency of ferroptosis stress induced by iron-based nanozymes is limited due to the special tumor microenvironment, mainly caused by the deficiency of Fenton activity and the overexpression of GSH. To overcome this limitation, Zhu et al. prepared nickel single-atom nanozymes (S-N/Ni PSAN) enriched with marginal sulfur (S) and nitrogen (N) modifications by a strategy of anion exchange from the viewpoint of improving the intrinsic activity of single-atom nanozymes ^[23]. NiCo Prussian blue analog (NiCo PBA) was first used as a precursor, and then NiS nanocubes were prepared by etching Co atoms using Na₂S via anion exchange. Then, a polydopamine (PDA) layer was coated on the surface of NiS nanocubes, and the polydopamine layer was pyrolyzed to a nitrogen-doped carbon (N-C) backbone by high-temperature pyrolysis. During calcination, volatile S species (bp 444.7 °C) are more inclined to the edge-selectively sulfated N-C backbone, anchoring Ni atoms to the edge S-rich N-C skeleton. S species are essential components of many natural enzymes and critical in transferring electrons from the substrate to the enzyme active center. The vacancies and defective sites of the nitrogen sulfide atoms allow S-N/N/Ni PSAE to exhibit stronger POD-like activity and GSHOx-like activity than N/Ni PSAE. For POD-like activity, the SA value of S-N/Ni PSAE (115 U/mg) was 11.6 times higher than that of N/Ni PSAE (9.9 U/mg). S-N/NiPSAE could produce •OH and consume GSH more efficiently than N/Ni PSAE in ferroptosis-based tumor therapy, inducing GPx-4 inactivation and irreversible LPO, leading to ferroptosis of tumor cells and better inhibition of tumor growth. This work enhances the catalytic effect of multi-heteroatom doping and provides an effective strategy for ferroptosis-based anti-tumor methods ^[23].

3.1.3. X-ray Irradiation

For the purpose of enhancing the enzymatic activity of SANs, in addition to maximizing the atomic utilization by increasing the surface area, introducing external fields into the catalytic process to improve the catalytic efficiency is also a proven strategy. For example, under X-ray irradiation, the conversion of Cu II species in copper-based nanoparticles to Cu I is accelerated, thus enabling faster conversion of H₂O₂ to •OH ^[74]. Also, since X-rays do not have a depth limitation, such a strategy could be applied to treating deep tumors.

Given the similar kinetics between the conversion processes of Cu I/Cu II and Fe II/Fe III, Zhu et al. introduced X-rays into the catalytic reaction system of iron-based SANs (FeN₄-SAN) to increase the enzyme activity of Fe II/Fe III by accelerating the rate of its conversion, which is a decisive step in the generation of ROS ^[75]. Thus, FeN₄-SAzyme can produce -OH faster to consume GSH. To solve the problem of H₂O₂ insufficiency, FeN₄-SAN was compounded with natural glucose oxidase (GOD) to obtain a therapeutic agent with H₂O₂ self-supply ability, which ensured the continuous production of •OH and enhanced in situ apoptosis and ferroptosis. This external field-enhanced SANs catalysis paradigm can be extended to various external fields and other nanozymes to enhance enzyme activity.

3.1.4. Regulation of the Central Metal Atom

Recently, introducing secondary metal atoms can effectively improve the catalytic activity of SACs. DSACs can modulate the d-band center through the entanglement of electronic orbitals, which can effectively optimize the adsorption process of intermediates on the active site ^[76]. Therefore, DSACs can effectively improve intrinsic activity and selectivity. For example, introducing a single Cu site in Pd SACs transfers part of the density state of Pd to the Fermi energy level. Meanwhile, introducing Cu sites can also modulate the d-2π* coupling between Pd and adsorbed N₂, thus improving N₂ chemisorption and protonation, and delaying hydrogen precipitation. Ultimately, the Faraday efficiency and NH₃ synthesis efficiency of Pd-Cu DSACs were higher than those of Pd SACs ^[77]. It was also shown that the synergistic effect between Co and Ni sites led to a significant increase in the adsorption and desorption efficiencies and a decrease in the reaction thresholds of the monodispersed Co-Ni dinuclear catalysts ^[78].

Extension of SACs from single-atom to dual-atom sites is an effective method to enhance catalytic activity. Wang et al. prepared atomically dispersed Fe,Pt binuclear nanozymes ((Fe,Pt)SA-N-C) with a distance of 2.38 Å between Fe₁ (Fe-N₃) and Pt₁ (Pt-N₄) by employing a secondary doping strategy ^[26]. DFT calculations showed that the isolated Pt sites can modulate the 3D electronic orbitals of Fe-N₃ and enhance the activity of H₂O₂ and the adsorption of Fenton-like reaction intermediates on Fe-N₃. Thus, the activity out of (Fe,Pt)SA-N-C was enhanced by about 30% over the single Fe site. After PEG modification, (Fe,Pt)SA-N-C-FA-PEG was able to effectively catalyze the production of large amounts of toxic •OH from H₂O₂ in the TME and induce apoptosis of tumor cells.

3.2. Ameliorating the TME

Solid tumors are hypoxic, and the level of H₂O₂ in TME is usually below a certain threshold (≈100 × 10⁻⁶ M) ^[79]. Increasing the content of O₂ and H₂O₂ in the tumor site can further improve the catalytic therapeutic effect. NADH oxidase catalyzes the reaction between O₂ and NADH to produce NAD⁺ and H₂O₂, which plays a vital role in regulating cellular redox and maintaining normal cell growth. The NADH/NAD⁺ redox pair acts as an electron transporter, providing protons to the mitochondrial electron transport chain (ETC), and is also required for adenosine triphosphate (ATP) production in tumor glycolysis and oxidative phosphorylation metabolism. Therefore, disrupting the NADH/NAD⁺ balance not only effectively inhibits ETC and reduces mitochondrial aerobic respiration, but also interferes with the metabolic processes of tumor cells and reduces their ability to generate ATP ^[80]^[81].

Liu et al. encapsulated Ir(acac)₃ in ZIF-8 (Ir(acac)₃@MOF), and then, nitrogen-rich melamine and dried Ir(acac)₃@MOF were calcined at high temperatures to obtain IrN₅ SAN with axial N coordination ^[25]. IrN₅ SAN has an asymmetric electron distribution and exhibits OXD-like, POD-like, CAT-like, and NOX-like properties. The synergistic interaction between the central metal Ir atom of IrN₅ SAN and the axial N-coordinated structure efficiently optimizes the free energies of the various transition states on IrN₅ SAN, which exhibits a better enzyme-like catalytic activity than that of IrN₄ SAN. IrN₅ SAN could catalyze the decomposition of H₂O₂ to O₂ at the tumor site, effectively alleviating tumor hypoxia. Meanwhile, IrN₅ SAN could mimic NOX to catalyze the generation of H₂O₂ from NADH and inhibit mitochondrial ETC and aerobic respiration. The increased O₂ and H₂O₂ at the tumor site could enhance the OXD-like and POD-like activities of IrN₅ SAN, increase the level of ROS in tumor cells, and cause irreversible oxidative damage. The decrease in NADH would break the NADH/NAD⁺ balance and inhibit the ATP produced by tumor cells through the metabolic processes of glycolysis and oxidative phosphorylation. Even though IrN₅ SAN disrupts the normal energy metabolism of tumor cells, tumor cells can use fatty acid oxidation (FAO) to survive in nutrient-deficient environments through metabolic reprogramming. Therefore, the attenuated FAO metabolism of tumor cells, ceruloplasmin (Cer), was further loaded into IrN₅ SAN. Cer, as a fatty acid synthase inhibitor, could effectively inhibit phospholipid synthesis and lipid remodeling in tumor cells and reduce the migration and invasive ability of tumor cells. In order to improve the biocompatibility of IrN₅ SAN, the surface of IrN₅ SAN was further modified with a trithiol-terminated polymethacrylic acid. IrN₅ SAN/Cer significantly enhanced tumor therapy’s therapeutic effect by destroying the tumor redox and metabolic balance by mimicking the enzyme cascade reaction. With the dual function of breaking redox and metabolic homeostasis, this SAN provides a new perspective for nano-catalytic therapy ^[25]. One problem is that the reaction catalyzed by NOX is an oxygen-consuming process, and it is theoretically debatable whether the oxygen content of tumor cells can be increased even though aerobic respiration in mitochondria is inhibited.

SANs with POD-like activity can alter cellular redox balance and hold great promise for tumor therapy. However, the “cold” immune microenvironment and limited H₂O₂ in solid tumors severely limit its efficacy. Zhu et al. designed a light-controlled oxidative stress amplifier system that co-encapsulates Pd-C SANs and camptothecin in an agarose hydrogel to enhance synergistic anti-tumor activity by self-producing H₂O₂ and transforming “cold” tumors ^[82]. In this nano-enzymatic hydrogel system, the Pd-C SANs convert near-infrared laser light into heat, leading to the degradation of the agarose, which releases the camptothecin. The camptothecin increases H₂O₂ levels in the tumor by activating nicotinamide adenine dinucleotide phosphate oxidase, which improves the catalytic properties of SANs with POD-like activity.

3.3. Increasing the Specific Surface Area of SANs

Employing SANs-based ROS generators has become an effective strategy for mediating tumor therapy, but in physiological environments, problems such as biomass adsorption and micropore clogging occur, severely affecting substance transport and reducing the number of available active sites. Even if ROS are generated, they cannot diffuse out to act, owing to the limitations of the half-life time (<200 ns) and diffusion distance (≈20 nm) ^[83]. Here, modulating the morphology of SANs to increase the substrate accessibility as well as the diffusibility of ROS will further increase the tumor therapeutic effect of SANs.

3.4. Other Approaches to Regulating the Activity of SANs

Surface-modified DNA molecules modulate the activity of SANs. To cope with the low activity and uncontrollability of ferroptosis inducers, Cao et al. prepared an adaptive ferroptosis platform based on DNA-modified Fe SANs (macDNAFe/PMCS SANs)^[84]. PMCS SANs exhibited high OXD-like and POD-like activities, which were 70-fold and 50-fold higher than those of the Fe-based nanozymes, respectively, and GSH depletion capacity. Through van der Waals interactions, C-rich monolayer DNA (cDNA), ATP aptamer (aDNA), and MUC-1 aptamer (mDNA) were encapsulated on the surface of Fe/PMCS SANs, which enhanced the affinity of Fe/PMCS SANs for H₂O₂ and substrates and accelerated the generation of ROS. Meanwhile, mDNA increased the affinity of Fe/PMCS SANs for cancer cells and enhanced the selective killing of cancer cells. Subsequently, overexpression of ATP (100~500 × 10⁻⁶ M) and lysosomal acidity (pH ≈ 5) in tumor cells could remove the aDNA and cDNA shielding effects, exposing the active site of SANs and selectively removing GSH from tumor cells. macDNAFe/PMCS SANs selectively enhanced cancer cell ferroptosis in mouse colon and breast cancer models, showing prominent therapeutic effects. Integrating responsive molecules with SANs provides new insights for preparing iron death inducers with high activity, controllability, and selectivity.

4. Synergistic Treatment of SANs with Other Therapies

4.1. Photothermal Therapy (PTT)

The osteosarcoma malignancy damages a large percentage of the population, especially adolescents and young adults ^[85]. The development of osteosarcoma can lead to pain, fractures, and tumor metastasis. Osteosarcoma treatment requires effective anti-tumor therapy and advanced osteogenic techniques. At the same time, the accompanying antimicrobial properties are expected to ensure a good prognosis for osteosarcoma treatment in order to avoid frequent surgeries during bone repair and possible infections due to chronic osteomyelitis ^[86]. Wang et al. integrated highly active single-atom iron nanozymes (Fe SAN) into 3D-printed bioactive glass (BG) scaffolds for osteosarcoma treatment, bacterial killing, and subsequent osteogenesis ^[87]. The excellent Fenton-like catalytic activity and remarkable PTT effect of Fe SAC effectively eliminated osteosarcoma cells, exerting significant antibacterial and anti-osteomyelitis activities. The Fe SAN-BG scaffolds implanted into the bone defect site may accelerate bone marrow mesenchymal stem cells, accelerate osteoconduction and osteoinduction. This work broadens the application of SANs in integrated biomedical tissue engineering.

The NIR-II laser (1064 nm) has deeper tissue penetration and safety than NIR-I (808 nm) and produces thermal effects that can be synergized with other therapeutic modalities to eliminate tumors. Ye et al. successfully prepared PEGylated mesoporous manganese-based SANs (PmMn/SAN) using polydopamine via a coordination-assisted polymerization strategy ^[88]. PmMn/SAE exhibits excellent multi-enzymatic properties, including CAT-like, OXD-like, and POD-like activities, and not only catalyzes the conversion of endogenous H₂O₂ into O₂ to alleviate the intra-tumoral hypoxia, but also transfers electrons to O₂ to produce

O_{2}^{• -}

. Meanwhile, PmMn/SAE also induces apoptosis in cancer cells by generating highly toxic •OH through a Fenton-like reaction. PmMn/SAN also has excellent adhesion, biocompatibility, and photothermal conversion properties (η = 22.1%), and under laser irradiation at 1064 nm, the multiple ROS and photothermal properties synergized for better tumor inhibition. DFT calculations revealed the POD-like catalytic mechanism of PmMn/SAN, demonstrating the catalytic advantage of Pm Mn/SAE over H₂O₂. The in vitro and in vivo results demonstrated that PmMn/SAN could effectively kill cancer cells by photothermally enhanced catalytic therapy.

4.2. Sonodynamic Therapy (SDT)

Previous work has shown that metal element doping (e.g., Fe, Cu, Mn) can narrow the bandgap of C₃N₄ and facilitate the separation of e⁻ and h⁺ pairs, thereby improving ROS generation efficiency ^[89]. Based on this, Feng et al. synthesized single-atom Fe-doped C₃N₄ semiconductor nanosheets (Fe-C₃N₄ NSs), which acted as a chemical-responsive sonosensitizer, effectively separating the e⁻ and h⁺ pairs and achieving a large amount of ROS generation at the melanoma site under ultrasound irradiation ^[90]. The N-coordinated holes and high-density homogeneous “six-fold cavities” of the C3N4 can effectively trap Fe ions. The doping of single Fe atoms can significantly improve the separation efficiency of e⁻-h⁺ pairs and exerts its high-efficiency POD-like activity to catalyze the generation of a large number of •OH, synergistically enhancing the SDT-mediated therapeutic effect. DFT studies and experimental results show that the doping of Fe atoms induces charge redistribution in C₃N₄ NSs, which enhances their synergistic SDT/chemokinetic activity, thus showing significant anti-tumor effects, thereby showing significant anti-tumor effects. This work extends the application of semiconductor-based inorganic acoustic sensitizers in tumor therapy.

4.3. Chemotherapy (CT)

Motivated to enhance the efficacy of SANs CDT, Zhu et al. constructed hollow carbon nanospheres loaded with oleanolic acid (OA) single-atom Fe-anchored (OA@Fe-SAN) by a template-mediated carbonization strategy ^[24]. The erythrocyte membrane was further loaded on its surface (OA@Fe-SAN@EM), which both prevented the leakage of OA and enhanced the accumulation of OA@Fe-SAN@EM in the tumor. Firstly, SiO₂ nanoparticles were used as a template to introduce iron acetylacetonate during in situ polymerization of dopamine on its surface. Subsequently, it was pyrolyzed at 900 °C in a nitrogen atmosphere to anchor isolated Fe atoms on the N-doped C shell transformed from the PDA layer. Hollow N-doped carbon nanospheres supported by Fe SAN were obtained by etching SiO₂ core with 4% hydrofluoric acid. Finally, OA was loaded into the hollow nanostructured Fe-SAC, and EM was coated on the surface of the hollow nanostructure. Excessive H₂O₂ in cancer cells could pass through the EM layer and produce * OH catalyzed by Fe-SAN, leading to EM breakage and release of OA. OA could effectively increase the expression of endogenous acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) and enrich ROS-sensitive polyunsaturated fatty acids (PUFAs) to the cellular membranes, thus synergistically enhancing the CDT effect and exacerbating LPO by increasing the unsaturation of the cell membrane. In vivo experiments demonstrated that OA@Fe-SAN@EM NPs were able to inhibit tumor growth without significant side effects significantly. The strategy of enhancing CDT by adjusting membrane unsaturation proposed in this study opens up new ideas for enhancing the anti-tumor effect of SAN ^[24].

4.4. Sonothermal Therapy (STT)

Electron-rich SANs offer the possibility of STT under low-intensity ultrasound irradiation. Qi et al. synthesized boron imidazole skeleton-derived nanocubes anchored with a single atom of Cu by a “B-H” interfacial domain-limiting ligand strategy ^[91]. The Cu SANs exhibit excellent sonothermal conversion properties as a result of strong intermolecular lattice vibrations when irradiated with low-intensity ultrasound. Moreover, Cu SANs were able to exhibit strong biocatalytic activity, catalyzing the generation of large amounts of toxic •OH. In vitro and in vivo evaluations confirmed that the sonothermal–catalytic synergistic therapeutic strategy mediated by Cu SANs effectively inhibited tumor proliferation (tumor suppression rate of 86.9%) and enhanced the survival rate (100%) of the MDAMB-231 tumor-bearing nude mice after a single injection and irradiation. These findings provide a novel approach to designing multifunctional nanoplatforms for precision cancer therapy.

4.5. Gas Therapy (GT)

In order to enhance the targeting and the efficacy of SAN therapy, Chen et al. developed a cell membrane-encapsulated SANs targeted therapy system ^[92]. Firstly, the pyrolysis process prepared Cu SAN using polydopamine nanoparticles as a carbon source with a 0.9% mass fraction of Cu atoms, exhibiting high POD-like activity under weak acid conditions. Next, the targeted composite system was prepared by extruding platelet vesicles (PV), O₂ prodrug (benzothiazole sulfinic acid, BTS), and Cu SAN together through an extruder. Among them, p-selectin on the platelet membrane can specifically recognize CD44 receptors on tumor cells to achieve tumor targeting. The sulfite structure of water-soluble BTS is easily hydrolyzed to SO₂ in the weakly acidic environment of tumors. SO₂ further reacts with H₂O₂ to generate toxic •SO₃, which increases the expression of pro-apoptotic proteins calpain I, Bax, and p53 and inhibits the expression of anti-apoptotic protein bcl-2, thus inducing apoptosis. At the same time, it will consume excessive GSH in tumor cells, destroy the intracellular redox balance, and reduce the ROS tolerance of tumor cells, which further enhances the nano-catalytic therapeutic effect of Cu SAN. These properties of the composite system were verified in a mouse model of MFC peritoneal metastases, where the composite system inhibited 90% of the tumors and showed good biocompatibility.

4.6. Magnetic Resonance Imaging (MRI)

Among various biomedical imaging modalities, MRI is an effective and noninvasive diagnostic method for disease evaluation and diagnosis, especially for early detection and precise localization of tumors ^[93]^[94]. Due to the low sensitivity of MRI, scientists have utilized contrast agents (e.g., Gd-chelators) to enhance the lining of clinical imaging by increasing the spin relaxation rate of water molecules in vivo ^[95]. With the rapid development of nanotechnology, Gd-based nanomaterials exhibit better relaxation properties than Gd-chelates by increasing the rotational correlation time (τr) of geometrically confined Gd elements, and they can be enriched in tumors ^[96]. However, the inability of the Gd atoms inside the nanoparticles to contact water molecules leads to the waste of Gd atoms and increases the medical cost ^[97].

Therefore, Liu et al. prepared GaSA by loading single-atom Gd onto hollow N-doped carbon nanorods via a template-mediated nitridation strategy ^[98]. Subsequently, its surface was modified with DSPE-PEG₂₀₀₀-NH₂ to enhance its dispersibility and biocompatibility. Ga atoms are coordinated by six N atoms and two O atoms and thus exhibit higher stability than gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) and Gd₂O₃ nanoparticles, as well as minimal hematotoxicity, nephrotoxicity, and hepatotoxicity. Ga-SA has a longitudinal relaxation rate (r1) value of up to 11.05 mM⁻¹ s⁻¹ and exhibits a more pronounced magnetic resonance (MR) contrast enhancement on tumor tissues at 24 h after administration, which is due to the exchange of relaxed water molecules being faster in Gd-SA than in Gd-DTPA.

4.7. Immunotherapy (IT)

Although ROS can promote ferroptosis, intracellular overexpression of reduced glutathione (GSH) in tumor cells eliminates ROS bursts at the tumor site, making it difficult to activate ferroptosis with most current ROS-based therapeutic strategies, including PDT, CDT, and SDT. Therefore, consuming endogenous GSH while increasing ROS at the tumor site would effectively activate initial tumor immunogenic ferroptosis. Nanozymes can specifically react with excessive hydrogen peroxide (H₂O₂) and GSH under unique TME and play an essential role in ROS-mediated cancer treatment ^[99].

The formation of catalytic reaction intermediates with high energy barriers severely limits the catalytic activity of SANs due to the excessive binding strength between the transition metal monoatomic sites and the electron-donating intermediates. Compared with SANs, non-homogeneous dual-atom site catalysts can utilize two different adjacent metal atoms to achieve their functional complementarity and synergy. In particular, the energy barrier of the reaction intermediates can be modulated by the electronic interactions between the two neighboring metals ^[100]. Therefore, preparing non-heterogeneous diatomic nanozymes with ROS generation and GSH removal capabilities is important for ferroptosis-based antitumor IT.

4.8. Multiple Modality Therapy

Zhu et al. encapsulated Pd-C SANs and camptothecin in agarose hydrogel to synergistically enhance the anti-tumor activity by combining PTT, CT, and catalytic therapies ^[82]. The Pd-C SAN was able to convert near-infrared (NIR) laser light into heat, which led to the degradation of the hydrogel and the slow release of camptothecin. The camptothecin not only killed the tumor cells but also activated nicotinamide adenine dinucleotide phosphate oxidase, increased the H₂O₂ content in the tumor, further enhanced the POD-like activity of SANs, and promoted the immunogenic death of the tumor.

4.9. Other Therapeutic Approaches

Current SANs mainly rely on passive transport to the tumor site. The lack of active delivery capability can lead to limited depth of tumor penetration and reduce the efficacy of SANs. Nanomotors can convert a variety of energies into autonomous motions. Limited by the ionic strength in the human body, the two main mechanisms by which nanomotors are effectively self-driven in bioliquids are self-diffusion and self-thermophoresis, enabling them to target tumors actively, enhance cancer cell membrane adhesion and increase tumor penetration depth ^[101]^[102]. Therefore, by rationally designing the morphology of SANs and using the photothermal properties of SANs, SANs can be constructed into self-thermally driven nanomotors, combined with the high catalytic activity of ROS of SANs, to improve the tumor treatment effect of SANs further.

5. Application of SANs in Tumor Diagnostics

Nitric oxide (NO) is an endogenously produced signaling molecule that acts intracellularly and intercellularly ^[103]. NO is a natural biomolecule with redox activity, produced by the oxidation of L-arginine catalyzed by nitric oxide synthase (NOS) ^[104]. The controlled release of NO significantly impacts the maintenance of vascular homeostasis. In response to mechanical forces (circumferential stretch or fluid shear stress), endothelial cells produce excessive amounts of NO, triggering a cascade of biological reactions that can dysregulate oxidative homeostasis and lead to diseases such as neurodegenerative disorders, autoimmune processes, and cancer ^[105]. For example, NO in the brain, in the threshold concentration range (nM) regulates synaptic transmission and neuronal activity. However, if the NO concentration exceeds the threshold range (up to μM), it will induce oxidative stress and cause neuronal damage ^[106]. Therefore, developing real-time sensing platforms for NO under normal and pathological conditions is crucial for human health detection. Monitoring intracellular NO levels requires sensors with sufficient sensitivity, transient recording capability, and biocompatibility.

By modulating NO concentration in the in vivo microenvironment and utilizing its vasodilatory function, NO can be used for wound healing and anti-tumor therapy of vascular regulation. Therefore, accurate determination of NO concentration is of great significance for understanding its function and various life activities of organisms. Hu et al. used Co SAN to construct active materials for NO electrochemical sensors ^[107]. The constructed flexible sensor can be connected to portable electronic devices for the in situ processing of signals and wirelessly communicate with the user interface via Bluetooth, enabling highly sensitive in situ monitoring of NO at the cellular and organ levels.

SANs on MXenes show promising applications in cancer diagnostics. By calcination, single Au atoms are embedded into the Ti vacancies of MXene, redistributing the charge of MXene through metal–carrier interactions ^[108]. At the SA Au sites, H₂O₂ gains electrons and is converted into •OH, leading to a significant increase in electrochemiluminescence intensity, which is twice that of AuNPs-MXene. In addition, during the synthesis process, part of the Ti is oxidized to TiO₂, constructing a heterojunction of MXene and TiO₂, accelerating free radical generation, and facilitating the electrochemical signals. For the clinical detection of miRNA-187 in triple-negative breast cancer tumor tissues, the luminescence intensity was positively correlated with the concentration of miRNA-187.

MoSA-N₃-C was successfully applied for selective and sensitive analysis of xanthine in human urine samples, contributing to the early diagnosis of renal lesions ^[71].

Photoelectrochemical immunoassay is a novel detection platform based on changes in photocurrent induced by photosensitive nanomaterials recognizing antigens and antibodies. Due to their excellent catalytic activity and selectivity, SACs have also been used to construct novel photoelectrochemical sensor platforms. Zeng et al. synthesized single-atom platinum-supported hollow cadmium sulfide and constructed a photoelectrochemical biosensor using it as an etched substrate for detecting exosomes ^[109].

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