Hierarchical Nanobiosensors at the End of the SARS-CoV-2 Pandemic

Nanostructures have played a key role in the development of different techniques to attack severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Some applications include masks, vaccines, and biosensors. The latter are of great interest for detecting diseases since some of their features allowed us to find specific markers in secretion samples such as saliva, blood, and even tears. Herein, we highlight how hierarchical nanoparticles integrated into two or more low-dimensional materials present outstanding advantages that are attractive for photonic biosensing using their nanoscale functions. The potential of nanohybrids with their superlative mechanical characteristics together with their optical and optoelectronic properties is discussed. The progress in the scientific research focused on using nanoparticles for biosensing a variety of viruses has become a medical milestone in recent years, and has laid the groundwork for future disease treatments. This perspective analyzes the crucial information about the use of hierarchical nanostructures in biosensing for the prevention, treatment, and mitigation of SARS-CoV-2 effects.


Introduction
Sensors based on hierarchical nanostructures in the area of nanomedicine have been meticulously investigated in order to identify different enzymes and organisms such as bacteria or viruses.Biosensors are fascinating instruments that basically serve to detect biological or chemical parameters such as those related to molecules in tissues, microorganism cultures, and nucleic or acid chains [1].The characteristics related to biodetection like selectivity, response speed, and stability depend on the morphology and structure of the sensing materials [2].
A strong selective control of the manufacturing parameters of noble metals is possible [17], allowing their structure to be modified [18] to improve their physicochemical properties and adjust their shape [19].There are multiple techniques for designing nanobiosensors, but the most common ones are based on electrochemical deposition [20], electroless deposition [21], electrocatalysts [22], and physicochemical methods [23].
Besides different processing routes that have been extensively explored to improve biosensing effects, the use of the LSPR phenomenon is very attractive [24], and the development of hierarchical nanostructured biosensors can promote exceptional optical, electrical, and chemical properties based on LSPR.Some of the special characteristics exhibited by hierarchical nanostructures are derived from their ultra-high specific surface area, high flexibility, light weight, high electrical conductivity, and bio-compatibility [25][26][27][28][29][30].
The hierarchical nanostructures are replacing conventional random hybrids in counterparts thanks to their physical characteristics, stability, and efficient transfer of electronic and ionic charges [31,32].For example, their morphologies show a high surface area with adjustable porosity or packing density.Some hierarchical assemblies serve as programmable scaffolds that provide molecule-level control over the distribution of fluorophores and nanometer-scale control over their distance.Several strategies can be used to study imperfections and to stabilize various types of nanostructures, such as hollow ones [33] or cage frames to obtain a better performance [34].
It is worth noting that hierarchical metamaterials have been reported for the development of virus-based light learning systems, in plasmonic structures for application in high-performance metamaterials, and in binary nanoparticle networks and liquid crystal arrays for sensing technologies and imaging [35].With these procedures, diverse techniques have been demonstrated strong fluorescence intensity and mild levels of enhancement, which allows them to manipulate photonic excitation and photoemission [36].
Hierarchical nanostructures represent a potential key to the next generation of new nanomaterials.For example, a controlled structure in the agglomeration between nanoparticles can increase plasmonic effects while the stacking distance between other nanoparticles decreases; all of this can be used to develop new and effective detection methods.Some of the representative hierarchically structured shapes are nanopillars [37], nanocones [38], nanoholes [39], and gecko pillars [40], among others.
A hierarchy in nanostructures can be developed through in situ plasmon-driven syntheses [59] or through amino acids [60] to easily detect analytes at trace levels, such as pesticides, heavy metals, explosives, proteins, pathogens, and other chemical and biological contaminants [61].It is clear that nanomaterial sciences are essential for developing biosensors with high reliability and speed using innovative technology [62][63][64][65].
In the last two years, diverse experiments have been carried out in the development of biosensors using different hierarchical nanostructures.It is worth highlighting some examples that have been very useful in the commitment to developing biosensors with better properties.
It has been pointed out that biosensors can be used to see the effectiveness of the vaccines in healthy, convalescent, or vaccinated people [66].They can be used to monitor diseases, observe how many antibodies exist in people's fluids, as well as determine whether the vaccines are effective for the test subjects [67].In the faster biosensors, it takes approximately 20 min to obtain the result.The research has sought to develop biosensors with these nanomaterials to achieve a relatively rapid response, achieving a response time of 15 min.It has been observed that current biosensors also have some disadvantages such as not being capable of detecting analytes in samples when there are external stimuli.This has to be addressed with the development of different biosensors with the properties of nanomaterials, such as different probes, including plasmonic [68] and incorporated ones [69].Biosensors capable of detecting pathogens with very little genetic material compared to other assays have also been developed [70].Additionally, calorimetric strips for smartphones aimed at antibodies or antigens to combat the rapid spread of these diseases have been considered since wearable biosensors can constantly monitor patients [71].
With this motivation, this paper reviews different aspects of the cutting-edge biosensors in the detection of SARS-CoV-2, focusing in those based on hierarchical and hybrid nanoparticles.Figure 1 shows the main characteristics considered in our research.
sensors with these nanomaterials to achieve a relatively rapid response, achieving a response time of 15 min.
It has been observed that current biosensors also have some disadvantages such as not being capable of detecting analytes in samples when there are external stimuli.This has to be addressed with the development of different biosensors with the properties of nanomaterials, such as different probes, including plasmonic [68] and incorporated ones [69].Biosensors capable of detecting pathogens with very little genetic material compared to other assays have also been developed [70].Additionally, calorimetric strips for smartphones aimed at antibodies or antigens to combat the rapid spread of these diseases have been considered since wearable biosensors can constantly monitor patients [71].
With this motivation, this paper reviews different aspects of the cutting-edge biosensors in the detection of SARS-CoV-2, focusing in those based on hierarchical and hybrid nanoparticles.Figure 1 shows the main characteristics considered in our research.

Synthesis of Hierarchical Nanostructures and Multicomponent Assemblies for Biosensors
Materials with hierarchical nanostructures have excellent mechanical properties due to the functional adaptation of their structures into different hierarchical levels.Hierarchical structures can be observed in nature, such as in bones, wood, cork, and plant stems, or in glass sponges [72].Hierarchical nanomaterials show different architectural designs that are ordered at multiple length scales.They are grouped according to their main characteristics; in the case of porous materials, they contain interconnected pores with at least two levels of pore hierarchy from molecular (1-100 A), nano (10-100 nm), and meso (1-100 μm), to macropores [73].It should be noted that the construction of hierarchical nanostructures requires knowledge of particular principles to avoid limitations on their properties [74].Hierarchical materials can mimic the mechanical properties of their biological counterparts.Smart hierarchical materials can exhibit specific stimulus-response properties [75], such as self-healing and self-regeneration [76] in or-

Synthesis of Hierarchical Nanostructures and Multicomponent Assemblies for Biosensors
Materials with hierarchical nanostructures have excellent mechanical properties due to the functional adaptation of their structures into different hierarchical levels.Hierarchical structures can be observed in nature, such as in bones, wood, cork, and plant stems, or in glass sponges [72].Hierarchical nanomaterials show different architectural designs that are ordered at multiple length scales.They are grouped according to their main characteristics; in the case of porous materials, they contain interconnected pores with at least two levels of pore hierarchy from molecular (1-100 A), nano (10-100 nm), and meso (1-100 µm), to macropores [73].It should be noted that the construction of hierarchical nanostructures requires knowledge of particular principles to avoid limitations on their properties [74].Hierarchical materials can mimic the mechanical properties of their biological counterparts.Smart hierarchical materials can exhibit specific stimulus-response properties [75], such as self-healing and self-regeneration [76] in order to improve fracture resistance and increase strength [77].Arrays can be constructed using proteins and microscale mechanical constraints can be used to form ordered networks within macroscopic structures [78].The synthesis at different orders of magnitude from nanoscale to macroscale can be used to acquire outstanding characteristics through interacting with different analytes of different sizes [79], from small proteins to living cells.Different networks can be designed according to the geometry of the templates used [80].The nanoclusters can be protected by ligands that can be prepared with atomic precision, exhibiting well-defined structures and resulting in versatile building blocks to manufacture excellent structures capable of performing certain functions [81].For instance, nanofibers are used to construct multifunctional walkways with up to five levels of organization (depending on the method used).In the first level, there is a composite nanofiber; in the second level, a layer of composite material coated on the composite nanofiber that will result in the third level.The fourth level organizes the nanofibers to form an assembly and finally, in the last level, an assembly of nanofibers can be encapsulated within a matrix to form a massive structure by default [82].Nanotubes are commonly used for the manufacture of hierarchical materials since they consist of molecular blocks, whose characteristics can be related to an anisotropic supramolecular self-assembly behavior at a personalized nanoscale, which allows for the creation of a percolation network at the mesoscale.They are regulated by dynamic self-assembly into four hierarchical levels of self-organization [83].Nanosheets are composed of 2D building blocks, which have atomic or molecular thicknesses and they are considered the thinnest functional nanomaterials.They can be organized into various nanostructures or combined with a variety of materials at the nanoscale.Thanks to this, wide-range assemblies such as organic molecules, polymer gels, and inorganic nanoparticles can be designed [84].
Although hierarchical nanomaterials can be considered hybrid materials [85], nanohybrids are composed in a different way.Hybrid materials can have a variety of complex architectures with or without hierarchy.Their size varies from nanometers to several micrometers and several millimeters.Hybrid nanomaterials are combined through the synergistic mixture of two or more nanomaterials, which can be either inorganic or organic [86], that create a single material with properties that go beyond their properties as individual elements.They consist of groups of blocks with similar properties and structures with groups that cross-link the polymer into chains [87].Their properties are determined by a combination of structure and composition at each length scale [88].As a result, their properties are expressed in molecular length scale structures [89].This indicates that the new mixture has superior properties compared to the original mixture.The properties to look at are the advantages derived from nanomaterials at a macroscopic level, such as energy absorption performance.The lightweight structure maximizes its functionality and improves the efficiency of the material [90,91].
There are different forms of nanohybrids such as sandwich structures, foams, reticular structures, segmented structures, zero expansion [92], and meso-structured thin films [93].These structures serve different purposes, especially in integrated refractive and diffractive optical devices.Since these nanomaterials have a large thermal stability and better compatibility, they are typically used in the production of semiconductive devices [94].In order to characterize organic-inorganic materials, techniques such as FTIR, Raman spectroscopy, LSPR, and various techniques based on MS are used [95].
Hybrid nanomaterials are good candidates for developing nanomaterials in the fight against bacteria and viruses thanks to their high sensitivity, good stability, and selectivity.In particular, they can detect antigens in plasma since their good electrochemical activity helps in the immobilization of the chains of different aptamers [96].
Nanomedicine, based on hybrid and hierarchical nanomaterials, has achieved great progress in the field of biosensors for the diagnosis, prevention, detection [97], and treatment of diseases in the post-pandemic period [98].Compared to bulk materials, nanostructures are more precise, more reliable, less invasive, and easier to carry according to their chemical elements [99].The effectiveness of nanomaterials has advanced to detect diseases at a very early stage using new technologies based on nanobiosensors [100], whose physical principles at the nanoscale level allow the biological receptors to be highly sensitive [101].Nanobiosensors can be tailored by using different types of nanomaterials and structures [102].
Depending on their interactions, nanobiosensors can be classified into two different groups called biocatalytic or biophilic.These two groups can be classified according to recognition factors, for example, cells, organelles, tissues, enzymes, receptors, antibodies, nucleic acids, MIPs, PNAs, or aptamers.
Nanostructures are capable of obtaining information through molecular interactions in real time, and in normal and pathological biological states which provides an effective and relatively fast result.For example, in a drop of blood, an enzyme such as glucose oxidase, glucose dehydrogenase, or hexokinase can cause a reaction, which can be measure by a low-dimensional detector in a glucometer (biosensor) [103].
Because the manufacturing of biosensors has several drawbacks, efforts have been made to develop improvements in manufacturing [104][105][106][107][108]. Characteristics like adhesion ability, strong adsorption capacity, chemical catalytic efficiency, and corrosion and oxidation resistance facilitate the fabrication [109], chemical stability, and electron transfer kinetics [110].The challenges for optimizing highly selectivity binding properties are continuously being overcome to analyze nanoscale elements of biomolecules [111].
High crystallinity with insignificant structural defects can be relevant to detecting different samples such as glucose, proteins, and nucleic acids [112].The other main advantages of nanohybrid materials are the specific binding sites that generate a selective sensor signal, which also improves its magnitude and composition.The high surface-tovolume ratio of nanofibers can also improve the capture efficiency and it provides some surface area-related phenomena, including ion exchange and catalysis [113,114].
Heterounions in hierarchical nanomaterials can promote the selective formation of specialized structures and sensitive responses not found in other sensors [115][116][117][118]. Nanomaterials produced through molecular printing can create selectivity for specific enzymes.This method can be worked with 3D nanostructures and it is used to manufacture versatile materials for the construction of sensors to detect various analytes [119].It has been demonstrated that these nanostructures can eliminate pathogens and better detect enzymes compared to other nanomaterials [120].
The existing improvements found when assembling nanostructures are versatile, and they open new methods for different technologies to control their structure and combine physicochemical properties [121][122][123][124][125][126][127][128][129][130][131].On the other hand, some nanostructured systems based on organic polymers have been proposed [132], and applications for spectrochemical biosensing have been demonstrated.Biosensors based on RNA hybridization can be considered for several biological reactions and for generating analytical signals that are easily detected by different electrochemical aptasensors [133], electrochemical luminescence sensors [134], and optical transducers, among others [135].It has been pointed out that RT-PCR [136] can be used to amplify cDNA from virus RNA [137].This is of great interest in the studies that have to do with inhibitors that target the enzyme helicase since it is known to participate in the processes of duplication and cell reproduction [138].
Photonic nanobiosensors have been also highlighted with respect to their potential use against SARS-CoV-2.In addition to monoclonal antibody pairs, which are rapid antigen tests [139], it is important to look for more efficient ways to detect pathogens [140].In this direction, biosensors using some promising plasmonic nanoparticles are the most powerful tools employed for the detection of viruses [141].Moreover, polystyrene nanoparticles, graphene, and carbon nanotubes [142] present different advantages such as selectivity towards particular molecular expressions corresponding to an important challenge that requires high specificity, sensitivity, and a multiplex detection capability to offer good virus detection.The design of POC testing arrangements [143], such as LFIAs, should be mentioned as they offer fast and easy-to-use methods, as well as reliability.Each synthesis procedure can be functional, but inherent limitations in the quantitative analysis of the virus in the application of biosensors should be noted [144].
In summary, hierarchical nanostructures are formed by hybrid nanoparticles, which are good candidates for the development of nanobiosensors for pathogen detection.These nanoparticles are prepared through different synthesis methods, as it is illustrated in Figure 2.
Hierarchical and hybrid nanostructures allow for the improvement of biosensing performance by increasing the signal intensity and enhancing a variety of energy transfer processes.Hierarchical nanostructures have larger reaction interfaces in the specific active surface area, allowing for better biomolecular recognition, catalyst charge transfer, metal ion release, and virus or bacteria capture within the nanomaterials.Sensors developed with these nanomaterials have high sensitivity, as shown in Table 1.
Biosensors 2024, 14, 108 6 of 36 should be mentioned as they offer fast and easy-to-use methods, as well as reliability.
Each synthesis procedure can be functional, but inherent limitations in the quantitative analysis of the virus in the application of biosensors should be noted [144].In summary, hierarchical nanostructures are formed by hybrid nanoparticles, which are good candidates for the development of nanobiosensors for pathogen detection.These nanoparticles are prepared through different synthesis methods, as it is illustrated in Figure 2. Hierarchical and hybrid nanostructures allow for the improvement of biosensing performance by increasing the signal intensity and enhancing a variety of energy transfer processes.Hierarchical nanostructures have larger reaction interfaces in the specific active surface area, allowing for better biomolecular recognition, catalyst charge transfer, metal ion release, and virus or bacteria capture within the nanomaterials.Sensors developed with these nanomaterials have high sensitivity, as shown in Table 1.
Table 1.Advantages and disadvantages of hybrid nanomaterials, as well as their LOD for SARS-CoV-2 biosensing, focusing on the synthesis method employed for the preparation of the nanostructures.Table 1.Advantages and disadvantages of hybrid nanomaterials, as well as their LOD for SARS-CoV-2 biosensing, focusing on the synthesis method employed for the preparation of the nanostructures.

Rough electrodes were found to have high electroactive areas that improve sensitivity and increase the number of active sites capable of recognizing target molecules
The sensing layer has an overall negative charge.This makes it difficult for electrons to pass between the transducer and the electroactive species [145] DNA tetrahedron with Au-gC 3 N 4 and PEI-Ru@Ti 3 C 2 @AuNPs

Hierarchical Nanostructures for SARS-CoV-2 Biosensing
In particular, biosensors made from nanostructures have a good response speed, good mechanical and chemical stability, a simple manufacturing process, low cost, as well as selection of samples in situ [162].In order to develop nanobiosensors for detecting an infection, hierarchical nanostructures can be employed to assist in the synergistic enhancement of molecular enrichment [163].An example is polydimethylsiloxane (PDMS), a transparent and flexible substrate that can be wrapped on arbitrary surfaces and allows light to penetrate the contact surface for optical diagnosis in situ [164].Optical and plasmonic biosensors have been investigated with different nanostructures to combat diverse types of viruses, such as those that imitate different viruses called "virus traps" and elongated nanoparticles [165][166][167].Biosensors based on electrochemical detection have been developed for identifying different types of viruses such as nanobioconjugated nanostructures.Virus coat protein self-assemblies with nanostructures can be very symmetrical [168]; a good example is the gold-functionalized nanostructures with human ACE2 that have a detection limit below approximately 80 mL −1 copies.Another example is the nanostructured biosensing process in contaminated water, in which, the contaminant can be detected in a few minutes.Hierarchical assemblies are very promising in combating not only the SARS-CoV-2 virus, but also different pathogens.The evolution of the self-assembly pattern of the nanocomposite can alter their plasmonic response and can be used for molecular diagnoses [169].Table 2 compares the advantages and disadvantages of representative characteristics exhibited by hierarchical nanobiosensors.Hierarchical nanomaterials in detection platforms can be tailored for the construction of functional electrode nanomaterials [186].The aim of hierarchy in biosensing is to form nanomaterials that are biomolecular self-assemblies for the enhancement of sensing [187].Some hierarchical structures are inspired by nature since these nanostructures are functional [188] and because they contain properties that make them unique.As it can be seen in Table 2, hierarchical nanostructures are attractive for applications in the detection of pathogens.For example, biosensors using hierarchical metal nanoparticles that are monitored with SERS techniques are capable of accurately measuring and capturing un-known coronaviruses, as long as they contain the S protein and can combine with the ACE2 protein [189].There is efficiency in the transfer of resonance energy between nanomaterials made with noble metals.These nanomaterials exhibit enhanced electrochemical conductivity when combined with hierarchical materials such as graphene, resulting in pronounced absorption peaks in the hybrid materials.For example, their narrow pore size distribution results in faster direct electron transfer and better enzyme detection [190].Based on this, enzymatic biosensor platforms have been created, as well as highly conductive supports and nanofillers, which demonstrated the effectiveness of hierarchical nanostructures [191].This approach results in a linear and continuous reaction that increases the uptake of RNA from the viral material.The hierarchical nanostructures of certain hybrid nanomaterials enhance their synergistic effects [192], generate hydrophobicity and colloidal stability, and can be reprogrammed to detect any protein antigen if the corresponding specific monobody exists.They can increase colorimetric fluorescence signals [193], ensuring high sensitivity and stability for detection applications.Different nanomaterials can be used to detect metals and compounds such as copper [194], nickel oxide [195], etc.The modified assemblies are good candidates for chemical adsorption, and can produce good magnetization that generates a magnetic signal to detect pathogens such as SARS-CoV-2.The hierarchical nanostructures produce molecular enrichment through the capillary effect, resulting in good biocompatibility, stability, optical effects, and promising electrical properties.
The characteristics of hierarchical nanostructures can be observed through different techniques, as illustrated in Figure 3.

Heterostructures with Different Morphologies for Biosensing
A fundamental element of nanoscience and nanotechnology are structure and morphology [196].This is because nanostructured materials can be agonists due to their different shapes and the properties they acquire depending on their orientation.In this section, different types of nanostructures and nanomaterials are analyzed, such as nanowires, nanofibers, nanotubes, quantum dots, nanosheets, nanocomposites, and nanoparticles, and their different orientations, morphologies, and properties are discussed.Nanostructures come in a variety of shapes, sizes, structures, and origins.They can be spherical, conical, helical, cylindrical, tubular, flat, hollow, or irregular in shape.Their structures vary in size from 1 to 100 nm and are composed of elements such as carbon, metals, metal oxides, and organic or inorganic materials.
The development of biosensors using nanoparticles has become extremely im-

Heterostructures with Different Morphologies for Biosensing
A fundamental element of nanoscience and nanotechnology are structure and morphology [196].This is because nanostructured materials can be agonists due to their different shapes and the properties they acquire depending on their orientation.In this section, different types of nanostructures and nanomaterials are analyzed, such as nanowires, nanofibers, nanotubes, quantum dots, nanosheets, nanocomposites, and nanoparticles, and their different orientations, morphologies, and properties are discussed.Nanostructures come in a variety of shapes, sizes, structures, and origins.They can be spherical, conical, helical, cylindrical, tubular, flat, hollow, or irregular in shape.Their structures vary in size from 1 to 100 nm and are composed of elements such as carbon, metals, metal oxides, and organic or inorganic materials.
The development of biosensors using nanoparticles has become extremely important because nanostructured nanoparticles have properties that surpass other compounds such as a low detection limit, high sensitivity, biocompatibility, and a peculiar refractive index change.By being able to combine different materials to form heterostructures, it is possible to overcome the drawbacks of the individual materials and thus take advantage of their synergy [197].
The development of hierarchical nanostructures has become crucial for the tailoring of semiconductor-based nanostructures in the field of photoelectrochemical biosensing [198].The sensors with enhanced biosensing performance include electrochemical, surface plasma resonance, photonic, immunosensors, photoelectrochemical, nucleic acidbased and enzyme-based, electrochemiluminescent, protein-based, and aptamer biosensors.Their adaptability in terms of size, shape, and composition is relevant in controlling their physicochemical properties [199] and general behavior to adapt nanostructures to biological systems [200].Modifications of heterostructured effects such as the degree of exfoliation, crystallinity, phase, metallicity, sheet size, and decoration with metallic particles can be useful for biosensing [201].Moreover, the arrangement of semiconductor nanostructures in biomolecules can convert this adaptation into hybrid systems to improve detection [202].
There is a goal to fabricate biosensors at a low cost in the fight against highly infectious diseases [203].Different nanostructures have been proposed for designing multifunctional effects and nano-sculpted hybrids [204].
In this section, we will analyze the different types of heterostructures for biosensing, shown in Figure 4, which shows the particular morphologies of both hybrid materials and hierarchical structures.nanostructures in biomolecules can convert this adaptation into hybrid systems to improve detection [202].
There is a goal to fabricate biosensors at a low cost in the fight against highly infectious diseases [203].Different nanostructures have been proposed for designing multifunctional effects and nano-sculpted hybrids [204].
In this section, we will analyze the different types of heterostructures for biosensing, shown in Figure 4, which shows the particular morphologies of both hybrid materials and hierarchical structures.Multidirectional networks of nanoobjects like nanocrystals or nanoflowers can improve their functional characteristics, which are defined by the synergy of different elements.The synthesis of heterostructures can emerge from the sequential growth of different nanoparticles or by the sequential preparation of different self-assembled building blocks.Morphologies like core-shell, multiple-shell, forest, nanoflowers, nanograss, nanopyramids, janus, and branched-tree heterostructures are typical nanostructured architectures.Table 3 presents some advantages and disadvantages of different morpholo- Multidirectional networks of nanoobjects like nanocrystals or nanoflowers can improve their functional characteristics, which are defined by the synergy of different elements.The synthesis of heterostructures can emerge from the sequential growth of different nanoparticles or by the sequential preparation of different self-assembled building blocks.Morphologies like core-shell, multiple-shell, forest, nanoflowers, nanograss, nanopyramids, janus, and branched-tree heterostructures are typical nanostructured architectures.Table 3 presents some advantages and disadvantages of different morphologies of hierarchical nanostructured forms.The parameters related to the shape, size, distribution, and homogeneity of the building blocks are highlighted.

Discussion
The 2020 pandemic killed millions of people around the world, increasing the need to find more effective ways to combat the disease.This has served to curb deaths as new knowledge about the virus has been quickly found, opening new windows into the age of nanotechnology.During this pandemic, various applications have emerged to combat the risks caused by SARS-CoV-2.With the aim of developing various methods for the prevention, detection, treatment, and diagnosis of diseases, diverse solutions including vaccines, drugs, and biosensors have been engineered.One of these effective methods is the use of biosensors designed with hierarchical nanostructures that have unique properties to combat COVID-19, offering reliable, effective, and fast solutions [224].Currently, researchers are looking for ways to produce materials with a low cost, high production volume, efficient cultivation times, maximum durability, and profitability.Good candidates for meeting these objectives are hierarchical nanostructures, as they are selective and they reduce the time of detection of potentially infectious pathogens.The advantages of developing these hierarchical nanostructures are that they can develop double resonance effects or synergistic effects of the elements that are integrated into the system [225] and have a high potential for advanced photonic monitoring [226].A previous study mentioned several options for preparing hierarchical nanostructures, since each preparation has a specific purpose [227].
The preparation of these nanostructures is through different synthetic and analytical routes, which results in remarkable applications [228].The controlled synthesis of hierarchical nanostructures with stacked morphologies could serve as a basis for tuning effects and potentially controlling them using photonic signals [229].By designing complexes with multiple hierarchical levels [230], different nanomaterials can be developed.These complexes are envisioned with nanohybrid nanomaterials since their recent use in biosensors has facilitated the exploration of different techniques to produce them, including recycled materials [231].By joining nanoparticles, different properties can be obtained to obtain good biocompatibility and high covalent bio-bonds with specific proteins [232].
In addition to amplifying the detection signal, hierarchical nanostructures can be employed to label a specific sequence of a target during detection [233].Some of these nanomaterials feature combinable virus recognition targets such as bio-AuNP hybrid nanostructures with metal oxide and carbon nanotubes [234], which have been combined by pathogen DNA hybridization [235].These nanohybrids have improved oxidation catalytic activity, stronger signals, better colorimetry for virus detection [236], a wider linear range, a lower LOD, higher sensitivity, and a better response time [237].All these properties significantly contribute to new rapid and cost-effective methods and have provided smart nanomaterials with great advantages in biosensor fabrication [238].
An example of hybrid nanomaterials is carbon-based biosensors that provide a good effectiveness when the active detection point has a high surface-to-volume ratio, which increases the probability of adsorption to a specific molecule [239].Electrochemical biosensors mainly use porous carbonaceous materials, since the morphology of these biosensors, especially the pore volume and surface area, influences the electrochemical and catalytic activities.All of these properties are widely used for pathogen detection and surveillance.Biosensors with layered functionality have been developed for the detection of SARS-CoV-2.The methods used to improve performance are activation, doping, and dispersion of metal nanoparticles for the detection of various analytes, such as biomolecules, metal ions, contaminants, and food additives.
In addition to some analytical techniques to study the biosensing performance, optical interactions of hierarchical nanostructures can also be used to combat SARS-CoV-2 and other viruses, resulting in higher sensitivity [240].This can be seen when nanostructures are used in the development of nanotechnological therapies, such as the development of antiviral drugs and nanoarchitecture-based vaccines assisted by biosensing [241].An example of nanoparticles that contain these properties are those whose surfaces are coated with ionic nanoparticles.Metallic nanoparticles are used, which act as antiviral agents against RNA viruses because most recurrent respiratory diseases are RNA viruses that take advantage of the link between the virus and the host cell to enter the host cell [242].From this, various functionalization and rapid viral immunodiagnosis strategies can be used [243].
The development of several hierarchical microchips with good results has been demonstrated; these microchips have a high sensitivity due to a primed surface for covalent immobilization of primary antibodies and ensuring strong binding between substrates [244].
Currently, the pharmaceutical profile of antiviral drugs has been improved and nanomaterials have been improved in terms of their virucidal properties and effectiveness against viral infections [245].Figure 5 presents these different types of hierarchical nanostructures and how they are used for the development of nanobiosensors.

Conclusions
The development of hierarchical nanostructures is remarkable in the fight against SARS-CoV-2.In this paper, we reviewed different considerations for the development of hybrid nanostructures and their applications in biosensing.Nanomaterials with specific properties, such as noble metals, have become very useful for the development of vaccines and biomarkers thanks to their unique LSPR phenomena.In our analysis, we highlighted the advantages and disadvantages of the synergistic effects of the different elements integrated into nanoscale biosensors.The plasmonic properties exhibited by metallic nanoparticles together with the electronic or optoelectronic functions of carbonbased low-dimensional systems are good candidates for the advancement of biosensing technology.The use of hybrid nanomaterials for the development of biosensors for virus detection have resulted in great advantages, such as adaptability.In view of all these considerations we highlighted for hierarchical biosensing, we could obtain better results to combat the effects of some diseases using hierarchical biosensing, as was the case for COVID-19.

Figure 1 .
Figure 1.Representative characteristics exhibited by different nanostructures in biosensing applications.

Figure 1 .
Figure 1.Representative characteristics exhibited by different nanostructures in biosensing applications.

Figure 2 .
Figure 2. Representative processing routes for the synthesis of hierarchical nanostructures used in the development of biosensors.

Figure 2 .
Figure 2. Representative processing routes for the synthesis of hierarchical nanostructures used in the development of biosensors.

Figure 4 .
Figure 4. Representative characteristics exhibited by different types of nanostructures.

Figure 4 .
Figure 4. Representative characteristics exhibited by different types of nanostructures.

Figure 5 .
Figure 5. Different types of hierarchical structures for the development of biosensors.

Table 2 .
Advantages and disadvantages of hierarchical nanostructures, as well as their LOD for the detection of SARS-CoV-2, focusing on the biosensing method.

Table 3 .
Advantages and disadvantages of the hierarchical heterostructures for biosensing, as well as their LOD for the detection of SARS-CoV-2, focusing on the morphology of the building blocks of the nanostructures.