magnetochemistry Review Optical-Based (Bio) Sensing Systems Using Magnetic Nanoparticles Recep Üzek 1 , Esma Sari 2 and Arben Merkoçi 3,4, * 1 Department of Chemistry, Faculty of Science, Hacettepe University, Ankara 06800, Turkey; ruzek@hacettepe.edu.tr 2 Vocational School of Health Services, Medical Laboratory Techniques, Yüksek İhtisas University, Ankara 06800, Turkey; esma.sari@hotmail.com 3 Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIS, Bellaterra, 08193 Barcelona, Spain 4 Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain * Correspondence: arben.merkoci@icn2.cat; Tel.: +34-937374604  Received: 23 September 2019; Accepted: 22 October 2019; Published: 25 October 2019  Abstract: In recent years, various reports related to sensing application research have suggested that combining the synergistic impacts of optical, electrical or magnetic properties in a single technique can lead to a new multitasking platform. Owing to their unique features of the magnetic moment, biocompatibility, ease of surface modification, chemical stability, high surface area, high mass transference, magnetic nanoparticles have found a wide range of applications in various fields, especially in sensing systems. The present review is comprehensive information about magnetic nanoparticles utilized in the optical sensing platform, broadly categorized into four types: surface plasmon resonance (SPR), surface-enhanced Raman spectroscopy (SERS), fluorescence spectroscopy and near-infrared spectroscopy and imaging (NIRS) that are commonly used in various (bio) analytical applications. The review also includes some conclusions on the state of the art in this field and future aspects. Keywords: optical sensor; magnetic nanoparticle; imaging; surface plasmon resonance; surface-enhanced Raman spectroscopy; fluorescence spectroscopy; near infrared spectroscopy 1. Introduction In recent years, great interest has been shown in the field of nanotechnology in general and particularly its applications in the manufacturing of novel materials with added magnetic, electrical, optical, and biological properties for various areas. Among these nanomaterials with added properties, magnetic nanoparticles (MNPs) are quite interesting given their unique physico-chemical structure. The plethora of applications has been described for MNPs that are directly associated with modulation of the chemical structure, size distribution, and magnetic moment [1,2]. In addition, MNPs were found to possess a number of intrinsic properties such as biocompatibility, low toxicity, ease of surface modification, chemical stability, high surface area, high mass transference besides others [3]. Although all kind of MNPs, like other nanoparticles, can be used in different ways, size, and surface have a severe impact on the application area. For example, MNPs over 28 nm are ferrimagnetic and commonly used for magnetic separation and for electronic instruments as ferrofluids. MNPs below 28 nm, on the other side, are super-paramagnetic and are generally preferred for biomedical applications [4]. MNPs are generally divided, regarding their chemical structure, into metal oxides, pure metals, and magnetic nanocomposites. This distinct class of MNPs and application areas are depicted in Magnetochemistry 2019, 5, 59; doi:10.3390/magnetochemistry5040059 www.mdpi.com/journal/magnetochemistry Magnetochemistry 2019, 5, x FOR PEER REVIEW 2 of 26 Magnetochemistry 2019, 5, 59 2 of 25 MNPs are generally divided, regarding their chemical structure, into metal oxides, pure metals, and magnetic nanocomposites. This distinct class of MNPs and application areas are depicted in Figure 1. Metal oxides are most commonly used for biomedical applications, such as cell labeling Figure 1. Metal oxides are most commonly used for biomedical applications, such as cell labeling and imaging [5–8], diagnostic and therapeutic agents [9]. Among metal oxides, iron oxides are and imaging [5–8], diagnostic and therapeutic agents [9]. Among metal oxides, iron oxides are commonly used since they have better biocompatibility [10]. In contrast to metal oxides, pure metals commonly used since they have better biocompatibility [10]. In contrast to metal oxides, pure metals as a class of MNPs have limited application areas due to their chemical instability [11] and large as a class of MNPs have limited application areas due to their chemical instability [11] and large size size distributions [12]. Although rarely reported, the use of pure metal nanoparticles is generally distributions [12]. Although rarely reported, the use of pure metal nanoparticles is generally found found in electronic devices such as ultra-high-density magnetic storage devices [13–15]. In other in electronic devices such as ultra-high-density magnetic storage devices [13–15]. In other respects, respects, the use of magnetic nanocomposites, particularly in a sensor, biosensor and detection systems, the use of magnetic nanocomposites, particularly in a sensor, biosensor and detection systems, has has become increasingly common in recent years [16–19]. Disadvantages of MNPs, such as their become increasingly common in recent years [16–19]. Disadvantages of MNPs, such as their tendency to aggregate to reduce surface energies, and oxidation in air, are among the major obstacles tendency to aggregate to reduce surface energies, and oxidation in air, are among the major obstacles to the spread of their more frequent use in the applications [20]. Therefore, from the application point to the spread of their more frequent use in the applications [20]. Therefore, from the application of view,ofresearchers point have proposed view, researchers a new approach have proposed to the development a new approach of newof to the development materials by coating new materials by polymer, silica or other materials over MNPs, so-called magnetic nanocomposites [21–23]. coating polymer, silica or other materials over MNPs, so-called magnetic nanocomposites [21–23]. Figure1.1.The Figure Themain main applications applications of optical-based (bio) (bio) sensing sensing systems systemsusing usingmagnetic magneticnanoparticles nanoparticles (MNPs)in (MNPs) inbiomedical biomedicaland and environmental environmental fields. fields. Inpractice, In practice, the the feasible feasible features of MNPs MNPs are are not not only only affected affected by by their theirstructure structurebutbutalso alsoby by their fabrication their fabrication techniques techniques andandsurrounding surroundingenvironments environments [4,24,25]. MNPs [4,24,25]. MNPs can can be prepared in thein be prepared following the following three routes three to suit routes the final to suit desired the final application. desired The majority application. of theseofmethods The majority are based these methods are on the based onchemical methods the chemical or “bottom-up” methods or “bottom-up” synthesis synthesisprocedures, procedures, which which include includeco-precipitation, co-precipitation, high-temperaturethermal high-temperature thermal decomposition decomposition and/or and/or reduction, reduction, sol-gel sol-gel synthesis, synthesis, flow-injection flow-injection synthesis, synthesis,method, oxidation oxidation method, electrochemical electrochemical method, aerosol/vapor-phase method, aerosol/vapor-phase method, fluid method, supercritical supercritical method, fluid method, and synthesis using nanoreactors [5,25]. Chemical synthesis is controllable and synthesis using nanoreactors [5,25]. Chemical synthesis is controllable for almost all the processing for almost conditions, and indeed, there has been a report indicating that this may be one reason forone all the processing conditions, and indeed, there has been a report indicating that this may be the reason for the “popularity” of“popularity” of chemical chemical techniques fortechniques for synthesis synthesis [26]. [26]. Alternatively, Alternatively, MNPs can be MNPs can be formed via formed via physical methods through a simple non-chemical “top-down” dispersion physical methods through a simple non-chemical “top-down” dispersion technique, e.g., gas-phase technique, e.g., gas-phase deposition deposition and electron-beam and electron-beam lithographylithography [5,25,27].[5,25,27]. Traditionally, Traditionally, physical physical methods methods havehave been been the lessthe less preferred preferred synthesis synthesis techniques techniques for MNPs for MNPs given an given an inability inability to control to control the size the size of of particles particles down down to the to the nanometer nanometer scalethese scale using usingmethods these methods [27].the [27]. On Onother the other hand, hand, bio-reduction bio-reduction in in the the so-called microorganism approach, which has allowed large quantities so-called microorganism approach, which has allowed large quantities of production, ensures the of production, ensures the high high yield,yield, good reproducibility, good reproducibility, and stability, and stability, as well as aslow wellcostas[5,27]. low cost [5,27]. In optical-based In optical-based (bio)sensing (bio)sensing systems, multifunctional composites such as Fe 3O4@Ag, Fe3O4@Au, etc., are mainly systems, multifunctional composites such as Fe O @Ag, Fe O @Au, etc., are mainly prepared by 3 4 3 4 Magnetochemistry 2019, 5, 59 3 of 25 two methods: core-shell structure (1) and immobilization on the core (2) [28,29]. In both methods, magnetic nanoparticles are first coated with silica shells to increase the stability of the magnetic nanoparticles and to facilitate their modification. In the first of these directions, Ag or Au is reduced by using chemical compounds such as NaBH4 , citric acid, etc. on the surface of the magnetic core. In the second method, gold or silver nanoparticles are prepared in different forms such as spherical, cubes or nanorods and then immobilized to the surface of the magnetic core by physical or chemical methods. In physical immobilization, it is usually carried out by modification of the magnetic core with polymers such as oleic acid, etc., and then bonded to the magnetic surface by the secondary interactions. In chemical immobilization, the surface of magnetic and Au or Ag nanoparticles are first modified with functional groups such as carboxyl or amine, and then the chemical immobilization is performed by modification method such as 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide (EDC/NHS) coupling, etc. After synthesis of MNPs, the common analytical techniques used for the characterization of MNPs are: ultraviolet (UV)–visible spectrophotometry, dynamic light scattering (DLS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), powder X-ray diffraction (XRD), X-ray fluorescence (XRF) and energy-dispersive spectroscopy (EDS) [30,31]. There is no doubt that the extensive literature that can be associated with the term of biosensor shows that the related field of research is very attractive. In the first approach, a biosensor can be simply defined as a device that intimately combines a biological sensing element with a transducer [32]. In an efficient biosensor design, it is essential to convert the biological interaction to a signal which is transduced by physical, chemical, optical, thermal or electrochemical actions, into observable information and analyzed quantitatively [33]. Even though electrical and electrochemical platforms are the most advanced and used biosensor platforms, these systems have drawbacks owing to the extra reduction/oxidizing agent being involved [34]. While the biosensor can be built in a comparable manner based on optical and electrochemical transducers, it obviously demonstrates distinct working features [32]. Optical biosensors play a prominent role in sensing applications because they have distinct advantages: for example, high-precision detection and label-free design [34]. Optical biosensors also offer the possibility of immune electromagnetic interference, capable of remote sensing, and can perform multiplex detection within a single device [35]. The next generation of sensing equipment for daily use is optical biosensor platforms, based on absorbance, photoluminescence and surface plasmon resonance (SPR) [34]. In addition, coupling the synergistic effects of the optical properties and magnetic properties in a single method may offer new multitasking platforms for (bio)sensing, biolabeling/imaging, cell sorting/separation, and photothermal therapy [36]. In this comprehensive review, we will discuss optical biosensing systems based on the use of MNPs. Under this category, there exist a number of optical-sensing methods by using MNPs, including SPR, surface-enhanced Raman spectroscopy (SERS), fluorescence spectroscopy and near-infrared spectroscopy and imaging (NIRS). 2. Surface Plasmon Resonance (SPR) Surface plasmon resonance (SPR) is a complex physical phenomenon occurring on an electrically conductive noble metal layer at the interface between two media (i.e. high refractive indices of sensor’s glass surface and low refractive indices of buffer) when p-polarized light under conditions of total internal reflection [37,38]. Interest in the SPR effect started with an explanation as the energy of photons absorbed by the free electrons of the metallic layer reduced the amplitude of the incident light that comes with a certain angle. Despite the SPR effect being successfully explained in 1968, SPR as a method of determination in the field of biosensor was first mentioned in 1983 by Wijaya et al. Although fluorescence or absorbance based optical methods have been used since earlier times, SPR as surface-based optical method has been developed very rapidly and has attracted considerable interest in biosensing platform [38]. Investigation of biomolecular interactions with SPR is considered Magnetochemistry 2019, 5, 59 4 of 25 Magnetochemistry 2019, 5, x FOR PEER REVIEW 4 of 26 an exceedingly powerful analysis method due to SPR’s remarkable properties as an analytical tool such as its label-free properties as annature, real-time, analytical highly tool such precise, as its a short label-free time and nature, simplicity. real-time, Despite highly thea usefulness precise, short time of andSPR, the conventional simplicity. Despite the SPR methodsof usefulness areSPR, mainly hampered bySPR the conventional the detection methods areof low concentration, mainly hampered low molecular weight biomolecules due to trivial changes of the refractive by the detection of low concentration, low molecular weight biomolecules due to trivial changes index in the bindingof process. Several approaches to overcome this challenge have been offered by researchers the refractive index in the binding process. Several approaches to overcome this challenge have been based on the use of offered bynanoparticles [39,40]. researchers based on Until now, the use decorating SPR of nanoparticles surfaces [39,40]. with Until MNPs now, seems toSPR decorating be the most surfaces widely attested. Especially the application of MNPs in SPR sensing has attracted with MNPs seems to be the most widely attested. Especially the application of MNPs in SPR sensing great focus owing to hasadvantages which attracted great are owing focus (1) capture of the target to advantages molecules which from the are (1) capture of complex the targetsample and from molecules (2) high the refractive index and high molecular weight of MNPs to recruit the SPR signal complex sample and (2) high refractive index and high molecular weight of MNPs to recruit the SPR [41,42]. Due to the aforementioned signal [41,42]. Due desired to theproperties of MNPs, aforementioned these desired compounds properties are widely of MNPs, theseused for environmental compounds are widely monitoring, biomedical applications, used for environmental monitoring, food analysis, etc. biomedical [43–46]. Thefood applications, principle of theetc. analysis, SPR[43–46]. system with The MNPs was illustrated in Figure 2 [47]. principle of the SPR system with MNPs was illustrated in Figure 2 [47]. 2. Amplification Figure 2. Amplification of of the the surface surface plasmon plasmon resonance resonance (SPR) (SPR) response response signal signal with MNPs [47] with MNPs [47].. Reproduced with Reproduced with permission permission of of the the Royal Royal Society Society of of Chemistry. Chemistry. In 2018, Sun Sunand andco-workers co-workersreported reportedthe the SPRSPR biosensor biosensor based based on hollow on hollow goldgold nanospheres nanospheres and and improved improved sandwich sandwich assay assay withwith magnetic magnetic nanoparticles nanoparticles to to detectrabbit detect rabbitIgG. IgG.While While the the reduced graphene layer (rGO) (rGO) was was covered covered with with AgAgnanoparticles nanoparticlesto toobtain obtainSPRSPRsurface, surface,Fe Fe3 O 3O44 MNPs were utilized utilized toto capture capturethe theanalyte analyteofofinterest interesteasily from easily fromthethe medium. medium. In In order to bind order the the to bind antibody antibodyto the to surface the surfacewithout withoutmodification modification and and avoid agglomeration avoid agglomerationof nanoparticles, of nanoparticles,polydopamine polydopamine (PDA) was (PDA) used. was used.These researchers These researchersshowed thatthat showed the detection the detectionof rabbit IgGIgG of rabbit by gold by goldnanostructures nanostructures resulted in resulted the 132 times lower concentration when compared with a conventional in the 132 times lower concentration when compared with a conventional SPR biosensor. The SPR biosensor. The changes in the SPR changes in signal the SPR caused signalbycaused the magneto-sandwich by the magneto-sandwichimmunoassay were further immunoassay werecompared with the further compared signal with the of hollow signal gold nanospheres. of hollow Their investigation gold nanospheres. showed that the Their investigation 8 timesthat showed higher the enhancement 8 times higher in the SPR signalinwas enhancement therelated to the SPR signal magneto-sandwich was immunoassay [48]. related to the magneto-sandwich In another [48]. immunoassay study, Inaptamer another immobilized study, aptamer SPR-based immobilized biosensors were developed SPR-based biosensorsby utilizing were core-shell developed AuNPs and by utilizing MNPs (MNPs) core-shell AuNPs as the plasmonic coupling partners for the detection of thrombin and MNPs (MNPs) as the plasmonic coupling partners for the detection of thrombin as a modelas a model analyte. Aptamer immobilized analyte. Aptamer AuNPs-MNPs conjugate-based immobilized AuNPs-MNPs SPR biosensors exhibitedSPR conjugate-based a considerable biosensorsresponse exhibited to thea thrombin considerable with the limits response of detection to the thrombin(LOD) with theof limits 0.6 nM. ofAs compared detection (LOD) to the SPR of 0.6 nM.signal shift withto As compared a control group that is based on SPR signal without AuNPs-MNPs conjugate, the SPR signal shift with a control group that is based on SPR signal without AuNPs-MNPs AuNPs-MNPs conjugate based SPR angle conjugate, shift wasconjugate AuNPs-MNPs enlarged for 5 times based SPR at the 100 angle shiftnMwas concentration enlarged for[49]. A summary 5 times at the 100 of nM the different concentrationapplications [49]. Aofsummary the MNPsofbythe combining differentthe synergistic of applications effects the of the SPR MNPs by is summarized combining the in Table 1. effects of the SPR is summarized in Table 1. synergistic Table 1. Examples of the application of MNPs in SPR system. Magnetic Part SPR System Applications Advantages [R] Active layer consisting Silver-coated Target analyte of Fe3O4 + Polyethylene prism-coupled SPR Plant DNA could not be [50] glycol (PEG4000) System detected without Magnetochemistry 2019, 5, 59 5 of 25 Table 1. Examples of the application of MNPs in SPR system. Magnetic Part SPR System Applications Advantages [R] Active layer consisting of Fe3 O4 + Target analyte could not be detected without using a Silver-coated prism-coupled SPR System Plant DNA [50] Polyethylene glycol (PEG4000) magnetic part. Gold film of SPR chip was Polydopamine-Ag capped Fe3 O4 NPs Detection limit 132 times lower than conventional SPR electromagnetically coupled with hollow Rabbit IgG [48] reduced with graphene oxide and 8 times lower than immunosandwich assay. gold nanoparticles Gold capped Fe3 O4 SPR angle shift is enlarged for 5 times comparing with Conventional SPR system with gold chip Thrombin [49] nanoparticles (GMNPs) that of control group without GMNPs MNPs offer a sensing enhancement of 4 MNPs conjugated with antibody Conventional SPR system with gold chip Pathogenic Bacteria [51] orders of magnitude. Magneto plasmonic nanoparticles Antigen (Tuberculosis Implementation of magneto-plasmonic NPs outcomes in Conventional SPR system [52] (core shell gold capped MNPs) marker protein) 30-fold extension of the SPR signal at the limit of detection. Nanohybrids containing Fe3 O4 NPs SPR chip coated with carboxyl Detection limit is approximately 260-fold lower than that Human IgG [53] and hollow gold sphere nanoparticles. functionalized graphene oxide sheet. acquired with sandwich assay by routine SPR biosensors. Capture antibody-immobilized Minimum detectable SPR response for the concentration Polydopamine-wrapped magnetic Protein (Human cardiac SPR-sensing film modified by hollow of target molecule is 1000 times lower than that achieved [54] multi-walled carbon nanotubes troponin I, CTnI) gold nanoparticles and polydopamine by the traditional SPR immunoassay. Magnetic fluid photonic crystal Kretschmann configuration (prism The excellent benefit of elevated sensitivity is with the (i.e. kind of colloid compassed of MNPs ————– [55] coupling) SPR system. combination of magnetic fluid photonic crystal and SPR. dispersed in carrier liquid) Aptamer-immobilized Fe3 O4 Kretschmann configuration (prism Protein (prion disease associated The SPR scheme involves magnetic NPs-organic clusters [46] nanoparticles with organic clusters coupling) SPR system. isoform, PrPSC ) that allow for a 215-fold rise in the immediate SPR signal. Grating-coupled SPR (GC-SPR) with Target could not be detected with the direct SPR detection Streptavidin-coated MNPs Lipid (Extracellular vesicles, EVs) [56] wavelength interrogation. platform at such low concentrations. The detection sensitivity of PrPSC has been improved by Protein (prion disease associated Fe-C core shell–aptamer conjugation Prism-coupling SPR system about 10 times relative to the direct format of [57] isoform, PrPSC ) SPR detection. Antibody-immobilized SPR The MNPs showed outstanding ability to amplify Antibody-functionalized MNPs Hormone (Estradiol) [45] immunoassay the SPR signal. SPR set up device in Kretschmann Microalgae population has been successfully monitored PEG-4000 functionalized Fe3 O4 MNPs Microalgae [58] configuration and He/Ne laser beam. with the proposed system. To differentiate ovarian cancer, this multiplexed scheme MNPs antibody conjugates Conventional SPR spectroscopy Cancer Biomarkers accomplished sensitivity and specificity of up to 94% and [59] 98%, respectively. Magnetochemistry 2019, 5, 59 6 of 25 3. Surface-Enhanced Raman Spectroscopy (SERS) Surface-enhanced Raman scattering (SERS) based on the enhancement of molecular Raman scattering by surface plasmons after the interaction between light and nanostructures is a surface-sensitive technique that is used for the detection of target with high molecular sensitivity and specificity at ultra-trace concentrations, including single molecules and provides more details on the chemical structure and conformation of target molecule [60]. The enhancement of the Raman signal is explained by two mechanisms: chemical enhancement arising from the charge transfer between the nanostructures and the adsorbed target and electromagnetic enhancement stemming from the electromagnetic field effect of the adsorbed target by stimulating the surface plasmons of nanostructures [61,62]. Since the enhancement of molecular Raman scattering mainly occurred by electromagnetic enhancement, novel nanostructures have been developed to achieve high enhancement factors by changing the plasmonic properties. The surface plasmons of nanostructures can be changed with the physical and chemical properties of nanostructures such as shape, size, type, and composition, etc. thus directly affecting the sensitivity and selectivity of SERS [63]. Because of their higher enhancement factors and the accessibility of plasmonic resonances in the visible and NIR areas, the plasmonic nanostructures (PNS) based on Au and Ag are most often preferred to produce SERS substrate [64]. Because of their higher enhancement factors and the accessibility of plasmonic resonances in the visible and NIR areas, the plasmonic nanostructures based on Au and Ag are most often preferred to produce SERS substrates. The SERS substrates have been successfully manufactured for the detection of targets such as biomolecules, cells, microorganisms, environmental pollutants, etc. Although SERS has many important advantages, there are still needs for improvement of the reproducibility and stability of SERS substrates and the analysis of biological fluids and real environmental samples. These improvements can be achieved using MNPs or magnetic nanocomposites because of their unique properties such as strong superparamagnetic property, low toxicity, biocompatibility, easy preparation, and high adsorption ability. As outlined in Table 2, MNPs in SERS analysis have been used for the detection of proteins [65–68], cells [69–71], toxins [72], drugs [73,74], microorganisms [75–78], illegal additives [79,80], antigens [81,82], pesticides [83], and genes [84,85]. Magnetochemistry 2019, 5, 59 7 of 25 Table 2. Selected examples of surface-enhanced Raman spectroscopy (SERS) sensors based on MNPs. Type of PNS Size of PNS, nm Forms of MNPs Size of MNPs, nm Reporter 1 Analyte Detection limit [R] γ-Fe2 O3 covered with silica shell and Au NPs 15 64 DTNB Tau protein 25 fM [65] polymer shell γ-Fe2 O3 MNPs covered with silica and Au NPs 20 160 DTNB Telomerase activity 1 cell/mL [67] Au shell Triangular Ag 40 γ-Fe2 O3 MNPs MNPs 21 MBA Tumor cells 1 cell/mL [69] nanoprisms Au NPs 20 γ-Fe2 O3 covered with silica shell 25 MBA Microcystin-LR 2.0pg/mL. [72] Fe3 O4 magnetic microspheres covered with Au NPs 20 500 Cyanine Sildenafil citrate 10 nM [74] SiO2 shell and Au nanoparticles Au NPs 31 γ-Fe2 O3 encapsulated with polymer 330 MBA and DSNB S. typhimurium 10 cells/mL [77] Au NPs 30 γ-Fe2 O3 MNPs 500 DP Chloramphenicol 1.0 pg/mL [79] Ag NPs 20 Fe3 O4 MNPs covered with GO and Ag NPs 500 - Chloramphenicol 0.1 nM [80] West Nile virus Antigen and Au NPs 60 ParaMNPs 200 IR-792 and NB 5 fg/mL [81] Rift Valley fever virus Antigen Au NPs 30 γ-Fe2 O3 MNPs 500 DP PSA antigen 5 pg/mL [82] Ag/SiO2 core-shell NPs 35 γ-Fe2 O3 MNPs covered with silica shell 50 Rhodamine B DNA 5 µM [84] Ag shell 30 γ-Fe2 O3 MNPs covered with Ag shell 300 Cyanine miRNA 0.3 fM [85] Ag shell 8 γ-Fe2 O3 MNPs covered with Ag shell 300 PATP Thiram 1.0 nM [86] Au@Ag core-shell NPs 32 γ-Fe2 O3 MNPs covered with polymer shell 36 MBT Kanamycin 2 pg/mL [87] Ni@Au and Ni@Ag NPs 212 and 222 Ni MNPs 89 rhodamine 6G rhodamine 6G 1 mM [88] Au Shell 35 γ-Fe2 O3 MNPs covered with Au shell 50 - Microcystin-LR 3 fM [89] Au Shell 15 Fe3 O4 MNPs covered with Au shell 17-30 pthiocresol Pthiocresol 4.5 pM [90] Au nanocubes and 51 DNA modified Fe3 O4 magnetic beads 1000 Cyanine DNA 1pM [91] nanospheres Silver layers on MBA, DTNB, and 60 Protein G modified Fe3 O4 magnetic beads 1000 Cytokines 4.5 pg mL [92] reporter-coated AuNPs TFMBA 1 DTNB: 5,5-dithiobis(2-dinitrobenzoic acid); DP: 4,40 -dipyridyl; MBA: 4-Mercaptobenzoic acid; NB: Infrared-792(IR-792) and Nile blue; PATB: p-aminothiophenol. Magnetochemistry 2019, 5, 59 8 of 25 As mentioned above, gold (Au) nanostructures in the manufacture of SERS substrates are one of the most widely used metallic nanostructures for the plasmonic substrate. As an example, Zengin et al. [65] applied a sandwich assay for the ultrasensitive detection of tau protein by using monoclonal anti-tau immobilized hybrid MNPs as a probe and polyclonal anti-tau functionalized Au nanoparticles as SERS tags. Firstly, MNPs (γ-Fe2 O3 ) were coated with silica for easy modification and then the hybrid structure was coated with polymer shell by Reversible Addition–Fragmentation chain Transfer (RAFT) polymerization. After the modification of the polymer shell, the monoclonal anti-tau was immobilized on the surface of the hybrid MNPs to obtain the capture probe. Gold nanoparticles were synthesized by citrate reduction with a diameter of 15 ± 8 nm and then, the gold nanoparticles were first modified with a layer of Raman reporter, 5,5-dithiobis(2-dinitrobenzoic acid) (DTNB) to obtain the homogeneous sandwich assay. Finally, their surfaces were functionalized with polyclonal anti-tau to prepare SERS tags. In this study, the MNPs used in sandwich assay provided easy and rapid detection of the tau protein with a detection limit of 25 fM. As another example, Yang et al. [79] performed a similar approach for the detection of chloramphenicol (CAP) by using magnetic separation. For the preparation of SERS tags, gold nanoparticles were first modified with 4,40 -dipyridyl (DP) as SERS reporter and then functionalized with chloramphenicol-bovine serum albumin (BSA) conjugate. CAP antibody was immobilized on the surface of carboxyl-functionalized magnetic beads (average diameter 500 nm) by EDC/NHS coupling reaction for magnetically and selectively separation of CAP. The limit of detection was obtained as 1.0 pg/mL for CAP in aqueous solution and also this SERS immunosensor system based on MNPs was applied to detect CAP in real samples and CAP was detected in the CAP concentration range of 0–5x105 pg/mL. The selectivity experiment and real sample analysis indicate that this immunosensor is fast, sensitive and specific for the detection of CAP in the aqueous solution. As an example of toxin analysis, He et al. [72] developed an aptasensor based on SERS with MNPs for the detection of microcystin-LR (MC-LR) (Figure 3). After the synthesis of Au nanoparticles, its surface was modified with SERS reporter, MBA and then functionalized with MC-LR aptamer as SERS probe. MNPs were first covered with silica for easy immobilization of biomolecule and then the complementary DNA to MC-LR aptamer was immobilized on the surfaces of MNPs by biotin/avidin affinity as a capture probe. The developed aptasensor based on magnetic SERS was successfully applied to the selective and specific detection of MC-LR in tap water with the limit of detection, 2.0 pg/mL. As another approach, Yang et al. [81] developed an aptasensor based on magnetic SERS for the detection of prostate-specific antigen (PSA). PSA-aptamer was immobilized on the surface of the magnetic nanoparticle by EDC/NHS coupling reaction for the specific separation of PSA in the matrix. Au NPs were functionalized with DNA of PSA-complementary as a signal probe. The sandwich assay was applied for detection of PSA and LOD was obtained as 5.0 pg/mL and 25 pg/mL in aqueous solution and human serum, respectively. In another study for the detection of antigens, Neng et al. [82] performed the multiplex detection of antigens by using two sets of a spectrally distinct reporter for the preparation of the SERS probe. For the preparation of the SERS probe, the Raman reporter dyes Infrared-792 (IR-792) and Nile blue (NB) were bound separately on the surface of Au NPs and IR-792-coated Au NPs were modified with anti-E IgG and the NB-coated Au NPs were functionalized with anti-N IgG for specific recognition of each target antigen. For capture probe, paramagnetic nanoparticles were first coated with silica and then functionalized with anti-E and anti-N IgG. Briefly, the following procedure was applied for the assay: the antigens were first separated magnetically with the capture probe and then mixed with the antigen modified Au NPs. In the developed SERS sensor, LOD was around 5 fg/mL for both antigens. This study demonstrated the suitability of magnetic particles in SERS for the multiple detection of targets. In a study to examine the performance of SERS based on MNPs in the detection of microorganisms, polymeric MNPs were synthesized as a capture probe and Au NPs were modified with SERS reporter and specific antibody for the detection of S. typhimurium in the food product [77]. MBA (4-mercapto benzoic acid) and 5,5’-dithiobis(succinimidyl-2-nitrobenzoate) (DSNB) were used as SERS reporter. After the application of sandwich assay for the detection of microorganism, the limit of detection (LOD) of MBA and DSNB Magnetochemistry 2019, 5, 59 9 of 25 Magnetochemistry 2019, 5, x FOR PEER REVIEW 10 of 26 was obtained cells/mL, as 100 cells/mL, respectively, and 10food in a spiked cells/mL, respectively, product. in a spiked The enhanced food product. sensitivity of DSNB Theasenhanced a SERS reporter is due to its molecular characteristics that provide higher Raman scattering. In this Raman sensitivity of DSNB as a SERS reporter is due to its molecular characteristics that provide higher study, scattering. higher In this study,ishigher reproducibility reproducibility obtained as it providesis obtained as it provides better solubility better in water solubility by coating inmagnetic the water by coating cores thepolymer with magneticfilm. cores with polymer film. Illustration of Figure 3. Illustration of the the principle principle for for the the analysis analysis of of microcystin-LR microcystin-LR (MC-LR) (MC-LR) based based on the SERS-based aptasensor. Reprinted [72] [72] © © 2019, with permission from from Elsevier. Elsevier. In SERS In SERS substrate, substrate, the the other other widely widely usedused nanostructures nanostructures are are silver silver nanostructures nanostructures to to create create plasmonic surfaces. As an example, Liang et al. [84] developed plasmonic surfaces. As an example, Liang et al. [84] developed a DNA hybridization assay based a DNA hybridization assay on based on magnetic magnetic SERS forSERS DNA for sequences DNA sequences relatedrelated to HIV.to HIV.In In thisstrategy, this strategy, Ag/SiO Ag/SiO22 core-shell core-shell nanoparticle-modified with nanoparticle-modified with Raman Raman tags tags (Rhodamine (Rhodamine B) B) were were prepared prepared as as SERS SERS probe probe and and MNPs MNPs covered with silica shell were functionalized with oligonucleotides covered with silica shell were functionalized with oligonucleotides related HIV as capture probe.related HIV as capture probe. The hybridization reaction The hybridization reaction was wasperformed performedbetween betweenthese theseprobes. probes.After After thethe magnetical magnetical separation separation of of DNA related to HIV from 3 µM solution, the DNA was successfully DNA related to HIV from 3 µM solution, the DNA was successfully detected via the SERS probe. detected via the SERS probe.In In another another approach approach forfor thethe detection detection ofof genes,Pang genes, Pangetetal.al.[85] [85]developed developedaa SERS SERS sensor sensor basedbased on on functionalized Fe O @Ag magnetic nanoparticle for the detection of functionalized Fe3O4@Ag magnetic nanoparticle for the detection of microRNA (miRNA) in total 3 4 microRNA (miRNA) in total RNA extractextract RNA from cancerfromcells. In this cancer application, cells. In this unlike the others, application, unlikeMNPsthewere not only others, MNPs functionalized were not only with the capture agent functionalized butthe with alsocapture functionalized agent but with thefunctionalized also SERS signal reporter. with theThis SERSstudy has reporter. signal demonstrated This the advantage of MNPs which are used to concentrate, capture and study has demonstrated the advantage of MNPs which are used to concentrate, capture and purify purify the target gene with the detection limit of 0.3 fM by using a single hybrid nanostructure. the target gene with the detection limit of 0.3 fM by using a single hybrid nanostructure.Furthermore, a similar strategy has been applied to Furthermore, the detection a similar strategy ofhas microorganisms been applied [76]. to theIndetection another example, a seed-mediated of microorganisms [76]. In strategy another was example, a seed-mediated strategy was applied to obtain an Ag shell2 on the surfacethe applied to obtain an Ag shell on the surface of MNPs after the SiO coating to use detection of MNPs of after pesticide thiram to the SiO2 coating [86] useandthethe limit of of detection detection pesticide was achieved thiram as 1.0the [86] and nM for of limit thiram. detection was achieved The SERS as 1.0 nM for thiram. applications of plasmonic nanostructures in different shapes are becoming quite attractive because of increasing the enhancement factor of SERS. The SERS applications of plasmonic nanostructures in different shapes are becoming As an example, Ruan et al.quite [69] developedbecause attractive SERS sensor based on the of increasing triangular silver nanoprisms enhancement (AgNPR) factor of SERS. As an and superparamagnetic example, Ruan et al. iron [69] oxide nanoparticles with a function of capture, enrichment, detection, developed SERS sensor based on triangular silver nanoprisms (AgNPR) and superparamagnetic and release for the tumor cells analysis. iron oxideFirstly, AgNPR was nanoparticles withmodified a function with MBA andenrichment, of capture, functionalized with rBSA detection, and (i.e., reductive release for the bovine tumor serum albumin) and FA (i.e., folic acid) generating the SERS probe. Then, cells analysis. Firstly, AgNPR was modified with MBA and functionalized with rBSA (i.e., reductive MNPs were also modified with bovinerBSA andalbumin) serum FA generatingand FA the(i.e., capture folicprobe acid) to be used for generating thethe SERScapturing, probe. enriching Then, MNPs andweredetecting also modified with rBSA and FA generating the capture probe to be used for the capturing, enriching and detecting of cancer cells from blood samples. The LOD was obtained as 1 cell/mL and the results Magnetochemistry 2019, 5, 59 10 of 25 Magnetochemistry 2019, 5, x FOR PEER REVIEW 11 of 26 of cancer cells from blood samples. The LOD was obtained as 1 cell/mL and the results demonstrate that nanoprisms demonstrate thathave strongerhave nanoprisms electromagnetic enhancementenhancement stronger electromagnetic compared tocompared nanospheres due to their to nanospheres asymmetric due to their shape. In anothershape. asymmetric exampleInofanother the SERSexample applications of of theplasmonic nanostructures SERS applications of in different plasmonic shapes, the dual-mode nanoprobes based on SERS and fluorescence detection were nanostructures in different shapes, the dual-mode nanoprobes based on SERS and fluorescencedeveloped by using Raman reporter-tagged Au@Ag core–shell nanorods and quantum dots onto the detection were developed by using Raman reporter-tagged Au@Ag core–shell nanorods and silica nanospheres for IgG detection quantum dotsas mentioned onto the silicaFigure 4 [66]. Infor nanospheres this IgGstudy, LOD as detection was obtained as mentioned 0.1 pg/mL Figure 4 [66].byIn applying this study,a sandwich assay. LOD was obtained as 0.1 pg/mL by applying a sandwich assay. Figure 4. Figure 4. (a) (a) Synthesis Synthesis and and surface surface functionalization functionalization procedure procedure of of the the dual dual mode mode nanoprobe; nanoprobe; (b)(b) the the synthesis and surface modification procedure of the magnetic beads (MBs); (c) illustration synthesis and surface modification procedure of the magnetic beads (MBs); (c) illustration of the of the structure of the sandwich type nanocomplex formed during the immuno-reaction. For structure of the sandwich type nanocomplex formed during the immuno-reaction. For simplicity, only a simplicity, only ananoprobe, single single nanoprobe, antigen, antigen, and and MB MB particle particleinisthe is drawn drawn in (d) picture; thethe picture; (d)phase aqueous the aqueous phase immunoassay immunoassay protocol. protocol. Reprinted [66] Reprinted [66]permission © 2013, with © 2013, with from permission Elsevier. from Elsevier. Zong et et al. al.[67] [67]developed developeda dual-mode a dual-mode sensor sensorsystem based system on colorimetry based and magnetic on colorimetry SERS and magnetic for the SERS fordetection the detectionof telomerase. Au Au of telomerase. NPs were NPs werefunctionalized functionalizedwith withDTNB DTNBandand telomeric telomeric repeat oligonucleotide to produce a bifunctional complementary oligonucleotide bifunctional reporting reporting tag tag in in SERS SERS and and colorimetry. MNPs were first coated coated withwith silica silica and and AuAu shell shell and and then then modified modified with with telomerase telomerase substrate substrate oligonucleotide as oligonucleotide as capture capture prob. prob. The coating of Au shell provides easy modification and colorimetric detection via color change after the the capturing. capturing. LODs LODsofofSERS SERSand andcolorimetry colorimetrywerewereobtained obtainedasas1 tumor cell/mL and 10 tumor cells/mL, respectively. 1 tumor cell/mL and 10 tumor cells/mL, respectively. consequence, MNPs are generally used in two different approaches in SERS applications. As a consequence, In the first first one, one, ititisisdesigned designedasas a capture a capture probe probefor for enrichment, enrichment,purification and and purification separation, and separation, thenthen and the detection process the detection by interacting process with with by interacting SERSSERStag based on the tag based onsandwich assay.assay. the sandwich In theIn other the approach, other the magnetic approach, core iscore the magnetic modified with SERS is modified with SERSreporters such such reporters as BMA, DTNB, as BMA, DP, etc. DTNB, DP, and etc. plasmonic and plasmonic nanostructures nanostructures suchsuch as Au as Auor or AgAg shell shelland and used useddirectly directlyasasaacapture capture probe probe and SERS probe. The approaches have advantages in itself as well as the approach being determined according probe. analysis to to the analysis to be be performed. performed. 4. Fluorescence Spectroscopy 4. Fluorescence Spectroscopy Various Various investigations investigations have been conducted conducted to address the impacts of the dual dual signal signal strategy strategy to ameliorate the detection performance of the sensing system ameliorate the detection performance of the sensing system [93,94]. [93,94]. Different techniques techniques that that merge with with MNPs MNPs havehave been been used used to to serve serve as as an an all-in-one all-in-one sensing sensing system system [95,96]. [95,96]. Among Among these these techniques, signal amplification labels relying on the enzyme or DNA labeling, dye labeling, and fluorophore labeling have exhibited great promise thanks to the synchronous properties [94,97,98]. Among numerous composite materials, the magneto-fluorescent nanocomposites have a great Magnetochemistry 2019, 5, 59 11 of 25 techniques, signal amplification labels relying on the enzyme or DNA labeling, dye labeling, and fluorophore labeling have exhibited great promise thanks to the synchronous properties [94,97,98]. Among numerous composite materials, the magneto-fluorescent nanocomposites have a great potential application due to their merits such as optical activity (biolabeling and bioimaging of fluorescent particles) and magnetic field guide opportunity [99–102]. Fluorometric assays have many advantages for biological applications such as higher sensitivity caused by their robust chemical and optical properties. Apart from their intrinsic properties, fluorescent particles have been frequently used for a sensing platform due to their outstanding advantages such as rapid, sensitive and low cost [103–105]. However, there are still some challenges such as an inevitable false signal caused by non-specific adsorption in real samples. Thus, the magnetization of particles was utilized to capture and separated target agents from complex matrices to avoid false signals [106–108]. Furthermore, MNPs can be adopted to utilize as contrast agents for magnetic resonance imaging (MRI) [100,109,110]. Magneto-fluorometric methods for sensing of numerous materials such as heavy metals [111,112], toxins [113], drugs [114,115], pesticide [116], biological materials i.e. DNA [117,118], cell [119,120], bacteria [121], etc. have been investigated. A summary of the different applications of fluorescence-based MNPs is given in Table 3. Magnetochemistry 2019, 5, 59 12 of 25 Table 3. Some examples of fluorescence-based MNPs sensors. Types of NPs Capture probe Size nm Signal Probe Size nm Method Target LOD [R] Fluorescent copper Streptavidin and MNPs@CuNCs Folate receptor functionalized MNPs 300 20 Sandwich assay 0.47 nM and 3.1 nM [93] nanoclusters biotin Monoclonal antibodies (MAbs) PAbs functionalized Microfluidic biosensor- smartphone Salmonella MNPs@FMs 150 150 58 CFU/mL [122] immobilized Fe3 O4 MNPs fluorescent microspheres (FMs) based fluorescent microscopic system typhimurium SNP@RhX@antibody MNP@SiO2 @BSA@Au-Myo-SNP@RhX Fe3 O4 MNP@SiO2@BSA@Au@antibody 292 85 Sandwich assay myoglobin 0.28 ng/mL [123] conjugates NaYF4 : Ce/Tb modified Fe3 O4 MNPs functionalized with ZEN MNPs-aptamer/TRFLNPs-cDNA 55 complementary DNA 34 Sandwich assay Zearalenone (ZEN) 0.21 pg/mL [124] aptamers (TRFLNPs-cDNA) Fe3 O4 MNPs functionalized MNPs@ssDNA-FAM 50 carboxyfluorescein (FAM) - Sandwich assay Total mercury (Hg) 0.49 nM [125] with ssDNA Specific aptamer modified fluorescent Staphylococcus Aptamer-conjugated FMNPs 100 - - Smartphone-based detection 10 CFU/mL [126] magnetic nanoparticles (FMNPs) aureus CoFe2 O4 @dopamine@HSA@PDI-4NH2 CoFe2 O4 @dopamine@HSA@PDI-4NH2 190 PDI-4NH2 (Perylene diimide) - Fluorescence imaging Cell imaging - [127] carboxyfluorescein modified Fe3 O4 @aptamer 1@ IFN-γ@aptamer- Aptamer/protein/aptamerpolymer Interferon gamma Fe3 O4 –aptamer 1/ IFN-γ/ aptamer 100-300 aptamer and dsDNA - 0.175 fM [128] FAMs@dsDNA supersandwich fluorescence sensor (IFN-γ) (FAMs@dsDNA) Fe3 O4 @SiO2 -NH2 -morin Fe3 O4 @SiO2 -NH2 78 Morin - Fluorescence titrations Cu2+ 7.5 nM [129] Fe3 O4 @SiO2 @Au MNPs Fe3 O4 @SiO2 @Au MNPs 11 BSA-Au NCs - H2O2 quenching glucose 3.0 µM [130] First target-specific DNA probe MNP-2nd DNA probe-target DNA-1st Second target specific DNA probe Exotoxin A gene 45 1 (1pDNA) and bio-barcode 23 Sandwich assay 1.2 ng/mL [131] DNA probe-GNP-barcode DNA modified Fe3 O4 MNPs sequence DNA coated Au NPs (GNP) MNPs-PEI-ssDNA MNPs-PEI-ssDNA 78 dye-labeled DNA - Sandwich assay lipopolysaccharide 35 ng/mL [132] MNPs@CuNCs: Magnetic nanoparticles-fluorescent copper nanoclusters; Rhodamine Red-X: RhX; SNP: Silica nanoparticle. Magnetochemistry 2019, 5, 59 13 of 25 Liu et al. synthesized magnetic-fluorescent nanoparticles that were able to separate DNA. These research findings have indicated that the adsorption capacity was increased by using this approach. These nanoparticles also allowed to perform an experiment with only a small amount of nanocomposite except the necessity of radioactive probe [98]. According to the work of Cao et al., MNPs and highly fluorescent copper nanoclusters were prepared respectively by following approaches, streptavidin immobilization onto the surface afterward of the co-precipitation method and polymerization by using poly(T) as a template. The primary benefits of this research are that the dual-signal obtained from the supernatant and the re-dispersed precipitate confirmed each other and be integrated in order to result in a solid and quantitative detection [93]. In the case of Kim et al. research, dye-doped silica nanoparticles as fluorescent tagging and MNPs as a concentrating agent were utilized. The nanoparticles mentioned were used for the determination of enrofloxacin by combining with laser-induced fluorescence microscopy. The proposed technique has greatly improved the detection limit when it’s compared with conventional methods such as ELISA [133]. A publication by Zarei-Ghobadi et al. has reported the fabrication of a genosensor for detection of target DNA based on the photoluminescence quenching of fluorescent dots in presence of Fe3 O4 MNPs. The described nano(bio)sensor highlights the utilization of MNPs coated by the gold layer which enabled higher surface area as a quencher of fluorescent carbon dots. Also, the proposed sensor system was introduced as a good candidate for biosensing applications due to their advantages such as ease-synthesis, high biocompatibility, cost-effectivity and strong adsorption ability [134]. Another example of fluorescence shell tagging on MNPs was used to distinguish three cancer cell lines with different expression levels. A significant advantage in this study consists of the dual-mode nanoprobe which can be employed not only in the fluorescence measurements but also magnetic resonance-based cancer cell targeting [94]. Wang’s group developed a bio-nanocomposite that has two parts i.e. superparamagnetic Fe3 O4 nanoclusters as core and fluorescent dye molecule covalently doped onto silica layers to use an imaging and a photothermal therapy agent. In this contribution, bio-nanocomposite obtained were successfully applied in the specific photothermal therapy of colorectal cancer cells with high stability and reproducibility advantages [107] Another genomagnetic separation based on fluorescence assay was offered by Liu et al. for the detection of mercury in the canned fish sample. The proposed system was successfully applied for monitoring of trace amounts of mercury even after reused for 6 cycling times [125]. Niazi et al. were also developed a novel magneto fluorescent nanosphere by combining aptamer functionalized Fe3 O4 and NaYF4 :Ce/Tb fluorescence nanoparticles for the detection of mycotoxin called zearalenone. Time-resolved fluorescence (TRFL) nanoparticles were labeled with complementary DNA to obtain the signal probe while amine-functionalized MNPs were labeled with zearalenone (ZEN) aptamer to obtain the capture probe. This novel bio-nanocomposite exhibits distinctive features such as stable, specific, convenient and rapid measurements. The schematic protocol for this magneto-fluorescent assay is shown in Figure 5 [124]. Fluorescent chemosensor assay was performed for the detection of target molecules which was based on internal charge transfer. Briefly, in the presence of target molecules interaction between magneto-fluorescent particles and Cu2+ that causes quenching due to the coordination with sensing platform was decreased distinctly because of the decomplexation result with an increase in the fluorescence intensity. The developed chemosensor in this study was successfully used for the monitoring of glutathione oxidized as a template molecule [135]. Another approach to use MNPs in combination with fluorescent structures has been proposed by Wang et al. Major novelty in this research was reported as utilizing not only fluorescent DNA nanotag but also enriched MNPs with DNA for the first time. Among various advantages, such as low non-specific adsorption, ultra-high sensitivity, easy preparation i.e., the proposed technique offers significant promise due to allowing the detection of even a single protein, in that case, human IgG [136]. aptamer functionalized Fe3O4 and NaYF4:Ce/Tb fluorescence nanoparticles for the detection of mycotoxin called zearalenone. Time-resolved fluorescence (TRFL) nanoparticles were labeled with complementary DNA to obtain the signal probe while amine-functionalized MNPs were labeled with zearalenone (ZEN) aptamer to obtain the capture probe. This novel bio-nanocomposite exhibits distinctive features Magnetochemistry such as stable, specific, convenient and rapid measurements. The schematic 2019, 5, 59 14 of 25 protocol for this magneto-fluorescent assay is shown in Figure 5 [124]. Figure 5. The The detection detection principle principle based based on on MNPs MNPs as as capture capture probe probe and fluorescent nanoparticles as a signal probe [124] [124].. Wang and Jiang Fluorescent investigated chemosensor solvothermal assay synthesizes was performed of detection for the CePO4 :Tb,ofGd hollow target nanospheres molecules whichwhich was showed based onsignificant properties internal charge such Briefly, transfer. as peroxidase in the mimetic presenceactivity andmolecules of target magnetic-fluorescent abilities interaction between into one nano-entity. particles magneto-fluorescent The aforementioned and Cu2+ that properties made the prepared causes quenching due to thecomposite nanomaterials coordination with sensingas potential applications in biocatalysis and bioimaging [110]. platform was decreased distinctly because of the decomplexation result with an increase in the Other promising fluorescence intensity.research was reported The developed localized magnetic chemosensor field distributions in this study in a microchannel was successfully used for the by using nickel powder [137]. They have captured the monitoring of glutathione oxidized as a template molecule [135]. red fluorescent MNPs with the proposed platform [138–140]. Another Results approach have to use shown MNPs inacombination great potential application with in chemistry, fluorescent structuresbiology, has been biomedicine proposed andWang by tissueetengineering. al. Major novelty in this research was reported as utilizing not only fluorescent DNA nanotag but also enriched MNPs with DNA for the first time. Among various advantages, such as 5. Near Infrared Spectroscopy (NIRS) and Imaging Near-infrared spectroscopy (NIRS) based on the measurement of absorption of electromagnetic radiation, including wavelengths of 750 to 2500 nm is a type of vibration spectroscopy. The absorption bands originate mostly from the vibrations of molecular bonds such as C-H, O-H, C-O, and N-H within the structure [141]. The Spectra consisting of absorption bands allows the quantitative and qualitative analysis of the molecule being analyzed. However, the NIR radiation can easily penetrate into the body and also NIR radiation is scattered less than UV or visible radiation. Hence, the information based on imaging from the inner body can be obtained by analyzing its spectrum of NIRS [142]. Besides these features, NIRS has important advantages such as being fast and simple, and requiring little sample amount without pre-treatment. There are many applications for the analysis of raw material and product quality in food, pharmaceutical and agricultural industries [141,143,144]. Some applications are summarized in Table 4. In recent years, the new generation NIRS devices developed as functional near-infrared spectroscopy (fNIRS) have been also used for the diagnosis especially in biomedical applications such as neuroimaging, sugar blood, etc. Magnetochemistry 2019, 5, 59 15 of 25 Table 4. Some applications of near-infrared spectroscopy (NIRS) sensors based on MNPs. Types of NPs* Size, nm MNPs form NIR agent Target Methods Advantages [R] Specific cancer-targeting and Dual imaging, excellent magnetic resonance/ structural stability with CMNPs 45 Fe3 O4 Cy5.5 Tumor cells [145] near-infrared(MR/NIR) biocompatible and imaging biodegradable Combination of combined the Fenton reaction and Polypyrrole Photothermal therapy, Fe3 O4 @PPy-PEG 89 Fe3 O4 Tumor cells photothermal and [146] (PPy) magnetic targeting magnet-guided cancer therapy Time and cost effective Magnetic SiNc4 and Photodynamic/photothermal MFG-SiNc4 40 Tumor cells treatments with a minimal [147] graphene fluorescein therapeutic therapy dose In situ drug release and Fast and effective Hydrophobic Doxorubicin DOX-Fe3 O4 @PAAP 170 Fe3 O4 combined thermosensitive [148] Fe3 O4 (DOX) photothermal-chemotherapy drug delivery Magnetic Drug delivery, optical layered Quantum dots Slow-release curative effect CdHgTe@DMF 100 Tumor cells bioimaging and magnetic [149] double of CdHgTe and good cell imaging targeted therapy hydroxide Detection, magnetic Fe3 O4 -Aurods-Fe3 O4 Au Nanorods Multiple Tunable nanoprobes for 70 Fe3 O4 separation, and photokilling [36] nanodumbbells (Aurods) pathogens multiplex detection of multiple pathogens * CMNPs: PSI-g-C12-PEG-folate cross-linked magnetic nanoparticles; MFG-SiNc4 : magnetic and fluorescent graphene (MFG) functionalized with SiNc4 ; PAAP: poly (acrylamide-co-aniline)-g-PEG; DMF: dextran-magnetic layered double hydroxide-fluorouracil; PEG: Polyethylene glycole. MNPs are widely used in NIRS due to their superior properties as targeting and MRI agent to improve the resolution and therapy by the development of dual-mode imaging and therapy systems. As an example, Zhou et al. [150] developed the multimodal theranostic platform by using the Fe3 O4 magnetic nanoparticle as an MRI contrast agent and Indocyanine Green (IR820) as an NIR imaging agent. Firstly, Fe3 O4 -chitosan quaternary ammonium salt (CSQ-Fe) conjugate was synthesized to increase the stability and biocompatible of MNPs. Then, CSQ-Fe modified with IR820 and fluorescein isothiocyanate (FITC), separately. IR-CSQ-Fe and FITC-CSQ-Fe have similar size distribution and zeta potential and also their behavior in cellular uptake is quite comparable. Therefore, FITC-CSQ-Fe was used to determine the cellular uptake of IR820-CSQ-Fe. As a result, cell viability, long-time stability, MRI imaging, and photodynamic therapy tests indicate that IR-CSQ-Fe can be used as MRI and contrast agent for cancer diagnosis and detection. In another study, Zhou et al. [151] synthesized the Fe3 O4 MNPs modified with NIR dye for sentinel lymph node mapping via the dual-mode imaging probe including MRI and NIR imaging. These conjugates performed better than small conventional dyes. Yang et al. [145] prepared biodegradable and biocompatible polymer-modified MNPs and functionalized with NIR dye Cy5.5 for specific cancer targeting and dual-mode imaging in vivo. Firstly, poly(succinimide) (PSI)-g-C12 -PEG-folate was synthesized to improve biodegradable and biocompatible characteristics and then modified with Fe3 O4 MNPs and NIR dye Cy5.5 for dual imaging. Consequently, MNPs were coated with a polymer and this hybrid material has an efficient NIR signal, high MRI sensitivity, an active targeting function, and good structural stability. Wu et al. [146] developed a new strategy for cancer imaging and therapy based on a combination of Fe3 O4 MNPs and polypyrole (PPy) in vivo Fenton reaction as illustrated in Figure 6. Fe3 O4 magnetic core used for targeting the tumor site by applying the magnetic field was coated with PPy shell as near-infrared (NIR) light absorber for converting into heat for the photothermal ablation of tumors (PTT) and then modified functionalized with polyethylene glycol. Moreover, PPy coating not only provided PTT but also prevented Fe2+/3+ release from Fe3 O4 MNPs. This approach indicated the first time that the releasing of iron ions from Fe3 O4 in acidic medium and the Fenton reaction were enhanced by the photothermal effect. As a result, this hybrid nanoparticle obtained the combination of Fenton reaction and PPy as photothermal therapy provided efficient tumor damage without the effecting of normal organs. In another study, Huang et al. [152] synthesized chlorin e6 (Ce6) as a photosensitizer coated on the surface of Fe3 O4 MNPs for gastric cancer imaging and therapy. As in other NIRS applications, MNPs have been used as targeting and MRI agents in this application and final multifunctional nanocarriers exhibited good water solubility and less cytotoxicity and good biocompatibility with high photodynamic and the Fenton reaction were enhanced by the photothermal effect. As a result, this hybrid nanoparticle obtained the combination of Fenton reaction and PPy as photothermal therapy provided efficient tumor damage without the effecting of normal organs. In another study, Huang et al. [152] synthesized chlorin e6 (Ce6) as a photosensitizer coated on the surface of Fe3O4 MNPs for gastric cancer2019, Magnetochemistry imaging 5, 59 and therapy. As in other NIRS applications, MNPs have been used 16 of as 25 targeting and MRI agents in this application and final multifunctional nanocarriers exhibited good water solubility and less cytotoxicity and good biocompatibility with high photodynamic efficiency. efficiency. As a consequence, As a consequence, the synthesized the synthesized multifunctional multifunctional nanocarriers nanocarriers performed performed targeting targeting PDT PDTand and dual-mode NIR fluorescence imaging and MRI of gastric cancer tissue in vivo. dual-mode NIR fluorescence imaging and MRI of gastric cancer tissue in vivo. In another similar In another similar study, study,graphene graphene oxide was was oxide modified with ferrocene modified for targeting with ferrocene for and functionalized targeting with fluorescein and functionalized for with NIR fluorescence imaging [147]. After these modifications, the surface of nanoparticles fluorescein for NIR fluorescence imaging [147]. After these modifications, the surface of was modified with silicon 2,3-naphthalocyanine nanoparticles was modified with siliconbis (trihexylsilyloxide)(SiNc 2,3-naphthalocyanine4 )bis as (trihexylsilyloxide)(SiNc a photosensitizer. SiNC4 was 4) as a an ability to use SiN photosensitizer. in the photodynamic (PDT) and photothermal (PTT) therapies. This theranostic C4 was an ability to use in the photodynamic (PDT) and photothermal (PTT) nanocarrier was used for therapies. This theranostic cost and time-effective nanocarrier was treatments used for with cost dual-mode imaging and and time-effective phototherapy treatments with of cancer cells by a single light source. Cho et al. [153] designed the injectable dual-mode imaging and phototherapy of cancer cells by a single light source. Cho et al. [153] nanocarrier based on hydrogel designed and collagen the injectable for drugbased nanocarrier delivery, phototherapy, on hydrogel and imaging. and collagen In this study, for drug delivery, the high phototherapy, drug-loading capacity of hydrogel was utilized. and imaging. In this study, the high drug-loading capacity of hydrogel was utilized. Figure 6.6.Schematic Schematicillustration illustration of synthetic of the the synthetic route route of of Fe3O4@P−P Fe3O4@P−P NPs andNPs and the synergistic the proposed proposed synergisticmechanism antitumor antitumorofmechanism Fe3O4@P−Pof Fe3O4@P−P NPs. NPs. permission Reprinted with Reprinted from with[146]. permission from Copyright [146]. American CopyrightSociety, Chemical American Chemical Society, 2018. 2018. In In addition addition totocell cellimaging imagingandandphototherapy, phototherapy, magnetic magnetic nanoparticle-mediated nanoparticle-mediated NIRS waswas NIRS used for used pathogen detection. As an example, Wang and Irudayaraj [36] developed multifunctional for pathogen detection. As an example, Wang and Irudayaraj [36] developed multifunctional nanoparticles based on gold based nanoparticles nanorods and Fe on gold 3 O4 MNPs nanorods andfor Fethe 3O4 simultaneous MNPs for thedetection of multiple simultaneous pathogens detection in a of multiple single sample, pathogens in abased on sample, single plasmonbased absorbance, magnetic on plasmon separation,magnetic absorbance, and thermal ablation. and separation, In this study, thermal the plasmonic properties of gold nanorods were an ability to undertake multiple detections ablation. In this study, the plasmonic properties of gold nanorods were an ability to undertake and MNPs were useddetections multiple for targeting, and imaging MNPs wereandused photothermal therapy. for targeting, imaging and photothermal therapy. Due Due tototheir theirsmall sizesize small and motility with the and motility potential with of the biomedical the potential applications,applications, of the biomedical microrobots have microrobots have recently attracted attention. In vivo studies are especially prominent for and recently attracted attention. In vivo studies are especially prominent for the diagnosis the treatment diagnosis of anddisease. In a of treatment study, Lee etInal.a [154] disease. developed study, Lee et al. a thermosensitive [154] developedhydrogel-based a thermosensitivesoft microrobot for targeting and drug delivery by applying NIR stimuli. The microrobot was mainly fabricated with alginate and NIPAM hydrogel for the thermosensitivity and drug loading and Fe3 O4 MNPs were encapsulated into perfluoroalkoxy (PFA) tube for the targeting with a magnetic field. For drug release, a therapeutic drug, doxorubicin (DOX), was loaded into the microrobot. In this study, the drug delivery with the microrobot was performed efficiently in cancer cell treatment through in vitro Hep3B cell testing by NIR and electromagnetic actuation systems. Magnetochemistry 2019, 5, 59 17 of 25 In conclusion, MNPs have been effectively used to develop multifunctional dual imaging and targeting systems for the purpose of drug release, targeting, thermal therapy, and imaging in NIRS applications. 6. Conclusions and Future Challenges In recent years, MNPs have attracted much attention because of their unique properties such as biocompatibility, low toxicity, chemical stability, high surface area, easy synthesis, and modification, etc. to develop the multifunctional nanoparticle-based optical-sensing systems. Studies in this field generally consist of two main steps: (1) easy pre-modification process to improve low toxicity, solubility, and stability; (2) a second modification step with a specific recognition agent for targeting, imaging, diagnosis, separation, purification, and treatment. The most important disadvantage of MNPs is the aggregation and this problem can be overcome by the first modification such as silica or polymer coating, etc. The main disadvantage of optical sensors is the low sensitivity and selectivity of complex matrices such as body fluids, environmental samples, etc. and this problem is largely overcome by using the MNPs with a magnetic field. Moreover, the synthesis and characterization of MNPs need to be improved in (bio) sensing devices. In the future, optical sensors tend to miniaturization, implantability or wearability with high measuring accuracy for the multiple detections in (bio) sensing applications. Therefore, MNPs need to be adapted to such modifications for the integration of this field. Author Contributions: Conceptualization, writing—review and editing R.Ü., E.S., A.M.; funding acquisition, A.M. Funding: The ICN2 is funded by the CERCA Programme / Generalitat de Catalunya. The ICN2 is supported by the Severo Ochoa program of the Spanish Ministry of Economy, Industry and Competitiveness (MINECO, grant No. SEV-2017-0706). Financial support was obtained under MINECO project MAT2017-87202-P. Conflicts of Interest: The authors declare no conflict of interest. References 1. Koh, I.; Josephson, L. Magnetic nanoparticle sensors. Sensors (Basel) 2009, 9, 8130–8145. [CrossRef] 2. Nikiforov, V.N.; Filinova, E.Y. Biomedical Applications of Magnetic Nanoparticles. In Magnetic Nanoparticles; Gubin, S.P., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany, 2009; pp. 393–444. 3. Mou, X.; Ali, Z.; Li, S.; He, N. Applications of Magnetic Nanoparticles in Targeted Drug Delivery System. J. 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