An Overview of the Production of Magnetic Core-Shell Nanoparticles and Their Biomedical Applications

Abstract

Several developments have recently emerged for core-shell magnetic nanomaterials, indicating that they are suitable materials for biomedical applications. Their usage in hyperthermia and drug delivery applications has escalated since the use of shell materials and has several beneficial effects for the treatment in question. The shell can protect the magnetic core from oxidation and provide biocompatibility for many materials. Yet, the synthesis of the core-shell materials is a multifaceted challenge as it involves several steps and parallel processes. Although reviews on magnetic core-shell nanoparticles exist, there is a lack of literature that compares the size and shape of magnetic core-shell nanomaterials synthesized via various methods. Therefore, this review outlines the primary synthetic routes for magnetic core-shell nanoparticles, along with the recent advances in magnetic core-shell nanomaterials. As core-shell nanoparticles have been proposed among others as therapeutic nanocarriers, their potential applications in hyperthermia drug delivery are discussed.

1. Introduction

Nanomaterials are of great scientific interest as they possess unique properties compared to their bulk counterparts. Sized in a nanodomain with at least one dimension in the range of a few nanometers (1–100 nm), they usually have size- and shape-dependent physical properties. Among the physical properties reliant on size are superparamagnetism (in magnetic particles), surface plasmon resonance (in several metallic particles), and quantum confinement (in semiconductor particles). While nanomaterials are usually perceived as late inceptions, this is not the case for most of them. The use of nanomaterials dates back to the fourth century AD when Romans started using metallic particles in glass constructions such as cups. The Lycurgus cup is the oldest known case [1], produced from silver and gold nanoparticles (NPs) embedded in glass, just like stained-glass windows. The production process of such materials back then was based on empirical methods as there was a lack of fundamental scientific knowledge. Some of those methods were discovered by an accidental mixture of the glass with pulverized metallic dust. Nowadays, with the evolution of nanotechnology, there is a defined scientific methodology underlining the production of nanoparticles. Additionally, while the production of nanoparticles and thin films (ranging up to 100 nm) has been stressed repeatedly in the literature, there is still a need for updated inclusive reviews, such as the one presented here, focusing on the production of core-shell and nanohybrid particles for biomedical applications.

Furthermore, there has been a staggering increase in the development of complex materials based on various metallic core-shell or nanohybrid particles. Some of them are prominent for their magnetic and electrochemical properties, which render them ideal for applications such as hyperthermia [2], lithium-ion batteries [3], microwave absorption [4], catalysis [5], et cetera. At the same time, other NPs are attractive for their antibacterial and UV-protection properties, which make them ideal for biomedical [6] and cosmetic applications [7,8], respectively. The above stems from their superior biocompatibility as their shell material can be modulated to provide preferable interactions with biological tissue. Their magnetic core material, in return, allows the precise administration of these nanocarriers to a specific anatomical site. The combination of nanocore with nanocoatings renders these particles as advanced materials as it allows application-specific surface functionalization [9], while shielding the core from the particles’ environment. As such, core-shell nanoparticles and nanohybrids are usually multifunctional as their properties can be easily modulated because both the core and the shell of the particle can contribute to their physicochemical characteristics. For instance, their reactivity and thermal stability depends on the coating material and can thus be tailored to meet the application’s requirements. Therefore, the use of coatings on the core materials is manifold, with increased dispersibility, functionality, stability, and surface modification being only some of the elements that can be affected through the applied coating.

2. Scope of this Review

Reviews have an essential role in keeping researchers up to date on the current state of developments in a fairly focused scientific field. While many researchers have also published reviews [10,11,12,13] and book chapters [14,15] on core-shell nanoparticles, they emphasize primarily the applications, the physical and chemical properties, or the specific groups of magnetic materials. Nevertheless, there is a lack of literature that compares the size and shape of magnetic core-shell nanomaterials synthesized via different routes. To this end, the current review provides a systematic overview of the available production methods of magnetic core-shell nanoparticles. As the nanoparticle’s shape and size depend on the production method, the primary aim is to compare the different techniques with respect to the characteristics of the NPs. Consequently, this review can serve as an introduction to core-shell nanoparticle synthesis or as a starting point for researchers seeking alternative production routes for magnetic core-shell nanoparticles, while portraying the importance and future potential of these materials in biomedical and cosmetic applications.

3. Basic Strategies for Producing Nanostructured Materials

Two basic strategies/approaches are used to produce nanoparticles, core-shell nanoparticles, and nanohybrid materials alike: “top-down” and “bottom-up”(Figure 1), with the combination of both strategies being a prevalent route as well. In the top-down approach, a macroscopic material or group of materials decreases from the macroscale to the microscale and then to the nanoscale. With this approach, traditional industrial methods such as microfabrication take place, which use various tools to shape, cut, or resize a bulk material into particles. Several techniques fall within the above approach, with the most prevalent being associated with nano-lithographic techniques such as optical lithography, electron beam lithography, optical near-field lithography, scanning probe lithography, nanoimprint lithography, and others. Besides lithographic techniques, laser-beam processing and several mechanical techniques, such as grinding, milling, machining, and polishing, also produce nanoparticles.

Bottom-up methods utilize the chemical and physical properties of nano-sized molecules to drive their self-assembly and to grow functional structures. This route produces distinct, manifold, and complex structures from atoms or molecules, at high precision, and results in refined control over the shape and size of the NPs. Over the past decades, many bottom-up strategies have been introduced, extending from condensing vapors on surfaces to the coalescence of atoms in liquid solutions.

Some of the most prevalent bottom-up methods are aerosol processes, chemical synthesis (including precipitation techniques, reduction reactions, sol-gel processes, hydrothermal and solvothermal reactions, et cetera), molecular self-assembly, laser-induced assembly, chemical and physical vapor deposition techniques, et cetera.

4. Top-Down Processes

4.1. Milling Processes

Those processes produce nanoparticles by sequentially reducing the size of bulk materials into smaller, yet stable structures. The above is achievable by the interacting of the raw materials (usually a powder with a grain size of several μm) with a mechanical device called a mill. These powders undergo plastic deformation through a series of impacts that lead to their fracture, ultimately reducing their particle size. Consequently, the size can decrease even below 100 nm, producing nanoparticles. The milling processes produce nanocrystalline materials in solid-state at standard ambient conditions, using inexpensive equipment, and they are fully scalable to the industrial level. However, the disadvantage of the milling process is material contamination as lengthy processing and high temperatures result in the diffusion of materials from the grinding medium and the container surface. In addition, milling does not comprehensively control the particle shape and yields powders with relatively broad particle-size ranges. Some of the above drawbacks can be eliminated through wet milling, where a small amount of organic solvent and surfactants is added to the mixture to stabilize the nanoparticles formed by the impact and prevent their agglomeration.

High-energy milling techniques, such as vibrating, planetary, and friction milling, are usually preferred, with planetary high-energy ball milling being the most prominent. High-energy ball milling contains a low number of balls (Figure 2), functioning as the grinding medium inside the container, that move freely and have adequate space to gain a high momentum before any impact. A motor that shakes the container in a planetary motion provides the system with high energy levels capable of milling even the most challenging materials. Usually, those mills have both a container and grinding balls composed of steel or tungsten carbide.

4.2. Lithographic Processes

In material science, the term lithographic processes refers to the manufacturing techniques for inducing desired patterns in micro- and nanoscale. Therefore, they are usually referred to as microlithography or nanolithography, depending on the target size scale of the process. While the above processes are typical for producing nanostructured patterns, they can also produce nanoparticles [16]. In lithographic techniques, a distinct procedure is used to mark thin films of barrier materials that cover substrates during the deposition, implantation, or etching procedures. In contrast with other methods, lithography provides consistency and full control of the pattern’s shape and size but requires costly equipment and demanding infrastructure. Well-defined nanoparticles can be fabricated by lithographic methods independently or with the assistance of other processes, such as physical vapor deposition [17] (PVD), reactive ion etching [18], and other assorted methods. Some of the most popular lithographic methods used to produce nanostructures and nanoparticles are photolithography, electron beam lithography, nanoimprint lithography, interference lithography, nanosphere lithography, nanostencil lithography, and others.

The semiconductor industry widely uses lithographic processes, especially photolithography, to produce state-of-the-art semiconductors and, consequently, electronics [19]. For the above reason, photolithography is one of the most mature techniques, maintaining high reliability. Photolithography or optical lithography uses light (usually UV radiation) and a mask to sculpture a geometric pattern on a light-sensitive coating of a substrate. Depending on its chemistry, the light-sensitive material disintegrates or hardens due to exposure, while solvents remove the excess coating, creating a pattern. The remaining pattern layer acts as a guide to producing the desired micro- and nanostructures via deposition, etching, and other procedures. The radiation’s wavelength defines the minimum feature size to engrave the photoresist layer.

Interference or holographic lithography is a photolithography variation that does not require the usage of masks. Instead, it uses short exposure of coherent light waves to produce nanoscale patterns in a photoresist over a large area. Two coherent beams, created from a laser source by a beam splitter, are piloted to superimpose and interfere with one another, creating a spatial interference pattern consisting of periodically distributed intensity on the photoresist.

Apart from interference lithography, electron beam lithography is a common mask-less technique. In the above process, a focused beam of electrons is used to mark a layer of an electron-sensitive film, anointed as resist, changing its solubility. Then, the resist’s exposed or non-exposed areas can be removed using a solvent. Eventually, evaporation of the desired material on the patterned resist can produce functional nanoparticles, and a lift-off process can clear the resist. It is also attainable by transferring the patterns to the functional layer with dry or wet etching processes.

The Figure 3 below illustrates photolithography and electron beam lithography.

5. Bottom-Up/Chemical Production Processes

5.1. Sol-Gel

The colloidal gel technique (sol-gel) is a wet chemical process initially used to synthesize inorganic materials such as glass, ceramics, ceramic nanostructured polymers, porous nanomaterials, and oxide nanoparticles. The low temperature and mild conditions required for this method enable the synthesis of hybrid coatings from organic/inorganic materials incorporating low molecular weight organic compounds. The sol-gel process mainly transforms a colloidal liquid state of dispersed particles (sol) to a solid-state (gel) interconnected network of polymer chains with an average length of more than one micrometer and a pore size of less than one micrometer. The precursors used for sol-gel synthesis are metals or metalloids attached with organic compounds. Metal alkoxides (metallic compounds of alcohol, with silicon, titanium, or aluminum) are the most prevalent because of their high reactivity with water.

Inserting organic substances into the wetting process produces an organometallic compound from an alkoxide solution. Subsequently, the solution’s pH is adjusted with an acidic or basic solution. Next to the pH regulation, these media also work as catalysts, triggering the transformation of the alkoxide. The reactions involved in this are hydrolysis, followed by condensation and polymerization. The polymer oxide or the particles grow as the reaction proceeds until a gel is formed. It is noteworthy that the hydrolysis and the condensation reaction depend on the initial solution’s composition, catalyst volume, temperature, and reactor-mixing geometry. In the case of coatings, the alkoxide solution is applied even to geometrically complex surfaces. Once applied to a surface, the growth of a porous network materializes via the gel formation. Thicker layers can be produced by repeated wetting and drying. A drying step always follows the gel formations (wetting).

With the ability to process every step separately in the formation of the sol and gels, it is possible to modify the entire technique to produce powders, fibers, ceramics, coatings, and even highly porous nanomaterials (Figure 4). Furthermore, the porous network created from the gel step allows the production of new composites by filling the pores during or after the gelling process, due to the low operating temperature. However, one major drawback of the sol-gel processes is the controlling of the synthesis and drying steps, combined with the organic contaminants that remain in the gel. Ultimately, thermal post-treatment is usually required, adding to the complexity of scaling up those processes.

Over the years, multiple sol-gel variations have emerged, with the Stöber process being one of the most efficient [20]. The Stöber method is a sol-gel process in which the molecular precursor (usually tetraethylorthosilicate) reacts first with water in an alcohol solution; then, the consequent molecules agglomerate to build larger structures. The aforementioned method is employed to prepare SiO₂ nanoparticles in a controllable shape and size, and it is quite an efficient sol-gel variation.

5.2. Co-Precipitation

This technique is relatively straightforward for nanoparticle synthesis and involves dissolving metal precursors in a polar solvent, usually water, along with a reducing agent. AS a polar solvent is utilized, the most common precursors are ionic compounds such as metal salts. The process is quite efficient and lasts from a few minutes to a few hours. The cores of the nanoparticles are formed from the reduction of the metals. Thereupon, the particles settle as a precipitate in the solution. At the final stage of the procedure, the particles are collected by ultra-centrifugation or by a magnet in the case of magnetic materials and thermally post-treated. The nanoparticles’ size, shape, crystallinity, and composition depend on the type of salts (chlorides, sulfates, and nitrates), the ionic compound ratio, the reaction temperature, the pH, and the ionic strength of the solvent [21]. This method has the edge on high repeatability and the quantities of nanoparticles produced. However, it is challenging to control the shape in this approach because only the kinetic factors are modified during synthesis. Furthermore, higher temperatures would lead to agglomeration succeeding in destroying the nanostructure. Therefore, co-precipitation remains one of the most frequently utilized production processes for nanomaterials.

5.3. Emulsions

Those processes involve a thermodynamically stable dispersion of two immiscible liquids, usually oil and water, with the presence of a surfactant. The surfactant stabilizes the interface between the two liquid phases. For example, in oil and water microemulsions, the organic phase is dispersed in microdroplets, enclosed by a layer of surfactant molecules, separating them from the aqueous phase. This separation occurs so that the surfactant’s hydrophilic part is inside the aqueous environment, while the hydrophobic part is inside the organic phase, resulting in the formation of micelles. The molecular fraction of the aqueous phase to the surfactant and the surfactant’s chemical structure defines the micelle’s size and structure. Fundamentally, micelles are formed due to amphiphilic (containing both hydrophobic and hydrophilic groups) surfactants, as shown in Figure 5. The surfactants, and the micelles that they create, are excellent tools of reaction that can work as nanoreactors as they manage to increase the solubility of the reactants and organize them within their structure. The above is achievable as micelles deliver constant mobility when they collide, unite, and redissolve. Consequently, a precipitate eventually forms inside them and is finally isolated by centrifugation, filtration, or magnetic separation in post-treatment. There are two types of micelles, regular and reverse micelles. In the latter, the aqueous phase is trapped in droplets inside the organic phase.

Even though emulsions can synthesize multiple types of nanoparticles, they do not deliver reasonable control over size and shape while maintaining small production yields. Nevertheless, it is worth noting that while emulsion processes can produce magnetic nanoparticles for various applications [22], they are among the preferred production routes for nanoparticles in biological [23,24] and cosmetic applications [25].

5.4. Hydrothermal—Solvothermal

Hydrothermal synthesis refers to the heterogeneous reaction in an aqueous solution inside a closed system (autoclave) when the temperature and the pressure exceed 100 °C and 1 bar, respectively. The autoclave (a high-pressure steel container, as shown in Figure 6) essentially ensures controlled crystal growth. The above is due to the high pressure favoring the formation of complex structures with the desired crystallinity at a relatively low temperature. In addition, one quite distinctive advantage is that hydrothermal synthesis is a straightforward process with low cost, environmentally friendly reagents, and satisfactory repeatability, despite its low production yield. If an organic solvent is used instead of water, the process is termed solvothermal. A critical difference between the two methods is the pressure inside the autoclave. In hydrothermal synthesis, the system’s pressure is determined externally, while in solvothermal it is autogenous (self-dependent) and cannot be modified.

Furthermore, it is typical for the hydrothermal and solvothermal synthesis of inorganic nanoparticles to occur at higher temperatures than the solvent’s boiling point. In this way, the solvent is in a supercritical state, and its properties (density, surface tension, viscosity, and dielectric constant) change drastically, greatly facilitating the consummation of the reactions. Moreover, the solvent’s properties vary between gases and liquids in their supercritical state. Therefore, even though accurate knowledge of the reactions during hydrothermal and solvothermal synthesis is complicated, they can be classified merely into redox reactions, hydrolysis, thermolysis, complex formation reactions, and permutation reactions. The parameters that affect the synthesis fall into two categories: chemical and thermodynamic. The chemical parameters depend on the nature of the reactants and the solvent. In addition, the chemical composition and concentration of the precursors in the solution affect the characteristics of the nanoparticles produced. Thus, choosing the correct solvent takes effect by assessing the molecular weight, boiling point, dielectric constant, bipolar moment, and polarity of the solvent. The thermodynamic parameters include the temperature, the pressure, and the reaction time, which affect the morphology and the composition of the NPs. Eventually, any mixture of reactants and solvents under precise experimental conditions can lead to new nanoparticles.

5.5. Thermal Decomposition

Thermal decomposition is the method that utilizes the high-temperature decomposition of precursors, such as salts, metal, and organometallic compounds, through a series of chemical reactions. These reactions occur in organic solvents in the presence of surfactants, which are often fatty acids such as oleic acid or amines. As the process mandates an inert atmosphere, the equipment used is more complex and therefore more expensive than the equipment used on other techniques, such as co-precipitation or sol-gel. Furthermore, the produced nanoparticles are mainly hydrophobic; so, their surface needs further processing for biomedical applications. The morphology of the produced NPs depends on the concentrations of the precursors and the solvent, temperature, and reaction time, whereas the pressure is autogenous and, therefore, is not controllable. The main advantage of thermal decomposition over other bottom-up methodologies is the narrow size distribution and the shape homogeneity of the produced nanoparticles. However, one major drawback of the process is the poor repeatability due to numerous parameters affecting the synthesis.

Thermal decomposition is usually based on a hot-injection technique, where the precursor compounds are added to a pre-heated solvent and surfactant solution [21]. The above leads to an abrupt nucleation, separating the growth stage from the nucleation. The apparatus utilized in this procedure is illustrated in the figure below, revealing that it is possible to insert components during the reaction through the right nozzle of the three-nozzle spherical flask.

Figure 7 portrays the hot-injection setup that allows the control of the reactions to a certain degree, while also facilitating visual observations, such as the solution’s color change. In addition, the ability to insert precursors during the proceeding reaction allows the separation of the nucleation into two steps, with the second step initiating after the intake of new precursors. In this manner, it is possible to prepare heterometallic nanoparticles, with the second metal compound infused at a specific reaction stage.

5.6. Gas-Phase—Vacuum Processes

Gas-phase methods are industry-standard techniques for producing nanomaterials in powder or film form. However, most of them require an inert atmosphere or even vacuum pressures to deliver the desired results, which significantly increases the cost of equipment and consumables. Nevertheless, the production consistency and high purity of the synthesized NPs have rendered these techniques highly popular. In gas-phase processes, the vapor from the precursor compounds produces nanomaterials employing either chemical or physical mechanisms. Nanoparticles are mainly synthesized in liquid or solid state through homogeneous nucleation, with various additional mechanisms such as chemical reactions on the surface, adhesion of two or more particles, particle fusion, and condensation leading to the final nanomaterials. Some of the most frequent gas-phase techniques involve hot-wall, plasma, laser, and flame reactors, with Chemical Vapor Deposition (CVD) being the most widely used of all of them.

Chemical Vapor Deposition is a vacuum deposition technique that produces materials through the chemical reactions of gaseous reagents. Usually, the substrate is exposed to gaseous precursors and solid materials (thin films or nanoparticles) produced along with volatile by-products, which are removed from the reactor with pumps. Despite several variations, all CVD processes require an energy source to break down the gaseous reagents and initiate the chemical reaction. The substrate can be heated with either one of two methods: directly or indirectly (Figure 8). In direct methods, the substrate absorbs energy either inductively or through another heating source at its base surface. This type of CVD employs cold-wall reactors, and the chamber wall remains at ambient temperature. In indirect methods, the entire chamber is externally heated, with the substrate temperature increasing through radiation from the chamber, which is part of a hot-wall reactor. CVD processes usually involve high temperatures and low pressures. Depending on the pressure deployed in the reaction chamber, CVD is classified into the following types: Ultra-High Vacuum CVD (UHVCVD), where the pressure drops below 10⁻⁸ Torr and Low-Pressure CVD (LPCVD), with the chamber pressure ranging between 10⁻² -10 Torr. Notably, in low-pressure conditions, the unwanted gas-phase reactions are restricted and the film uniformity across the substrate is improved, whereas UHVCVD creates high-purity products. Another less popular type of CVD is atmospheric pressure CVD.

CVD processes have numerous variations, such as the plasma-enhanced CVD, laser CVD, metal-organic CVD, and others that fall beyond the scope of this review. However, chemical vapor deposition techniques deliver high-quality, high-performance, and high-purity solid nanomaterials. As a result, they are popular in the semiconductor industry, where they are employed to produce semiconductors, metals, oxides, nitrides, and organic nanomaterials.

6. Concentrated Table

The following table includes the most popular synthesis methods for magnetic core-shell nanoparticles. It is noteworthy that magnetic core-shell nanoparticles are usually multifunctional. Even though not all the articles cited in

Table 1. Overview of production methods for magnetic core/shell nanoparticles.

			Core		Shell
Core/Shell	Shape	Average Size	Method	Basic Reagent	Method	Basic Reagent	Ref.
Fe/C	irregular spherical	16–41 nm	thermal decomposition	FeCl3·6H2O		fructose, glucose, and sucrose	[26]
Fe/C	spherical	25 nm	DC plasma arc discharge method	Fe powder (high purity)		carbon powder	[27]
Fe/C	spherical	200 nm	reduction with CVD	Fe3O4		carbon powder	[28]
Fe/C	spherical	50–60 nm	thermal decomposition	Ferrocene, silicon wafer	thermal decomposition	heavy oil	[29]
Fe/SiO2	spherical agglomerates	97 nm	gas-phase hybridization	Fe powder	gas-phase hybridization	SiO2 powder	[30]
Fe/SiO2	spherical	10–40 nm	reduction by KBH4	FeCl2·4H2O	hydrolysis, condensation polymerization	TEOS	[31]
Fe/SiO2	spherical	10–90 nm	arc discharge	Fe powder		SiO2 powder	[32]
Fe/FeO, Fe3O4	spherical	30–80 nm	solar vapor phase condensation	Fe powder	solar vapor phase condensation	Fe powder, Fe3O4 powder	[33]
Fe/Ag	spherical	33 nm	reduction by NaBH4	FeSO4·7H2O		AgNO3	[34]
Fe/Ag	spherical	10 nm	reduction by LiBEt3H	FeCl2	reduction in organic media	AgNO3	[35]
Ag/Fe	spherical	30 nm	reduction via phytochemicals	Fe(NO3)3		AgNO3	[36]
Fe/Pt	spherical	≈2 nm	reduction by NaBH4	FeSO4	reduction transmetalation	K2PtCl4	[37]
Fe/Pt	spherical	3 nm	reduction	C15H21FeO6	reduction	PtCl4	[38]
Fe/PIB	spherical	20–100 nm	thermal decomposition	Fe(CO)5		PIB	[39]
Fe/PS	spherical	20–100 nm	thermal decomposition	Fe(CO)5		polystyrene (PS)	[39]
Fe-CBC/SdC	nanoparticles on fibers	<100 nm fiber diameter (NPs << 50 nm)	cellulose-assisted hydrolysis, polymer wrapping	FeCl3, BC hydrogels	carbonization	PEDOT, EDOT	[40]
Ni/C	spherical	14 nm	reduction with CVD	Ni(acac)2	annealing		[41]
Ni/C		15–35 nm	thermal decomposition	Ni(C5H7O2)2	thermal decomposition	Ni(C5H7O2)2	[29]
SiO2/Ni	spherical	150 nm	Stöber method	TEOS	deposition, precipitation	Ni(NO3)2·6H2O	[42]
Ni/SiO2	spherical	80 nm	WEE technique	Ni wire	Stöber method	TEOS	[43]
Ni/SiO2	elliptic and spherical	≈300 nm (20–80 nm shell)	reduction by citric acid	NiCl2·6H2O	Stöber method	TEOS	[44]
Ag/Ni	spherical	50–100 nm 95–165 nm	reduction by NaBH4 in microemulsion	Ni(NO3)2	reduction by NaBH4 in microemulsion	AgNO3	[45]
Ag/Ni	nanowire (and spherical)	<300 nm (50–150 nm shell)	hydrothermal method	AgNO3	hydrothermal method	Ni(AC)2	[46]
Ni/Pt	irregular spherical agglomerated	<10 nm	reduction by NaBH4	Ni(CH3COO)2	reduction by NaBH4 and N2H4	H2PtCl4·6H2O	[47]
Co/CoO@FeNC	spherical core onion-like shells	50 nm	microemulsion, pyrolysis	FeCl3, CoCl2·6H2O, RuO2, Pt/C, cyclohexane			[48]
Co/SiO2	spherical	≈60 nm	cryogenic melting method	Co bulk metal	Stöber method	TEOS	[49]
Co/CdSe	spherical	≈15 nm	high-temperature thermal decomposition	Co2(CO)8	precipitation	Cd(CH3)2, Se	[50]
CoNi/SiO2/TiO2	spherical	1.35 µm/100 nm shell	solvothermal	C4H6NiO4 4H2O, C4H6CoO4 4H2O	Stöber method, solvothermal	TEOS, TIP	[51]
CoNi@Air@TiO2	Spherical yolk type	1.35 µm/200 nm shell	solvothermal	C4H6NiO4 4H2O, C4H6CoO4 4H2O	Stöber method, solvothermal, hydrothermal via NaOH	TEOS, TIP	[51]
Au/Co	spherical	65 nm	reduction by sodium citrate	HAuCl4	reduction by N2H4, H2O	CoCl2	[52]
Au/Ni	spherical	65 nm	reduction by sodium citrate	HAuCl4	reduction by N2H4, H2O	NiCl2	[52]
Co/Au, Pd, Pt, Cu	spherical	≈6.5 nm	Hydrothermal decomposition	Co2(CO)8	Reduction transmetalation	Au precursor Pd(hfac)2, Pt(hfac)2, Cu(hfac)2	[53]
ZnCo2O4/C	nanowire arrays	100 nm	hydrothermal, annealing	Zn(NO3)2·6H2O, Co(NO3)2·6H2O, urea	CVD	C2H2	[54]
FeNi/C	spherical	50 nm	precipitation, reduction with NaOH	FeCl2, NiCl2, aniline, hydrochloric acid, formaldehyde	pyrolysis		[55]
FeNi/SiO2	spherical	≈60 nm	cryogenic melting method	Fe, Ni bulk metal	Stöber method	TEOS	[49]
Fe, Cu/ Au, Pt, Pd, Ag	cubical, spherical	5–50 nm, 50–60 nm	reduction by vitamin C	Fe(NO3)3 9H2O, CuCl2	reduction by vitamin C	Na2PtCl6·6H2O, HAuCl4·3H2O, AgNO3, PdCl2	[56]
FePt/CdS	spherical	<10 nm	thermal decomposition with reduction	Fe(CO)5, Pt(C5H7O2)2	precipitation	sulfur, Cd(C5H7O2)2	[57]
Fe58Pt42/Fe3O4	spherical	4–7 nm	reduction with thermal decomposition	Pt(C5H7O2)2, Fe(CO)5	thermal decomposition	1,2-hexadecanediol, oleic acid, Fe(C5H7O2)3 , oleylamine	[58]
MnFe2O4/TEHA-co-PDLLA @PTX	spherical, irregularly shaped particles	<160 nm	solvothermal	acetylacetonate iron (III), manganese (II), Fe(acac)3, Mn(acac)2	emulsion	TEHA-co-PDLLA block copolymer, Paclitaxel	[2]
Fe3O4/SiO2	spherical	30 nm	co-precipitation	FeCl2⋅4H2O, FeCl3⋅6H2O	Stöber method	TEOS	[59]
Fe3O4/SiO2	spherical	30 nm	thermal decomposition	Fe(C5H7O2)3	sol-gel	TEOS	[60]
Fe3O4/SiO2	acicular	<5 nm	chemical reaction in microemulsion	FeCl3, FeSO4	sol-gel reaction in microemulsion	TEOS	[61]
Fe3O4/SiO2	spherical	15–20 nm	wet chemical reaction	FeCl3, FeSO4	hydrolysis	Na2SiO3	[62]
Fe3O4/SiO2	spherical	7–12 nm	wet chemical reaction	FeCl3, N2H4	sol-gel	TEOS	[63]
Fe3O4/SiO2	spherical	80 nm	co-precipitation	FeCl2·4H2O, FeCl3·6H2O	sonication, hydrolysis	TEOS	[64]
Fe3O4/SiO2	stellate	100 nm	thermal decomposition	FeSt3	sol-gel	TEOS, CTATos	[65]
Fe3O4/Polyaniline/Au	irregular spherical	200 nm (4 nm Au NPs as shell)	solvothermal	FeCl3·6H2O, sodium acrylate, CH3COONa	reduction by Na3C6H5O7, NaBH4	HAuCl4	[66]
Fe3O4/Au	octahedral	100–150 nm	physical grinding	commercial Fe3O4	calcination	HAuCl4	[67]
Fe3O4/Au	spherical	7 nm	solvothermal	Fe(C5H7O2)3, phenyl ether, oleic acid, oleylamine	hydrolysis with thermal decomposition	Au(OOCCH3)3, 1,2-hexadecanediol, oleic acid, oleylamine	[68]
Fe3O4/Au	spherical	8 nm	wet chemical reaction	FeCl3	reduction by NaBH4	HAuCl4	[69]
Fe3O4/Ag	octahedral	100–150 nm	physical grinding	commercial Fe3O4	calcination	AgNO3	[67]
Fe3O4/C	spherical	~20 nm	co-precipitation	FeCl3·6H2O, FeCl2·4H2O	hydrothermal	glucose	[70]
Fe3O4/C	rod, diamond, spindle	2 μm, 3 μm, 600 nm	MOF-derived method and solvothermal	FeCl3·6H2O, fumaric acid, dimethyl formamide	pyrolysis		[71]
Fe3O4/C	spherical	52, 80, and 110 nm	High-temperature solution-phase reaction	Fe(acac)3, oleic acid, dibenzyl ether, 1-Octadecene, hexane	carbonization		[72]
Fe7C3/FexOy/C	spherical	12–45 nm	thermal decomposition	Fe(C5H5)2	thermal decomposition		[73]
FexOy/C	spherical	7 nm @6 um spheres	wet chemical reaction	Fe(NO3)3·6H2O	thermal decomposition	glucose	[74]
Fe3O4/TiO2	spherical	20 nm	wet chemical reaction	FeCl3·6H2O, FeCl2·4H2O	precipitation	Ti(SO4)2, CO(NH2)2	[75]
Fe3O4/SiO2/TiO2	irregular spherical	≈30 nm	wet chemical reaction	FeCl3, FeSO4	sol-gel	TEOS, TBOT	[62]
Fe3O4/SiO2/Al2O3	irregular spherical	20–25 nm	wet chemical reaction	FeCl3, FeSO4	sol-gel with precipitation	TEOS	[62]
Fe3O4, γ-Fe2O3/NaYF4:Yb, Er	spherical	68 nm	co-precipitation	FeCl2, FeCl3	co-precipitation	NaF, YCl3, YbCl3, ErCl3, EDTA	[76]
Fe3O4/PEG	spherical	10–40 nm	wet chemical reaction	FeCl2·4H2O, FeCl3·6H2O		PEG-400	[77]
Fe3O4/PEG	spherical	2–10 nm	co-precipitation	FeCl2·4H2O, FeCl3·6H2O	co-precipitation, sonication	PEG-400	[78]
Fe3O4/PEG	irregular spherical	12 nm	co-precipitation	FeCl3		PEG (mol wt. 4000)	[79]
Fe3O4/PLA	spherical	10 nm	co-precipitation	FeCl3·6H2O, FeCl2·4H2O	ring-opening polymerization	L-lactide	[80]
Fe3O4/Dextran	spherical	≈35 nm		Fe3O4 powder	vibration ball milling	Dextran 60000	[81]
Fe3O4/MPEG	spherical	7.8 nm	wet chemical reaction	FeCl3·6H2O, FeCl2·4H2O		MPEG (mol wt. 5000)	[69]
Fe3O4/PEGMA	quasi spherical	15 nm	co-precipitation	FeCl3·6H2O, FeCl2·4H2O	RAFT	PEGMA	[82]
PEGMA/PS/Fe3O4	quasi spherical	3.7 um (90 nm Fe3O4 NPs)	polymerization	GMA, EDMA	co-precipitation	FeCl3, NaNO2	[83]
Fe3O4/PHEMA-g-PCL	spherical	4 nm	Hydrothermal degradation	Fe(OCOCH3)3	polymerization	pentamethyldiethylenetriamine	[84]
Fe3O4/PEO-PPO-PEO	spherical	45–20 nm	reduction	FeCl3		block polymer PEO-PPO-PEO	[85]
CoFe2O4/DTPA-CS	spherical	70 nm	low temperature solid-state method	CoCl2·6H2O, FeCl3·6H2O, NaCl	emulsion cross-linking polymerization	chitosan, DTPA	[86]
Fe3O4/Fe2O3	nanorod	30−50 nm (diameter), 0.8−1.2 μm (length)	hydrothermal	FeCl3·6H2O, Na2SO4	electrodeposition	FeOOH, FeCl2	[87]
CaO/Fe2O3	irregular	9–16 nm		bulk CaO	thermal decomposition	Fe(C5H7O2)3	[88]
MgO/Fe2O3	irregular	6–9 nm	aerogel/hypercritical drying/ dehydration	Mg(OCH3)2	thermal decomposition	Fe(C5H7O2)3	[88]
Fe2O3/Au	spindle	80 nm × 500 nm	hydrolysis in KH2PO4 solution	FeCl3 6H2O	reduction by formaldehyde	HAuCl4	[89]
Fe2O3/POS	spherical	15–26 nm	co-precipitation	FeCl2, FeCl3	polycondensation	TMMS, DEDMS, ClBz-T	[90]
γ-Fe2O3 /polyMAOETIB	spherical	≈56 nm	precipitation	gelatin, iron oxide	emulsion polymerization	2-MAOETIB	[91]
γ-Fe2O3/PEI+PEO-PGA	Irregular spherical	≈45 nm	co-precipitation	FeCl2, FeCl3	suspension polymerization	PEO-PGA	[92]
iron oxide-SiO2 composite/PS	spherical	≈268 nm	Massart with Stöber method	FeCl2, FeCl3, TEOS	polymerization	styrene	[93]
FeO/Ag	spherical	20–30 nm	wet chemical reaction with peel extract (PEP)	FeCl3		AgNO3	[94]
FeO/Au	spherical	<100 nm	wet chemical reaction with peel extract (PEP)	FeCl3		AuCl3	[94]

Abbreviations: CVD = Chemical Vapor Deposition; TEOS = tetraethoxysilane; PIB = polyisobutylene; GMA = glycidyl methacrylate; EDMA = ethylene glycol dimethacrylate; PEO-PPO-PEO = poly(ethylene oxide)-poly(propylene oxide)-poly-(ethylene oxide); DTPA = diethylenetriaminepentaacetic acid; TMMS = trimethoxymethylsilane; DEDMS = diethoxydimethylsilane; ClBz-T = (chloromethylphenyl)trimethoxysilane; 2-MAOETIB = 2-methacryloyloxyethyl(2,3, 5-triiodobenzoate); PTX = Paclitaxel; TEHA-co-PDLLA = thioether-containing ω-hydroxyacid-co-poly(d,l-lactic acid); CBC =carbonized bacterial cellulose; SdC = S-doped carbon; EDOT = 3, 4-ethoxylene dioxy thiophene; hfac = 1,1,1,5,5,5-hexafluoroacetylacetonat; CTATos = cetyltrimethylammonium tosylate; PHEMA-g-PCL = poly (2-hydroxyethyl methacrylate)-graft- poly(e-caprolactone); POS = polyorganosiloxane.

refer to core-shell particles utilized for biomedical applications, even the methodologies presented for the non-biomedical ones can be extended to purposes that fall within the scope of this review if combined with a proper shell. For instance, iron oxide nanoparticles can be utilized for lithium-ion batteries [3], microwave absorption [4], catalysis [5], and even for wastewater treatment [9] and many more applications, with the synthesis method remaining unaltered across different applications. Therefore, the following table contains core-shell nanoparticles for various applications. Its main objective is to provide a handy tool for comparing different sizes, shapes, and synthetic methods on various magnetic nanoparticles.

7. Biomedical Applications

Nanomaterials have been suggested for a variety of bio-related applications, whether for medical applications [95,96], agro-biotechnology [97], or cosmetic ones [98]. Regulatory concerns have, however, so far restricted their wide use to high added-value applications, conventionally found in biomedical applications. Among these are therapeutic delivery systems, to which nanomaterials have been suggested since the early 90s [99,100], with core-shell nanoparticles following only a few years after [101]. However, as far as it concerns biomedical or pharmaceutical applications, the main advantage of core-shell nanoparticles over other materials ranging in the nano-domain, is affiliated with their biocompatibility [102]. The above can be attributed to the combination of a magnetic core with bio-inspired shells, ensuring favorable interaction with biological systems.

The latest research regarding these nanocarriers has focused mainly on diseases where conventional medication yields a low therapeutic index, i.e., cancer treatment [103]. Next to targeted drug delivery, core-shell nanoparticles have elicited attention due to their superparamagnetic properties, which they exhibit in the presence of a magnetic core (e.g., iron oxides and sulfides). The advantage offered by ferrous core material is bifold: (a) administering the nanocarrier to a specific anatomical site (or even target cell) through the application of an external magnetic field that navigates the particles as desired [104] and (b) through their exposure to an oscillating magnetic field, which increases their temperature and induces controlled hyperthermia [105]. Hyperthermia has lately emerged as a valid alternative to radiotherapy and chemotherapy, as malignant cells are prone to temperatures beyond 41 °C. Furthermore, the site-specific heat administration, along with the restriction of temperature ranges to below 44 °C, can preserve the surrounding tissue far more effectively than other oncotherapies [106].

7.1. Hyperthermia

While hyperthermia is a rather old concept, introduced with the injecting of iron oxide nanoparticles into lymphatic channels [107], nowadays it has evolved rapidly. Modern research has progressed significantly in improving efficiency and productions methods.

Interestingly, Simeonidis et al. [33] recently reported a heating efficiency of approximately 0.9 kW/g in large spherical iron/iron-oxides core−shell nanoparticles. This was achieved by exploiting the interactions between the core and shell phases. Their group proved that the final particle size, the core−shell ratio, and the interposition of a thin wüstite interlayer are correlated to specific absorption rates. They used Solar Vapor Phase Condensation (Solar PVD) as a green, cost-effective, and scalable technique, that can produce large quantities of dry nanoparticle powders with a narrow size distribution without the purification steps.

Apart from the previously mentioned progress, recent advances in the production of magnetic materials for hyperthermia include improvements in the synthesis of the popular silica-coated nanoscale zero-valent iron oxides. Specifically, Tajabadi et al. [108] managed to optimize the synthesis, revising the molar ratio of the precursors; using response surface methodology, they created various modified samples with a high maximum saturation magnetization of 99.3 emu/g. Furthermore, they achieved SAR values of 354.7 and 419.9 W/g for the most optimized samples, which are relatively high for Fe@SiO₂ nanoparticles. In addition, the above samples had enough silica coating to protect the inner core from erosion and prevent the release of iron ions. Yet, the core-shell particles with a dense silica shell revealed an acceptable cytocompatibility of up to 250 lg/mL. It is noteworthy that all the above optimizations were possible with synthesis simulation techniques such as response surface methodology.

7.2. Drug Delivery

Several novel concepts other than hyperthermia have come to light as numerous research groups globally investigate drug delivery. Some include magnetic core/shell nanoparticles that combine photo-induced hyperthermia and drug delivery [65]. For example, in the above study, Adam et al. produced iron oxide@stellate mesoporous silica nanocarriers to deliver doxorubicin (a chemotherapy medication used to treat cancer). The photothermia was induced through near-infrared light and correlated to the energy of the applied field. Moreover, the pH-induced delivery of the antitumor drug was then tailored through the surface functionalization of their core-shell systems. In particular, the mesoporous silica’s stellate shape (Figure 9), the surface functionalization, and the pH tuning made the doxorubicin loading possible to an extended degree. Therefore, with the nanoparticles mentioned above, it is possible to include drug delivery and hyperthermia applications simultaneously.

In a similar study, Chen et al. [109] utilized a microfluidic technology to synthesize composite materials composed of a thermosensitive hydrogel with incorporated magnetic core/shell nanoparticles. These crosslinked polymers were used as single emulsions, encapsulating an aqueous drug or double emulsions loaded with a water-soluble drug in the shell and an oil-soluble one in the core. The core and shell layers of the emulsions are filled with two drugs, camptothecin and doxorubicin hydrochloride, to perform simultaneous delivery of hydrophobic and hydrophilic medicines. In addition, the drug delivery of the composites is possible by employing Fe₃O₄ nanoparticles in the shell layer of the emulsions. Finally, the magnetic field-induced hyperthermia was used, along with its anti-cancer properties, to increase the temperature of the hydrogel in a controlled manner, thus dictating a targeted medicinal effect through the controlled release of the encapsulated drugs.

8. Concluding Remarks and Perspective

Multifunctional magnetic core-shell nanoparticles are emerging platforms for many applications. However, despite a plethora of available fabrication routes that can be employed for their production, some (e.g., co-precipitation or reduction of the core) are favored more than others as they are more productive and cost-efficient.

The acceptance of core-shell nanoparticles from the biomedical sector was driven mainly by their exceptional (shell-based) biocompatibility, combined with their outstanding guidance potential and traceability, based on their magnetic cores. In addition, while some biomedical applications in drug delivery [101] and hyperthermia [107] are decade-old concepts, their research output has escalated to promising clinical trials [110]. The above is valid due to the favorable biocompatibility of core-shell nanoparticles when compared to other nanomaterials [102], usually attributed to the composition of their shell. Despite the numerous challenges, magnetic core-shell nanoparticles are regarded as a promising class of materials for many other research areas, e.g., catalysis, radio absorption, and energy storage systems. Therefore, efficient and controlled production methods for core-shell nanoparticles continue to pose a scientific challenge.