Fe₃O₄ Core–Shell Nanostructures with Anticancer and Antibacterial Properties: A Mini-Review

Abstract

Core–shell nanoparticles are functional materials with tailored properties, able to improve the requirements of various applications. Both core and shell components can be inorganic or organic, and there are numerous studies in this field regarding their synthesis methods, properties, and applications. This review aims to study core–shell nanostructures with Fe₃O₄ cores and different shell types, observing their antibacterial and anticancer properties. By the type of coating, Fe₃O₄ core–shell nanoparticles (NPs) are classified into four categories: metal-coated NPs, metal-organic framework (MOF) coated NPs, metal oxide coated NPs, and polymer-coated NPs. Each category is briefly presented, emphasizing anticancer or antibacterial properties and specific applications (cancer diagnosis or therapy, drug carrier). Moreover, synthesis methods and particle size for both core and shell nanostructures, as well as the magnetic properties of the final core–shell material, are summarized in this review. Most of the consulted papers discussed sphere-like core–shell nanoparticles obtained by chemical methods such as coprecipitation, hydrothermal, and green synthesis methods using plant extract. These types of core–shell nanoparticles could be used as drug nanocarriers for tumor-targeted drug delivery, hyperthermia treatment, or contrast agents. Further work needs to be conducted to understand nanoparticles’ interaction with living cells and their traceability in the human body.

1. Introduction

Fe₃O₄ nanoparticles, due to their physical–chemical properties, low toxicity, and high saturation magnetization values, have received great attention in the biomedical field. Their pharmaceutical applications, such as anticancer agents against various cancer cells and antiviral (e.g., influenza virus, HBV, HIV) or antibacterial agents, have been recently considered. They are studied in several areas of interest from a medical point of view, such as magnetic hyperthermia, drug delivery, magnetic resonance imaging, photothermal therapy of tumors, magnetic bioseparation, magnetofection agents, DNA molecule detection, infectious diseases, and cancer therapy [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30].

In chemotherapy, several drug delivery systems can be used, but among them, one has shown great potential in nanomedicine: superparamagnetic iron oxide nanoparticles, also known as SPION, have become a priority choice for the delivery of cancer drugs because they effectively target cancer cells, through a magnetic field, improving the accumulation of magnetic nanoparticles at the target site. Moreover, these nanoparticles (NPs) also make simultaneous drug delivery and magnetic resonance imaging possible [31,32]. SPIONs have been extensively studied for cancer treatment by magnetic hyperthermia. The principle of this technique is as follows: when iron oxide NPs are exposed to an external magnetic field, magnetic losses are dissipated as heat appears. If SPIONs are placed near tumors, they raise the temperature of the tumor to a therapeutic level (42–45 °C) and induce weakness or death of cancer cells without damaging the surrounding healthy tissue or cells [1,18,33,34,35]. Several studies have provided evidence that the overuse of antibiotics has led to the development of bacterial resistance to numerous drugs, as in the case of nosocomial infections in hospitals [36,37]. Recently, researchers found that iron oxide nanoparticles could be used as magnetic drug delivery systems for antibiotics (e.g., amoxicillin). It means that Fe₃O₄ is loaded with various antibiotics as agents for killing bacteria in the respective damaged tissue, reducing the dose of medication needed in the classical method. When the external magnetic field is applied, the affected tissue is heated, and antibiotics act as bacteria-killing heat agents. A new approach is represented by the green synthesis method of Fe₃O₄ in the presence of plant extracts [36]. For example, Fe₃O₄ prepared using garlic extract has potential antibacterial action and is tested in the antimicrobial therapy of numerous multidrug-resistant bacterial strains and fungi. However, bare SPION oxidizes easily in the air, losing its magnetic properties and dispersibility due to its high chemical activity [38]. Therefore, surface coating is recommended to maintain the stability of magnetic Fe₃O₄ and to improve iron oxide antimicrobial applications. Moreover, the surface coating prevents agglomeration of nanoparticles, protects nanoparticles against reticuloendothelial system (RES) uptake and elimination, and improves internalization efficiency [4,34]. One of the most popular surface coating techniques is the obtaining of core–shell nanostructures. Core–shell particles serve as storage and carrier platforms for many applications [39,40,41]. Several types of core–shell structures based on Fe₃O₄ (core) have been investigated and have been used in the field of chemotherapy due to both their antibacterial properties and their superparamagnetic properties [32,33,42,43,44,45,46]. This structure is frequently used as a platform for targeted drug delivery in cancer treatment [46]. Bacterial infections and cancer are connected diseases that have become a global health threat. Bacteria accelerate the development of cancer, prompting researchers to find an antibacterial and anticancer drug delivery agent. A lot of articles have studied organic coatings of iron oxide nanoparticles, the most popular being natural and synthetic polymers such as chitosan, dextran, starch, polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP), polyethyleneimine (PEI), poloxamers, polysorbate 20 and 80, thermo-responsive poly (N-isopropyl acrylamide) (PNIPAAm), or small organic molecules with functional groups, such as thiols, amines, or carboxyls [2,4,32,34,47]. In this mini-review, core–shell nanoparticles having Fe₃O₄ as a core will be discussed, describing briefly their properties, synthesis methods, and biomedical applications and focusing on the inorganic shell types. Each synthesis method can produce different sizes, shapes, or magnetic properties for a specific application. The main characteristics of the inorganic core–shell materials discussed in this paper are presented synthetically in the form of tables.

2. Different Types of Core–Shell Structures with Fe₃O₄ Core for Biomedical Applications

Core–shell nanostructures are defined as heterogeneous nanoparticles composed of two or more nanomaterials that can be identified and are separated by distinct boundaries. Both core and shell components can be inorganic (metals, metal oxides) or organic (polymers, biomolecules) [48,49,50]. Core/shell composite nanostructures (NSs) have attracted much attention in recent years due to their diverse and unique material properties not shown by the core or shell materials alone, such as good mechanical, thermal, and optical properties [48,51]. These properties are significantly enhanced compared to pure compounds [51]. The interaction between the core and the shell of a nanostructure can lead to new properties and functions [45].

There are numerous core–shell materials with various applications and much literature about their classification and detailed descriptions of the preparation method. This paper presents only inorganic core–shell materials with Fe₃O₄ as the core and their medical applications.

Fe₃O₄ can be coated with different types of shells, such as metals (Ag, Au) [52,53,54,55,56], metal–organic frameworks (Cu–MOF), metal oxides (SiO₂, TiO₂, ZnO), and organic polymers (polyethyleneimine: PEI, polyacrylic acid: PAA, etc.), to obtain core–shell nanostructures with desired properties [3].

Core–shell nanostructures with Fe₃O₄ as a core have been a popular research topic over the last decade, with more than 700 articles published in the field, as shown in Figure 1a. As can be seen from Figure 1b, most of the papers published on this topic were research articles (>700 papers) and short communications (>40 papers). The data presented in Figure 1 were obtained using the ScienceDirect database (https://www.sciencedirect.com/) and searching for “Fe₃O₄ core–shell nanoparticles for biomedical applications”. The results were refined by year (selecting from 2012 to 2023) in Figure 1a and by article type in Figure 1b. These data were collected in May 2023.

2.1. Metal-Coated Fe₃O₄

Silver-coated Fe₃O₄ nanohybrids have been used in a broad range of applications, including chemical and biological sensors [48,57], drug delivery—as successful drug carriers with focused antimicrobial, anticancer properties [48,58], diagnosis, and cancer therapy [48,59,60].

Different methods were used to synthesize Ag-coated Fe₃O₄ nanoparticles. Generally, a two-step synthesis procedure is applied: magnetite is prepared by a solvothermal, co-precipitation, or microemulsion route [57,61,62], obtaining spherical-shaped particles, and then Fe₃O₄ nanoparticles are dispersed in AgNO₃ solution in the presence of an organic solvent (ethanol, di-chlorobenzene), a surfactant (oleylamine, cetyltrimethylammonium bromide—CTAB), and a reduction agent for Ag (butylamine, sodium borohydride). Another approach uses combined phyto- and hydrothermal synthesis, preparing the magnetite core in the presence of a plant extract (neem leaf extract, leaf extract of Eryngium planum, Vitis vinifera (grape) stem extract, Euphorbia peplus Linn leaf extract), followed by hydrothermal synthesis of Fe₃O₄–Ag (silver nitrate was added in the magnetite suspension). Plant extract acts as a reducing agent for silver shells [44,59,63,64]. Spherical core–shell structures with 7–80 nm are obtained in these cases [44,57,59,61,62,63,64]. Moreover, brick-like Ag-coated Fe₃O₄ nanoparticles with ~13 nm in width and ~15 nm in length were prepared by single-step thermal decomposition of the magnetite precursors in the presence of AgNO₃ salt and 1,2-hexadecane-diol reduction agent [58].

It has been discovered that Fe₃O₄–Ag nanocomposites present a self-sterilizing property that avoids the formation of biofilms, which are the most dangerous source capable of spreading toxic bacteria into the environment [61], improving the contrast of magnetic resonance imaging (MRI) in cancer detection [48].

Similar synthesis methods as in the case of silver-doped magnetite core–shell structures (coprecipitation, thermal decomposition of Fe₃O₄), followed by reduction of HAuCl₄ or gold acetate with various agents (NaBH₄, sodium citrate, 1,2-hexadecane-diol), as well as combined phyto-hydrothermal synthesis (with Juglans regia green husk as reducing and stabilizing agent for HAuCl₄), were reported in [65,66,67,68,69,70,71,72] for gold-coated magnetite nanostructures. In 2023, Danafar et al. [65] prepared Fe₃O₄–Au hybrid nanoparticles coated with bovine serum albumin (BSA) by co-precipitation of magnetite at 60 °C followed by the reduction of HAuCl₄ with sodium citrate and NaBH₄, resulting in Fe₃O₄–Au hybrids that were further coated with BSA under magnetic stirring at room temperature. They studied their potential application as a contrast agent in magnetic resonance imaging (cancer diagnosis). Gold nanoparticles represent a good option for Fe₃O₄ coating due to their good biocompatibility, large specific surface area, “surface plasmon” property, and well-known attraction for thiol groups from organic molecules [66]. Fe₃O₄–Au core–shell nanoparticles can be used in biomedical applications such as magnetic resonance imaging, hyperthermia, biosensors, immunosensors, photothermal therapy, controlled drug delivery, targeted gene delivery, protein separation, DNA detection, and DNA/RNA interaction [67,68,69,70,71].

2.2. Metal–Organic Framework (MOF) Coated Fe₃O₄

Fe₃O₄ nanoparticle was used as a core for improving the physicochemical properties and the thermal stability of the Cu–MOF compound. Metal–organic frameworks (MOFs) are a class of crystalline, porous materials composed of metal ions surrounded by multi-dented organic molecules. The metal ions form nodes that bind the arms of the organic ligands which act as linkers in the cage-like network structure. MOFs have a high surface area, significant porosity, tunable pore size, and high thermal stability in comparison to other nanostructures. Azizabadi et al. [51] prepared Fe₃O₄–Cu–MOFs by an ultrasonic-assisted reverse micelle synthesis (ultrasonic irradiation time of 10 min, temperature of 25 °C, power of 80 W) and found that this core–shell composite has good antibacterial activities against both Gram-positive and Gram-negative bacteria, which recommends it for advanced biomedical applications.

2.3. Metal Oxide-Coated Fe₃O₄

One of the most studied metal oxides as a shell for the Fe₃O₄ core was SiO₂, due to the powerful attraction of magnetic nanoparticles to silica [73]. SiO₂ particles are non-toxic, highly biocompatible, and abundant in surface hydroxyl groups, which makes them an ideal surface functional coating for magnetic nanoparticles in the medical field [3,74,75,76,77,78,79]. Fe₃O₄ nanoparticles coated with SiO₂ shells obtained by Ta et al. through hydrolysis and condensation [75] showed increased biocompatible properties and provided new ideas for future bioconjugation studies [3]. Moreover, the Fe₃O₄–SiO₂ core–shell structure prepared by Lu et al. using an ultrasound-assisted method [80] has good opportunities in the field of biomedicine [3].

TiO₂ is another metal oxide with interesting properties such as biocompatibility, chemical inertness, high stability, and resistance to body fluids that lead to its use in cosmetics, pharmaceutics, and malignant tumor therapy [43,81,82]. The coating of magnetite nanoparticles with a TiO₂ shell protects the core from environmental damage and improves biocompatible properties [43]. Fe₃O₄–TiO₂ core–shell structures with various Fe₃O₄:TiO₂ molar ratios were synthesized by a modified sol–gel method [83] or hydrothermal process [84]. The obtained Fe₃O₄–TiO₂ core–shell nanorods are superparamagnetic and could be further used for magnetic hyperthermia applications [43].

Fe₃O₄–ZnO core–shell nanoparticles represent some of the most studied materials for magnetic hyperthermia and bio-imaging applications [33,85,86,87,88,89]. ZnO is well known for its anti-bacterial and biocompatible properties and possesses unique physical and chemical characteristics due to its wide bandgap and elevated exciton binding energy (piezoelectricity, photoluminescence, chemical stability) [90,91,92]. It has been demonstrated that ZnO–Fe₃O₄ composites combine the magnetic properties of Fe₃O₄ with the antibacterial activity of ZnO, resulting in a material with improved biocompatibility and enhanced antibacterial activity. ZnO–Fe₃O₄ composites inhibit microorganisms’ biofilm formation due to their synergetic activity of ion lixiviation (Fe³⁺, Zn²⁺) and oxidative activity. The material’s magnetic properties play a major role in reducing the ability of microorganisms to attach to different surfaces, inhibiting biofilm formation [85]. It is very important to hinder the formation of biofilm because its existence makes microorganisms more resistant to antibiotics. ZnO/Fe₃O₄ composites have shown enhanced antibacterial ability under visible light irradiation compared to single ZnO [93]. In 2021, Gupta et al. [33] reported the hydrothermal synthesis of Fe₃O₄–ZnO core–shell nanoparticles. The obtained material preserved the photoluminescence capacity of ZnO and the superparamagnetic properties of Fe₃O₄, demonstrating its potential use for hyperthermia therapy and fluorescent-based cellular imaging. Fe₃O₄–ZnO nanoparticles significantly reduced the viability of human cervical cancer cells (HeLa) under the applied AC magnetic field. However, in 2018, Madhubala et al. [87] found that only the lowest concentrations of Fe₃O₄–ZnO core–shell nanoparticles are non-toxic for cells and could be used for cancer treatment using magnetic hyperthermia therapy (MHT). Moreover, the authors concluded that Fe₃O₄–ZnO with a molar ratio of 1:20 has a small particle size and high crystallinity, and Fe₃O₄ is completely encapsulated in the ZnO nanoparticles [87].

2.4. Polymer-Coated Fe₃O₄

Magnetite surface coating with natural or synthetic polymers has been widely investigated [3,32,94,95,96,97,98,99,100] due to their good biocompatibility, biodegradability, non-toxicity, stability, and ability to modify physical-chemical surface properties. Covering magnetite with polymers improves the antibacterial and anticancer properties of core–shell nanoparticles. Different polymers such as polyethylene glycol (PEG), chitosan, poly-N-vinylpyrrolidone (PVP), hydroxyl ethylene cellulose (HEC), nanocrystalline cellulose (NCC), heparin-poloxamer (HP), poly(N-isopropyl acrylamide) (PNIPAAm), polyethyleneimine (PEI), and polyacrylic acid (PAA) have been coated on the Fe₃O₄ surface for tumor-targeted drug delivery. In 2021, Mohammadi et al. [95] synthesized magnetic nanoparticles with cross-linked PEG coatings using plasma treatment. The plasma-induced graft polymerization creates a cross-linked network of PEG chains, resulting in a rigid surface that hinders the burst release of the drug. The classical coprecipitation method of magnetite core followed by direct addition of chitosan or PEG shell and heating at 80 °C for 30 min [96] leads to an irregular and dendrimer-like surface morphology with small and large grain sizes. Fe₃O₄ surface functionalized with PEG has significant results at 20 mg/mL against antimicrobial activities. The anticancer activity was tested against HepG2 liver cancer cell lines, and magnetite-polymer nanoparticles are suitable for hyperthermia therapy to treat carcinoma.

When superparamagnetic iron oxide nanoparticles (SPIONs) were coated with heparin-poloxamer (HP) and the core–shell system was tested for anticancer drug delivery, doxorubicin (DOX) was entrapped in the polymer shell, showing a controlled release up to 120 h without any initial burst effect [98]. Moradi et al. [32] prepared Fe₃O₄ core–shell nanoparticles as drug nanocarriers, having PNIPAAm grafted with chitosan as a polymer shell. PNIPAAm is a thermo-responsive polymer, while chitosan is a pH-responsive moiety. Therefore, the highest release percentage of methotrexate (MTX) as a negatively charged anticancer drug has been observed at T = 40 °C and pH = 5.5.

A schematic representation of Fe₃O₄-based core–shell nanoparticles with various types of shells for biomedical applications is shown in Figure 2.

Table 1. Synthesis methods for Fe₃O₄ core–shell nanoparticles and their applications.

Type of Core–Shell Material	Core Synthesis Method	Shell Synthesis Method	Application	Reference
Fe3O4–Ag Molar ratios: 1:5, 1:10, and 1:20.	Fe3O4 nanoparticles were synthesized using neem leaf extract, FeSO4*7H2O, and Fe(NO3)3*9H2O.	Fe3O4–Ag was prepared by hydrothermal method, adding AgNO3 in Fe3O4 solution.	Promising anticancer agents.	[44]
Fe3O4–Ag	Magnetite was prepared using FeCl3*6H2O, sodium acetate, ethylene glycol, and polyethylene glycol PEG (MW~3000Da).	The silver coating was obtained by adding butylamine to a silver nitrate solution dispersed in ethanol.	Magnetic separation and magnetic resonance imaging (MRI).	[57]
Fe3O4–Ag	Fe3O4 was prepared by microemulsion technique using ferrous and ferric ammonium sulfate and surfactant CTAB.	Silver-coated magnetite nanoparticles were prepared by microemulsion technique using silver nitrate.	Biomedical applications	[62]
Fe3O4–Ag	Fe3O4 nanoparticles were prepared using an eco-friendly method. Precursors: V. vinifera stem extract, FeCl3*6H2O, and sodium acetate.	AgNO3 was added to the Fe3O4 solution, stirring for 2 h. The morphology of the core–shell nanoparticles is nearly spherical with ~32 nm diameter. Particle size is controlled by the addition of Vitis Vinifera stem extract which acts as the green solvent, reducing and capping agent.	High antibacterial activity against Gram-negative and Gram-positive pathogens.	[63]
Fe3O4–Au	Fe3O4 was prepared by coprecipitation method using FeCl3*6H2O and FeCl2*4H2O.	Fe3O4 was mixed with HAuCl4 at 90 °C for 5 min and then sodium citrate was added.	Cancer therapy	[71]
Fe3O4–Au	Coprecipitation method using FeCl3*6H2O and FeCl2*4H2O.	Green synthesis method: Fe3O4 nanoparticles were suspended in HAuCl4 solution using J. regia (walnut) as a reducing agent.	Cancer treatment	[72]
Fe3O4–Cu–MOF	-	Ultrasonic-assisted reverse micelle synthesis using Cu (NO3)2*5H2O, PVP (polyvinyl pyrrolidone), acetic acid, and Fe3O4 nanoparticles.	Good antibacterial activities against both Gram-positive and Gram-negative bacteria.	[51]
Fe3O4–SiO2	Fe3O4 was synthesized by coprecipitation method starting from FeCl3*6H2O and FeSO4*4H2O.	Fe3O4–SiO2 were obtained by in situ coprecipitation method, adding ethanol, NH3, and tetraethyl orthosilicate (TEOS) in ethanol.	immune-magnetic separation, separating biomolecules in biomedical and bioprocess engineering.	[73]
Fe3O4–SiO2	Fe3O4 was synthesized by coprecipitation method using FeCl3*6H2O and FeCl2*4H2O.	Fe3O4 was dispersed in a mixture of water, ethanol, and NH3. TEOS was added. Fe3O4 nanoparticles were coated with SiO2 through hydrolysis and condensation.	Bio-applications. Investigation of T cell removal in bone marrow transplantation.	[75]
Fe3O4–SiO2	Fe3O4 was prepared by a modified hydrothermal method, starting from FeCl3*6H2O, sodium acetate, and sodium citrate.	Fe3O4–SiO2 nanoparticles were prepared by an ultrasound-assisted method, using TEOS.	Potential use in the field of catalysis, gas separation, and biomedicine.	[80]
Fe3O4–SiO2	Fe3O4 was synthesized by coprecipitation method using FeCl3*6H2O and FeCl2*4H2O and carboxymethyl cellulose as capping agent.	Fe3O4 was dispersed in ethanol and then TEOS was added resulting SiO2 shell around Fe3O4 (modified Stöber process).	Biomedical and solar cell applications.	[78]
Fe3O4–TiO2 Different molar ratios: 1:5, 1:10, and 1:20.	Fe3O4 was prepared by phytogenic method using FeSO4, Fe(NO3)3 and neem leaf extract.	Hydrothermal synthesis of TiO2 in the presence of Fe3O4 to obtain Fe3O4–TiO2 core–shell nanorods.	Potential use for magnetic hyperthermia applications.	[43]
Fe3O4–TiO2	Fe3O4 was prepared by coprecipitation method using FeCl3*6H2O and FeCl2*4H2O.	For TiO2 coating, TiCl4 was diluted in ethanol and then mixed with Fe3O4 solution in ethanol (modified sol–gel synthesis).	Photocatalyst for treating the organic contaminant in the field of environmental protection.	[83]
Fe3O4–TiO2	Solvothermal method using FeCl3 and different surfactants (ethylene glycol, oleic acid, sodium dodecyl sulfate, polyvinylpyrrolidone, polyethylene glycol).	Hydrothermal synthesis using titanium butoxide and ethanol.	drug delivery, hyperthermia treatment, photocatalytic water purification.	[84]
Fe3O4–ZnO (molar ratio 1:1)	The hydrothermal approach using ferric (III) acetylacetonate.	Hydrothermal method using zinc acetylacetonate dihydrate.	Potential use in magnetic hyperthermia and bio-imaging.	[33]
Fe3O4–ZnO (molar ratio 1:1)	Microwave method using ferric (III) acetylacetonate.	Zinc acetate was added to the Fe3O4 suspension which was further subjected to microwave treatment.	Potential for anti-biofilm formulation.	[85]
Fe3O4–ZnO	Phyto-synthesis of Fe3O4 using FeSO4, FeNO3 and neem extract.	Hydrothermal synthesis of Fe3O4–ZnO using ZnCl2.	Useful for Magnetic Hyperthermia Therapy (MHT) for cancer treatment.	[87]
Fe3O4–chitosan–Ag	Suspension technique for Fe3O4–chitosan synthesis using commercial magnetite and chitosan powders.	Fe3O4–chitosan was dispersed in DMF (dimethylformamide) and mixed with AgNO3 and glucose.	potential antimicrobial agents or additives in medical, biological, food packaging, and textile applications.	[100]
Fe3O4–heparine–poloxamer (HP)	Fe3O4 was prepared by coprecipitation method using FeCl3*6H2O and FeCl2*4H2O.	Fe3O4–HP core–shell system was prepared by ultrasonication.	Drug delivery system for cancer treatment.	[98]
Fe3O4–PNIPAAm	Coprecipitation in Ar atmosphere, using FeCl2 and FeCl3.	Polymerization of NIPAAm in the presence of Fe3O4 at 90 °C for 5 days.	Targeted drug delivery against human lung and breast cancer.	[32]

shows the main synthesis methods and applications of Fe₃O₄ core–shell nanoparticles.

Table 2. Size and properties of Fe₃O₄-based core–shell nanostructures.

Type of Core–Shell Material	Synthesis Conditions	Core Diameter	Shell Thickness	Properties	Reference
Fe3O4–Ag	Hydro-thermal synthesis at 200 °C/18 h.	45 nm	5 nm.	Super-paramagnetic behavior at 300 K. magnetization: 12.64 emu/g. Cytotoxic behavior on liver cancer cells.	[44]
Fe3O4–Ag	polyol reduction technique using an ultrasonic bath.	Fe3O4 particles (spherical shape aggregates) is ~73 nm. The primary particle size is ~16 nm.	The Ag layers were estimated at ~3.5, 9, and 11 nm for molar ratios of the ethanolic Ag solution to butylamine of 1:0.5, 1:1, and 1:2, respectively.	Magnetic saturation of Fe3O4: 91 emu/g.	[57]
Fe3O4–Ag	Micro-emulsion method.	6 nm.	1.5 nm, 2 nm, and 8 nm.	Magnetic saturation: 55 emu/g for 1.5 nm Ag shell thickness; 53 emu/g for 2 nm Ag shell thickness. Nanocrystals with thicker nano-shells exhibit super-paramagnetic properties.	[62]
Fe3O4–Ag	Green synthesis, eco-friendly method.	The mean crystallite size of Fe3O4: 32 nm (XRD).	Core–shell particle size <50 nm (TEM).	ferromagnetic behavior; saturation magnetization (Ms) 15.74 emu/g.	[63]
Fe3O4–Au	Mild chemical synthesis (90 °C).	-	Core–shell size: ~9 nm.	Core–shell magnetic saturation (Ms): 42 emu/g. Ms = 46 emu/g for Fe3O4 core.	[71]
Fe3O4–Au	Green synthesis method (autoclave 120 °C/20 min).	5.77 nm (HRTEM).	Core–shell size: 6.08 nm (HRTEM).	Core–shell nanoparticles show the inhibitory concentration (IC)50 of 235 μg/mL against a colorectal cancer cell line, HT-29. High saturation magnetization (Ms): 45.06 emu/g.	[72]
Fe3O4–SiO2	In situ co-precipitation.	The average size of Fe3O4 core: 24 nm.	Mean thickness of SiO2 shell: 18 nm.	Superparamagnetic properties. Saturation magnetization = 66 emu/g for Fe3O4 and 45 emu/g for Fe3O4/SiO2.	[73]
Fe3O4–SiO2	Chemical synthesis.	Mean diameter of Fe3O4 core: 10 ± 3 nm.	SiO2 shell thickness: 35 ± 5 nm. the Fe3O4–SiO2 core–shell thickness: 80 ± 5 nm).	Saturation magnetization values (Ms): 61.2 emu/g for Fe3O4, and 18.4 emu/g for Fe3O4–SiO2.	[75]
Fe3O4–SiO2	Mechanical mixing followed by sonication (modified Stöber techniques).	Average particle size of Fe3O4: 11.3 nm (TEM).	SiO2 thickness: 4 nm (TEM). Average crystallite size of core–shell structure: 18 nm.	Optical conductivity of Fe3O4–SiO2 nanoparticles has the highest value (24.4 eV2) compared to the others.	[78]
Fe3O4–TiO2	Hydro-thermal synthesis 200 °C/18 h.	Rod-shaped morphology. diameter of the core–shell structure was ~18 nm; length ~70 nm.		The magnetic saturation value of one sample was 1.27, 5.51 and 12.75 emu/g for T = 300, 100 and 15 K.	[43]
Fe3O4–TiO2	Modified sol–gel method.	Diameter of Fe3O4 core: 7 nm.	TiO2 thickness: 5 nm.	Ms = 55 emu/g for Fe3O4 (at 300 K) and 20 emu/g (at 300 K) for Fe3O4–TiO2.	[83]
Fe3O4–TiO2	Hydro-thermal method at 220 °C/24 h.	Crystal size of Fe3O4–TiO2 varies between 8.14 nm (with oleic acid surfactant) and 34.85 nm (PEG surfactant).		Ms = 74.268 emu/g for Fe3O4 and 8.178 emu/g for Fe3O4–TiO2.	[84]
Fe3O4–ZnO	Hydro-thermal synthesis 250 °C/30 min, N2 atmosphere.	The average size of Fe3O4–ZnO: 10 nm (TEM).		Superparamagnetic behavior. Ms = 31.2 emu/g.	[33]
Fe3O4–ZnO	Microwave thermal treatment.	Spherical Fe3O4 core, diameter = 5 nm.	Spherical and rod-like ZnO shells with ~30 nm diameter and rod lengths ~70 nm.	Core–shell structures inhibit the growth of Gram-positive (S. aureus) and Gram-negative (H. pylori) pathogenic bacteria of clinical relevance.	[85]
Fe3O4–ZnO	Hydrothermal method, 200 °C/18 h.	The average crystallite size of Fe3O4–ZnO: 24 nm (molar ratio 1:5), 20 nm (1:10), and 18 nm (1:20 nm).		Only the lowest concentrations of Fe3O4–ZnO Core–shell nanoparticles are appropriate for biomedical applications.	[87]
Fe3O4–ZnO	Hydro-thermal method, 170 °C/10 h.	7 nm.	60 nm.	The magnetization saturation value of the core–shell nanoparticles is 5.96 emu/g.	[92]
Fe3O4–chitosan–Ag	Suspension technique.	-	-	Ms = 60.06 emu/g for pure Fe3O4; 40.39 emu/g for Fe3O4–chitosan and 46.72 emu/g for Fe3O4–chitosan–Ag bacterial and fungi inhibitors. 99.5% prevention of the growth of microorganisms. 100% inhibition rate of E. coli and S. cerevisiae.	[100]
Fe3O4–heparine–poloxamer (HP)	Ultra-sonication 6 h, room temperature.	The average size of Fe3O4 is 11.6 nm (from TEM).	The average size of Fe3O4–HP is 17.7 nm (from TEM).	Ms = 24.92 emu/g for core–shell structures. Ms = 68.9 emu/g for Fe3O4. DOX-loaded Fe3O4–HP showed a great anticancer effect against HeLa cells. Loading efficiency of DOX into Fe3O4–HP was 66.9 ±2.7%. controlled release up to 120 h without any initial burst effect.	[98]
Fe3O4–PNIPAAm	Polymerization of NIPAAm in the presence of Fe3O4 at 90 °C for 5 days, followed by dialysis. The monomer conversion was about 70%.	20 nm	Spherical particle size of 40 nm in diameter for Fe3O4– PNIPAAm nanoparticles. shell thickness: 10–15 nm.	Anticancer drugs. The highest release percentage of methotrexate (MTX) has been observed at pH = 5.5 and 40 °C. MTX was better for lung cancer than for breast cancer.	[32]

presents the sizes and properties of core, shell, and core–shell nanoparticles in correlation with the synthesis conditions of the core–shell nanostructure.

3. Conclusions and Perspectives

Core–shell nanoparticles are an important class of materials for biomedical applications. This mini-review has been focused on nanoparticles having Fe₃O₄ as a core and various types of shells, especially inorganic ones. It has been shown that medical applications of these nanostructures depend on their size, shape, and properties. The most common morphology is spherically shaped nanoparticles. The most efficient particle sizes seem to be in the range of 6–50 nm.

In some cases, the shell thickness was higher than the core diameter, leading to a decrease in magnetic saturation value, which affects its use as a contrast agent (MRI contrast ability is lower).

Generally, the most suitable nanoparticles for cancer therapy are those with diameters between 10 and 100 nm. Particles with around 10 nm diameter have a higher surface area-to-volume ratio and are more effective for drug delivery and imaging, while particles with approximately 50 nm diameter may be more effective in hyperthermia treatment.

Too small particles (less than 2 nm) can easily leak from the normal vasculature, and particles below 10 nm can be filtered by the kidneys. Particles larger than 100 nm can be cleared from circulation by phagocytes.

Fe₃O₄ core–shell nanoparticles are still under development regarding their use as magnetic contrast agents, hyperthermia agents, or drug delivery systems in clinical applications on human patients. It is necessary to investigate and understand the interaction between core –shell nanoparticles and human tissues before clinical trials.

In hyperthermia, the damaged body tissue is exposed to high temperatures in order to damage and kill cancer cells or make them more sensitive to radiation and anticancer drugs. In magnetic hyperthermia, an external magnetic field is used to control magnetic nanoparticles, which are introduced into the human body through intravenous injection, intratumoral injection, or targeted delivery to damaged organs or tissues. Fe₃O₄ nanoparticles absorb electromagnetic energy and convert it into heat (>41.5 °C). The inductive heating effect of iron oxide nanoparticles appears when an alternating magnetic field suddenly changes the magnetic orientation of the superparamagnetic magnetite particles. Rapid alternation of the magnetic orientation produces particle vibration and further generates heat after internalization, causing cell death when temperatures reach approximately 42 °C. The heat generated by the magnetic nanoparticles can kill cancer cells without damaging healthy tissue.

Another method to treat cancer using Fe₃O₄ core–shell nanoparticles is to apply mechanical pressure to cancer cells in order to cause magnetic particle vibrations, which will finally cause cell death.

Targeted cancer therapies are developed to interrupt the uncontrolled proliferation of cancer cells. Core–shell nanoparticles can be designed to deliver drugs only after entering the tumor tissues. This could reduce side effects and increase the accuracy of tumor targeting with improved treatment efficacy. Fe₃O₄ core–shell nanoparticles present various reactive sites for contact with drugs and can be triggered for binding to specific sites, release the drug at a certain time/temperature/pH, in a controlled manner (shell thickness dependent, ROS-mediated cytotoxicity, microwave-triggered), etc. The drugs embedded in core–shell nanostructures accumulate in cancer cells under the influence of the external magnetic field through enhanced permeability and retention effects.

For nanoparticles, as in the case of medicines, in parallel with the effectiveness, the safety of use is also evaluated. Over the past 40 years, the number and variety of controlled-release drug delivery systems have greatly increased, but despite all the successes achieved, the delivery systems have not been fully accepted due to issues with the regulatory process. Many of the nanoformulations of oncology drugs were retracted from the market, although they had already received Food and Drug Administration (FDA) approval. Newly investigated therapeutic nanoparticles with anticancer properties have some limitations and fail to pass clinical trials. The major drawback is the lack of understanding of the mechanism of nanoparticles’ interaction with biomolecules in the human body. Other important limitations are cellular internalization of the drug (heterogeneous accumulation in the tumor cells). Less than 1% of injected nanoparticles reach the tumor because of the complexity of the tumor; drug release rate; nanoparticles should remain in circulation long enough to allow for significant tumor accumulation; drugs should not be dispersed and distributed in the entire body; nanoparticles that serve as drug nanocarriers should be capable of targeting only tumor cells; and the prediction of the response of the immune system to the newly introduced nanoparticles in the human body tissues.

Researchers are investigating the possibility of creating multifunctional nanoparticles that, after detecting the tumor in the body, can also proceed to its treatment, a fact that would revolutionize oncological practice, replacing the classical therapeutic methods such as chemotherapy and radiotherapy that affect not only cancer cells but also those healthy, destroying them. With the help of nanotechnologies, cancer cells could be destroyed in a targeted manner without harming healthy tissue in any way.

It is necessary to enhance the selectivity and accuracy of delivery for core–shell nanoparticles to target cancer cells. The major challenges are to design nanoparticles that are stable in the patient’s bloodstream and possess improved precision and efficacy for the therapeutic treatment of tumors. Consequently, there is a need to improve synthesis methods to obtain new core–shell nanoparticles for local control of tumors and improved targeted delivery of agents for cancer therapy. Among the synthesis methods briefly presented in this review, hydrothermal synthesis of Fe₃O₄ core–shell nanoparticles combined with phyto-synthesis of one component (either magnetite or shell) using different plant extracts is eco-friendly, cost-effective, and can ensure control of particle size and morphology for tailored applications (drug delivery nanocarriers or magnetic hyperthermia therapy).

In the future, it should be used under mild synthesis conditions of the hydrothermal method: A shorter reaction time (≤3 h) and lower temperature (≤200 °C) coupled with supplementary pressure (from an external source through inert gas bubbling such as Ar or N₂) created in addition to the vapor pressure formed above the reaction system could lead to core–shell nanoparticles with improved properties. Inorganic core–shell precursors such as chloride, nitrate, and sulfate are cheaper than organic–metallic ones and should be further used to avoid any environmental problems created by organic solvents or precursors.

Future research should focus on biological, technological, and design aspects regarding the use of Fe₃O₄ core–shell nanoparticles in cancer treatment. Thus, biological aspects refer to the interactions of core–shell nanostructures in the human body with living cells, organs, and species. An important issue to be solved in the future is what happens with insoluble or very little soluble nondegradable nanoparticles in the human body. Moreover, the linkage between drug-loaded nanoparticles and cells should be studied to understand the mechanism of cellular uptake. Technological aspects refer to scale-up synthesis and performance predictions. It should be possible to find cost-effective synthesis routes capable of yielding large quantities of chemicals that can be produced by pharmaceutical companies. Currently, predicting nanoparticle efficacy and performance in real human tissues is hard because nanoparticle therapy is applied to patients after several classical routes (surgery, chemotherapy, phototherapy, and radiation therapy) have been administered and their immune systems have already been affected by the respective treatment. Computational or theoretical modeling, along with experimental results, can be designed to imitate physiological tissue and the surrounding environment or to study the interaction between drug carriers and cells. The design of drug nanocarriers based on core–shell nanostructures should consider colloidal stability, drug loading capacity, tracking, the release of drug components only at the target sites, biocompatibility, toxicity, and minimal risk (to avoid spreading or accumulation of the drug in other tissues or organs). The particle sizes and size distributions must be reproducible. Fighting cancer is an old dream of physicians and researchers, and it makes them confident that one day the cure for this disease will be discovered.