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) ^[1][2][3][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 ^[1][4][48,51]. These properties are significantly enhanced compared to pure compounds ^[4][51]. The interaction between the core and the shell of a nanostructure can lead to new properties and functions ^[5][45].

There are numerous core–shell materials with various applications and much literature about their classification and detailed descriptions of the preparation method.

Fe₃O₄ can be coated with different types of shells, such as metals (Ag, Au) ^{[6][7][8][9][10]}[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 ^[11][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.

Silver-coated Fe₃O₄ nanohybrids have been used in a broad range of applications, including chemical and biological sensors ^[1][12][48,57], drug delivery—as successful drug carriers with focused antimicrobial, anticancer properties ^[1][13][48,58], diagnosis, and cancer therapy ^[1][14][15][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 ^[12][16][17][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 ^{[14][18][19][20]}[44,59,63,64]. Spherical core–shell structures with 7–80 nm are obtained in these cases ^{[12][14][16][17][18][19][20]}[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 ^[13][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 ^[16][61], improving the contrast of magnetic resonance imaging (MRI) in cancer detection ^[1][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 ^{[21][22][23][24][25][26][27][28]}[65,66,67,68,69,70,71,72] for gold-coated magnetite nanostructures. In 2023, Danafar et al. ^[21][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 ^[22][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 ^{[23][24][25][26][27]}[67,68,69,70,71].

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. ^[4][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.

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 ^[29][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 ^{[11][30][31][32][33][34][35]}[3,74,75,76,77,78,79]. Fe₃O₄ nanoparticles coated with SiO₂ shells obtained by Ta et al. through hydrolysis and condensation ^[31][75] showed increased biocompatible properties and provided new ideas for future bioconjugation studies ^[11][3]. Moreover, the Fe₃O₄–SiO₂ core–shell structure prepared by Lu et al. using an ultrasound-assisted method ^[36][80] has good opportunities in the field of biomedicine ^[11][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 ^[37][38][39][43,81,82]. The coating of magnetite nanoparticles with a TiO₂ shell protects the core from environmental damage and improves biocompatible properties ^[37][43]. Fe₃O₄–TiO₂ core–shell structures with various Fe₃O₄:TiO₂ molar ratios were synthesized by a modified sol–gel method ^[40][83] or hydrothermal process ^[41][84]. The obtained Fe₃O₄–TiO₂ core–shell nanorods are superparamagnetic and could be further used for magnetic hyperthermia applications ^[37][43].

Fe₃O₄–ZnO core–shell nanoparticles represent some of the most studied materials for magnetic hyperthermia and bio-imaging applications ^{[42][43][44][45][46][47]}[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) ^[48][49][50][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 ^[43][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 ^[51][93]. In 2021, Gupta et al. ^[42][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. ^[45][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 ^[45][87].

Magnetite surface coating with natural or synthetic polymers has been widely investigated ^{[11][52][53][54][55][56][57][58][59]}[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. ^[54][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 ^[55][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 ^[57][98]. Moradi et al. ^[52][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.