Magnetic Iron Oxide Nanoparticles: Synthesis and Surface Functionalization Strategies
© to the authors 2008
Received: 8 July 2008
Accepted: 11 September 2008
Published: 2 October 2008
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© to the authors 2008
Received: 8 July 2008
Accepted: 11 September 2008
Published: 2 October 2008
Surface functionalized magnetic iron oxide nanoparticles (NPs) are a kind of novel functional materials, which have been widely used in the biotechnology and catalysis. This review focuses on the recent development and various strategies in preparation, structure, and magnetic properties of naked and surface functionalized iron oxide NPs and their corresponding application briefly. In order to implement the practical application, the particles must have combined properties of high magnetic saturation, stability, biocompatibility, and interactive functions at the surface. Moreover, the surface of iron oxide NPs could be modified by organic materials or inorganic materials, such as polymers, biomolecules, silica, metals, etc. The problems and major challenges, along with the directions for the synthesis and surface functionalization of iron oxide NPs, are considered. Finally, some future trends and prospective in these research areas are also discussed.
Nanoparticle are submicron moieties (diameters ranging from 1 to 100 nm according to the used term, although there are examples of NPs several hundreds of nanometers in size) made of inorganic or organic materials, which have many novel properties compared with the bulk materials . On this basis, magnetic NPs have many unique magnetic properties such as superparamagnetic, high coercivity, low Curie temperature, high magnetic susceptibility, etc. Magnetic NPs are of great interest for researchers from a broad range of disciplines, including magnetic fluids, data storage, catalysis, and bioapplications [2–6]. Especially, magnetic ferrofluids and data storage are the applied researches that have led to the intergration of magnetic NPs in a myriad of commercial applications. Currently, magnetic NPs are also used in important bioapplications, including magnetic bioseparation and detection of biological entities (cell, protein, nucleic acids, enzyme, bacterials, virus, etc.), clinic diagnosis and therapy (such as MRI (magnetic resonance image) and MFH (magnetic fluid hyperthermia)), targeted drug delivery and biological labels. However, it is crucial to choose the materials for the construction of nanostructure materials and devises with adjustable physical and chemical properties. To this end, magnetic iron oxide NPs became the strong candidates, and the application of small iron oxide NPs in in vitro diagnostics has been practiced for nearly half a century . In the last decade, increased investigations with several types of iron oxides have been carried out in the field of magnetic NPs (mostly includes the Fe3O4 magnetite, FeIIFeIII 2O4, ferrimagnetic, superparamagnetic when the size is less than 15 nm), α-Fe2O3 (hematite, weakly ferromagnetic or antiferromagnetic), γ-Fe2O3 (maghemite, ferrimagnetic), FeO (wüstite, antiferromagnetic), ε-Fe2O3 and β-Fe2O3) , among which magnetite and maghemite is the very promising and popular candidates since its biocompatibility have already proven.
However, it is a technological challenge to control size, shape, stability, and dispersibility of NPs in desired solvents. Magnetic iron oxide NPs have a large surface-to-volume ratio and therefore possess high surface energies. Consequently, they tend to aggregate so as to minimize the surface energies. Moreover, the naked iron oxide NPs have high chemical activity, and are easily oxidized in air (especially magnetite), generally resulting in loss of magnetism and dispersibility. Therefore, providing proper surface coating and developing some effective protection strategies to keep the stability of magnetic iron oxide NPs is very important. These strategies comprise grafting of or coating with organic molecules, including small organic molecules or surfactants, polymers, and biomolecules, or coating with an inorganic layer, such as silica, metal or nonmetal elementary substance, metal oxide or metal sulfide. Practically, it is worthy that in many cases the protecting shells not only stabilize the magnetic iron oxide NPs, but can also be used for further functionalization.
In the following, we focus mainly on recent development and various strategies in the preparation, structure and magnetic properties of various surface functionalized strategies of magnetic iron oxide NPs and their corresponding applications, as well as the research advances on functionalizations of magnetic iron oxide NPs worldwide. Further the problems and major challenges still should be solved are pointed out, and the directions in these researches are also discussed.
In the last decades, much research has been developed to the synthesis of iron oxide NPs, and many reports have described efficient synthesis approaches to produce the shape-controlled, stable, biocompatible, and monodispersed iron oxide NPs. The most common methods including co-precipitation, thermal decomposition, hydrothermal synthesis, microemulsion, sonochemical synthesis, and sonochemical synthetic route can all be directed to the synthesis of high quality of iron oxide NPs. In addition, these NPs can also be prepared by the other methods such as electrochemical synthesis [9, 10], laser pyrolysis techniques , microorganism or bacterial synthesis (especially the Magnetotactic bacteria and iron reducing bacteria) [12, 13], etc. As follows, we try to present typical and recent examples for the discussions of each synthetic pathway and the corresponding formation mechanism.
The most conventional method for obtaining Fe3O4 or γ-Fe2O3 is by co-precipitation. This method consists of mixing ferric and ferrous ions in a 1:2 molar ratio in highly basic solutions at room temperature or at elevated temperature. The size and shape of the iron oxide NPs depends on the type of salt used (such as chlorides, sulfates, nitrates, perchlorates, etc.), the ferric and ferrous ions ratio, the reaction temperature, the PH value, ionic strength of the media, and the other reaction parameters (e.g. stirring rate, dropping speed of basic solution). Recently we have reported the co-precipitation synthesis of Fe3O4 NPs and their corresponding morphology, structure, and magnetic properties at different reaction temperature was investigated .
This method would critically affect the physical and chemical properties of the nanosized iron oxide particles. Generally, the saturation magnetization (M S) values found in nanostructured materials are usually smaller than the corresponding bulk phase, provided that no change in ionic configurations occurs . Accordingly, experimental value for M S in magnetic iron oxide NPs have been reported to span the 30–80 emu g−1 range, lower than the bulk magnetic value 100 emu g−1. In addition, Fe3O4 NPs are not very stable under ambient conditions and are easily oxidised to Fe2O3 or dissolved in an acidic medium. In order to avoid the possible oxidation in the air, the synthesis of Fe3O4 NPs must be done in an anaerobic conditions. Based on this point, Fe3O4 NPs can also be utilized to prepare the Fe2O3 NPs by oxidation or anneal treatment under oxygen atmosphere. And oxidation is not the important influence factor for Fe2O3 NPs due to its own chemical stability in alkaline or acidic environment.
However, this method generates particles with a wide particle size distribution, which requires secondary size selection sometimes. A wide particle size distribution will result in a wide range of blocking temperatures (T B) due to T B depends on particle size and, therefore non-ideal magnetic behavior for many applications. Kang et al.  reported a synthesis of monodispersed, uniform, and narrow size distributional Fe3O4 NPs (the diameter of NPs was 8.5 ± 1.3 nm) by co-precipitation without surfactants, the reaction in an aqueous solution with a molar ratio of FeII/FeIII = 0.5 and a pH = 11–12, and the colloidal suspensions of the magnetite can be then directly oxidized by aeration to form colloidal suspensions of γ-Fe2O3. In contrast, many recent publications have described efficient routes to obtain the monodispersed NPs, surfactants such as dextran or polyvinyl alcohol (PVA) can be added in the reaction media, or the particles can be coated in a subsequent step [17, 18]. Surfactants act as protecting agent for controlling particle size and stabilizing the colloidal dispersions.
Additionally, the disadvantage of these aqueous solution syntheses is that the high pH value of the reaction mixture has to be adjusted in both the synthesis and purification steps, and the process toward uniformed and monodispersed NPs has only very limited success. On the other hand, wastewaters with very basic pH values are also generated in the experiment, which require subsequent treatments for protecting the environment.
An organic solution phase decomposition route has been widely used in iron oxide NPs synthesis, and decomposition of Fe(cup)3(cup = N-nitrosophenylhydroxylamine), Fe(acac)3(acac = acetylacetonate), or Fe(CO)5followed by oxidation can lead to high-quality monodispersed iron oxide NPs, which usually requires relatively higher temperatures and a complicated operation.
Sun and Zeng  have reported a general decomposition approach for the synthesis of size-controlled monodispersed magnetite NPs based on high temperature (265 °C) reaction of Fe(acac)3 in phenyl ether in the presence of alcohol, oleic acid, and oleylamine. With the smaller magnetite NPs as seeds, larger monodispersed magnetite NPs of up to 20 nm in diameter can be synthesized and dispersed into nonpolar solvent by seed-mediated growth method. The process does not require a size-selection procedure and is readily scaled up for mass production. The as-synthesized Fe3O4 nanoparticle assemblies can be transformed easily into γ-Fe2O3 NPs by annealing at high temperature (250 °C) and oxygen for 2 h.
Generally, direct decomposition of Fe(Cup)3 single precursor can lead to monodispersed γ-Fe2O3 NPs . The thermal decomposition of Fe(CO)5 produces iron NPs and the following oxidation by a chemical reagent can also lead to monodispersed γ-Fe2O3 NPs . For instance, Hyeon et al.  reported a synthesis of highly crystalline and monodispersed iron NPs without size-selection process by the thermal decomposition of iron pentacarbonyl in the presence of oleic acid at 100 °C. The resulting iron NPs were transformed to monodispersed γ-Fe2O3 nanocrystallites by controlled oxidation using trimethylamine oxide as a mild oxidant. Particle size can be varied from 4 to 16 nm by controlling the experimental parameters.
Although the thermal decomposition method has many advantages for producing highly monodispersed particles with a narrow size distribution, it has the big disadvantage that the resulting NPs are generally only dissolved in nonpolar solvents.
Microemulsion is a thermodynamically stable isotropic dispersion of two immiscible phases (water and oil) under the surfactant present, the surfactant molecules may form a monolayer at the interface between the oil and water, with the hydrophobic tails of the surfactant molecules dissolved in the oil phase and the hydrophilic head groups in the aqueous phase. As in the binary systems (water/surfactant or oil/surfactant), self-assembled structures of different types can be formed, ranging, for example, from (inverted) spherical and cylindrical micelles to lamellar phases and bicontinuous microemulsions, which may coexist with predominantly oil or aqueous phases . In this sense, microemulsion and inverse micelles route can be employed for obtaining the shape- and size-controlled iron oxide NPs.
Particularly, water-in-oil (w/o) microemulsions are formed by well-defined nanodroplets of the aqueous phase, dispersed by the assembly of surfactant molecules in a continuous oil phase. Vidal-Vidal et al.  have reported the synthesis of monodisperse maghemite NPs by the one-pot microemulsion method. The spherical shaped particles, capped with a monolayer coating of oleylamine (or oleic acid), show a narrow size distribution of 3.5 ± 0.6 nm, are well crystallized and have high saturation magnetization values (76.3 Am2/kg for uncoated NPs, 35.2 Am2/kg for oleic acid coated NPs, and 33.2 Am2/kg for oleylamine coated NPs). Moreover, the results show that oleylamine act as precipitating and capping agent. However, cyclohexylamine acts only as precipitating agent and does not avoid particle aggregation. Chin and Yaacob reported the synthesis of magnetic iron oxide NPs (less than 10 nm) via w/o microemulsion, furthermore, in comparison to the particles produced by Massart’s procedure , particles produced by microemulsion technique were smaller in size and were higher in saturation magnetization .
However, despite the presence of surfactants, the aggregation of the produced NPs usually needs several washing processes and further stabilization treatments.
Iron oxide NPs with controlled size and shape are technologically important due to strong correlation between these parameters and magnetic properties. The microemulsion and thermal decomposition methods usually lead to complicated process or require relatively high temperatures. As an alternative, hydrothermal synthesis includes various wet-chemical technologies of crystallizing substance in a sealed container from the high temperature aqueous solution (generally in the range from 130 to 250 °C) at high vapor pressure (generally in the range from 0.3 to 4 MPa). This technique has also been used to grow dislocation-free single crystal particles, and grains formed in this process could have a better crystallinity than those from other processes, so hydrothermal synthesis is prone to obtain the highly crystalline iron oxide NPs.
Several authors have reported the synthesis of iron oxide NPs by hydrothermal method [27–30]. There are two major methods according to whether or not use the specific surfactants. For example, Wang et al.  have reported a one-step hydrothermal process to prepare highly crystalline Fe3O4 nanopowders without using the surfactants. The nanoscale Fe3O4 powder (40 nm) obtained at 140 °C for 6 h possessed a saturation magnetization of 85.8 emu·g−1, a little lower than that of the correspondent bulk Fe3O4 (92 emu·g−1). It is suggested that the well-crystallized Fe3O4 grains formed under appropriate hydrothermal conditions should be responsible for the increased saturation magnetization in nanosized Fe3O4. On the contrary, Zheng et al.  reported a hydrothermal route for preparing Fe3O4 NPs with diameter of ca. 27 nm in the presence of a surfactant, sodium bis(2-ethylhexyl)sulfosuccinate (AOT). The magnetic properties of the NPs exhibited a superparamagnetic behavior at room temperature.
Moreover, hydrothermal treatment is one of the successful ways of growing crystals for iron oxide NPs. Recently Daou et al.  have reported that the magnetite particles with an average size of 39 nm and good monodispersity have been synthesized by co-precipitation at 70 °C from ferrous Fe2+ and ferric Fe3+ ions by a N(CH3)4OH solution, followed by hydrothermal treatment at 250 °C. The magnetite NPs before the hydrothermal step display an average size of 12 nm and are highly oxidized when they are in contact with air. Additionally, hydrothermal synthesis is conductive to prepare the unusual iron oxide nanostructures such as iron oxide nanocubes , iron oxide hollow spheres , etc.
As a competitive alternative, the sonochemical method has been extensively used to generate novel materials with unusual properties. The chemical effects of ultrasound arise from acoustic cavitation, that is, the formation, growth, and implosive collapse of bubbles in liquid. The implosive collapse of the bubble generates a localized hotspot through adiabatic compression or shock wave formation within the gas phase of the collapsing bubble. The conditions formed in these hotspots have been experimentally determined, with transient temperatures of 5000 K, pressures of 1800 atm, and cooling rates in excess of 1010 K/s . These extreme conditions were beneficial to form the new phase, and have a shear effect for agglomeration, which is prone to prepare the highly monodispersive NPs.
This method has been applied for the synthesis of various nanocomposites, and its versatility has been successfully demonstrated in iron oxide NPs preparation . For instance, magnetite NPs can be simply synthesized by sonication of iron(II)acetate in water under an argon atmosphere. Vijayakumar et al.  reported a sonochemical synthetic route for preparing the pure nanometer-size Fe3O4 powder with particle size of ca. 10 nm. The prepared Fe3O4 NPs are superparamagnetic and its magnetization at room temperature is very low (<1.25 emu g−1). Recently Pinkas et al.  developed a sonochemical synthetic method for preparing the amorphous nanoscopic iron oxide by sonolysis of Fe(acac)3 under Ar with a small amount of added water. The organic content and the surface area of the Fe2O3 NPs can be controlled with an amount of water in the reaction mixture, and it increases from 48 m2 g−1 for dry solvent up to 260 m2 g−1 when wet Ar is employed. Such surface modified ultrasmall (1–2 nm) NPs exhibit an unrecorded low magnetic transition temperature of about 25 K, below this temperature they behave as speromagnetic, highly magnetically disordered systems with a high contribution of the surface anisotropy, and this speromagnetic behavior can be observed by Mössbauer spectra.
The five above mentioned synthetic methods have several advantages and disadvantages for preparing iron oxide NPs, respectively. In terms of size and morphology control of the iron oxide NPs, thermal decomposition and hydrothermal synthetic route seems the optimal method. For obtaining the water-soluble and biocompatible iron oxide NPs, co-precipitation often was employed, but this method presents low control of the particle shape, broad distributions of sizes and aggregation of particles. As a time-competitive alternative, sonochemical route can also be used to synthesis iron oxide NPs with unusually magnetic properties. In addition, it is noteworthy that some green chemical synthesis routes and biological synthesis routes have been reported for environment protection purposes. For example, recently Bharde et al.  reported the bacterium Actinobacter sp. is capable of synthesizing maghemite under aerobic conditions when reacted with the ferric chloride precursors. Moreover, maghemite NPs show superparamagnetic characteristics as expected. Therefore, as the enviromental protection and eco friendliness-competitive alternative, green chemistry and biological methods such as bacterially induced synthesis based synthesis of iron oxide NPs are important advances.
In the following sections, the recent development and various strategies for obtaining surface functionalized iron oxide NPs by organic and inorganic materials will be discussed.
In the preparation and storage of ferrofluids, the stability is of utmost importance. Organic compounds are often employed to passivate the surface of the iron oxide NPs during or after the preparing procedure to avoid agglomeration. The main reasons for magnetic iron oxide NPs have hydrophobic surfaces with a large surface area-to-volume ratio if in the absence of any proper surface coating, and the hydrophobic interactions between the NPs will cause them to aggregate and form large clusters, resulting in increased particle size. Additionally, in order to expand the biological application scope of the iron oxide NPs, some biomolecules are also employed to enhance its biocompatibility.
Organic compounds functionalized iron oxide NPs provide not only the basic magnetism characteristics of magnetic NPs, but also possess good biocompatibility and biodegradability of the functional organic materials. Moreover, organic moleculars can provide the ensemble functional reactive group, e.g. aldehyde groups, hydroxyl groups, carboxyl groups, amino groups, etc. It is crucial that their groups can link to the active biosubstance such as antibody, protein, DNA, enzyme, etc., for the further application. In the following section, the organic small molecules, macromolecules or polymer and biological molecules functionalized iron oxide NPs and the corresponding properties will be discussed.
A suitable surface functionalization and choice of solvent are crucial to achieving sufficient repulsive interactions to prevent agglomeration so as to obtain a stable colloidal solution and further expand the scope of application. According to the surface characteristics of the functionalized NPs, small molecules or surfactants functionalized iron oxide NPs can be simply divided into three types: oil-soluble, water-soluble, and amphiphilic. Oil-soluble type refers to the surface of functionalized iron oxide NPs containing the molecular which have a weak attraction for the solvent environment, it is generally hydrophobic group, such as the fatty acid, alkyl phenol (n = 6–10, linear or branched). Conversely, water-soluble type refers to the surface of functionalized iron oxide NPs containing the chemical groups which have a strong attraction for the solvent environment, it is generally hydrophilic groups, such as the ammonium salt, polyol, lycine. Amphiphilic type refers to the surface of functionalized iron oxide NPs containing both hydrophilic and hydrophobic chemical groups, the main chain of these functionalized small molecules or surfactants showed concurrence of hydrophobic and hydrophilic structural regions, which also will make the functionalized NPs possess both oil-solubility and water-solubility, such as sulfuric lycine.
Oil-soluble type functionalization employed in order to prevent or decrease the agglomeration of iron oxide NPs and increase the stability give rise to the monodispersity, for instance, iron oxide NPs frequently dispersed in long-chain substance of hexadecane, the classic example being oleic acid (CH3(CH2)7CH=CH(CH2)7CO2H), which has a C18 tail with a cis-double-bond in the middle, forming a kink. Such kinks have been postulated as necessary for effective stabilization, and indeed stearic acid (CH3(CH2)16CO2H) with no double-bond in its C18 tail, cannot stabilize the iron oxide NPs [7, 40–42]. Additionally, Oleic acid is widely used in ferrite nanoparticle synthesis because it can form a dense protective monolayer, thereby producing highly uniform and monodisperse particles. However, relative to the naked iron oxide NPs, the average diameter of functionalized NPs will increase in the range of 0–5 nm, and its saturation magnetization (M S) almost unchanged.
Several authors have reported the magnetic iron oxide NPs coated or dispersed in the oil-soluble organic molecules. Shaoo et al.  have reported the surface-coated magnetite NPs with a 6–8 nm average diameter by oleic acid, lauric acid, dodecyl phosphonate, hexadecyl phosphonate, and dihexadecyl phosphate etc., they found that alkyl phosphonates and phosphates could be used for obtaining thermodynamically stable dispersions of magnetite NPs. The organic molecules’ ligands seem to form a quasi-bilayer structure with the primary layer strongly bonded to the surface of the NPs. This study demonstrates that alkyl phosphonates and phosphates bind efficiently to iron oxide particle surfaces, the good biocompatibility of phosphonate and phosphate ligands may advance the utilization of encapsulated magnetic NPs in medical applications, such as MRI and other biophysical purposes. Bourlions et al.  have reported the synthesis of capped ultrafine γ-Fe2O3 NPs under anaerobic conditions by the thermal treatment of a hydrated iron(III) hydroxide caprylate gel in boiling tetraline and by retention of the organophilic mantle around the parent particle throughout the final solid. The capped particles, which possessed a spherical morphology and an average size of 4 nm, were easily solvated in organic solvents to provide stable and homogeneous magnetic organosols.
However, the oil-soluble type functionalized iron oxide NPs are relatively easy to prepare and control. Currently the mainly research focus are the synthesis of water-soluble type functionalized iron oxide NPs with water solubility (good disperse in aqueous environment, can not produce agglomeration), biological compatibility (good for protein, antibody, biotin, DNA etc., low cytotoxicity, low effect their activity), and biodegradability. Water-soluble functionalized iron oxide NPs can be widely utilized in bioseparation and biodetection.
Several routes were employed for obtaining the water-soluble functionalized iron oxide NPs. One method is to directly add the biocompatible small organic molecules such as amino acid , citric acid [43, 46], vitamin [47, 48], cyclodextrin [49–51], etc. during the synthesis procedure. Recently Xia et al.  reported a facile synthetic approach for preparing water-soluble Fe3O4 NPs with a surrounded layer by use of polyethylene glycol nonylphenyl ether (NP5) and cyclodextrin (CD) in aqueous medium. Moreover, the author had also built nanostructured spherical aggregates (mosaic type structure) from individual functionalized NPs (core-shell type structure) and which can be tailored by the concentration of NP5 and CD. These mesoporous aggregates of magnetite NPs can be used in magnetic carrier technology. Though this direct method has many advantages, owing to small organic molecules do not have good stability especially in an alkaline or acidic environment, it often decomposes and results in the functionalized iron oxide NPs agglomeration. Furthermore, the morphology of functionalized iron oxide NPs often presents as an aggregate clusters.
We have prepared magnetite NPs with average diameter 25 ± 5 nm by modified chemical co-precipitation, and silane bridged surface tailoring are exploited to obtain amino-coated and thiolated magnetite NPs via corresponding APTES and MPTES modification, respectively. The result reveals that the surface functionalized magnetic particles have a slight dimensional increase in average diameter while retain almost original saturation magnetization; APTES is prone to maintain the morphology of the magnetite NPs, but MPTES has an outstanding hypochromic effect though it caused a slight decrease in the saturation magnetization. The finding is of practical significance for magnetic NPs applications associated with bioconjugation, target carriers, and biosensing . In addition, silanes were found to render the iron oxide NPs highly stable and water-dispersible, and it was also found to form a protective layer against mild acid and alkaline environments. Moreover, silane ligand-exchange reaction can make the hydrophobic iron oxide NPs into water-dispersible .
Although most studies have focused on the development of small organic molecules and surfactants coating up to now, recently polymers functionalized iron oxide NPs are receiving more and more attention, owing to the advantages of polymers coating will increase repulsive forces to balance the magnetic and thevan der Waals attractive forces acting on the NPs. In addition, polymers coating on the surface of iron oxide NPs offer a high potential in the application of several fields. Moreover, polymer functionalized iron oxide NPs have been extensively investigated due to interest in their unique physical or chemical properties. To make use of these materials for fundamental or applied research, access to well-defined NPs samples whose properties can be “tuned” through chemical modification is necessary. In a number of cases it has now been shown that, through careful choice of the passivating and activating polymers and/or reaction conditions, can produce NPs with tailored and desired properties.
Organic macromolecules and their advantages of functionalized iron oxide NPs
Enables optimum polar interactions with iron oxide surfaces, improves the blood circulation time, stability, and biocompatibility
Improves the biocompatibility, good for MRI, and drug target delivery
Used as a gelling agent, hydrophilic emulsifier, biocompatible
Non-toxic, alkaline, hydrophilic, widely used as non-viral gene delivery system, biocompatible, and hydrophilic
Enhance the hydrophilicity and water-solublility, improves the biocompatibility, blood circulation times
Poly(vinyl alcohol) (PVA)
Prevents agglomeration, giving rise to monodispersibility
Poly(lactide acid) (PLA)
Improves the biocompatibility, biodegradability, and low toxicity in human body
Improves the stability and biocompatibility
Generally used as thermosensitive drug delivery and cell separation
Polyacrylic acid (PAA)
Improves stability and biocompatibility as well as bioconjugation
Moreover, polymer are often employed to make up the deficiency of small organic molecules and surfactant for the purpose of obtaining the surface functionalized iron oxide NPs. Therefore, besides the above research focus, how to prepare the functionalized iron oxide NPs with ideal chemical stability and good biocompatibility remains the great challenges. The right choice of organic materials can provide a structure suitable for obtaining the well-controlled functionalized NPs. For example, Frankamp et al. [99, 100] developed an approach for direct controlling the magnetic interaction between iron oxide NPs through dendrimer-mediated self-assembly. The resulting assemblies featured systematically increasing average interparticle spacing over a 2.4 nm range with increasing dendrimer generation. This increase in spacing modulated the collective magnetic behavior by effective lowering of the dipolar coupling between the particles. The dependence of blocking temperature on interparticle spacing was found to point toward a much more dramatic interdependence at close interparticle spacing, and a weaker correlation at larger spacing. Overall, the development of other methods for constructing the surface engineering of iron oxide NPs is of great important.
Various biological molecules such as protein [101, 102], polypeptide , antibody [104, 105], biotin and avidin , etc., may also be bound to the surface of iron oxide NPs directly or indirectly by chemically coupling via some functional endgroups to make the NPs target specific. The biological molecules functionalized iron oxide NPs will greatly improve the particles’ biocompatibility. Such magnetic NPs can be very useful to assist an effective separation of proteins, DNA, cells, biochemical products, etc.
With appropriate surface chemistry, biomolecules can immobilize on iron oxide NPs. Zhang et al.  have reported a microemulsion approach to prepare a human serum albumin (HAS)-coated Fe3O4 magnetic NPs as a radioisotope carrier labeled with 188Re and explored the optimal labeling conditions with 188Re. The procedure for preparing HAS-coated Fe3O4 magnetic NPs as follows: With cotton oil as oil phase, a mixture of HSA and magnetite solution as water phase and Span-83 as emulsion agent. The mixture of the above two solutions was ultrasonicated for 15 min, then added rapidly dropwise into cotton oil at 130 °C under stirring condition. The diameter of HSA-coated magnetic NPs was about 200 nm. The particles can be labeled with 188Re for the purpose of in vivo regional target therapy.
In contrast, the major strategy for surface functionalization by biological molecules includes two steps, first synthesizing the small molecules or polymers functionalized NPs, and then coupled to the biomolecules by chemical bond or physical adsorption. Recently, Lee et al.  developed a route for conjugating the γ-Fe2O3 NPs with single strand oligonucleotides. The water-soluble magnetic NPs with carboxyl groups on their surfaces were prepared at first, and then by using 1-ethyl-3-(3-dimrthylaminopropyl)carbodiimide hydrochloride (EDC) as a liker reagent, they successfully modified a protein, streptavidin, on the surface of γ-Fe2O3 NPs. Streptavidin functionalized Fe2O3 can catch a biotin-labeled single strand oligonucleotides through the strong affinity between streptavidin and biotin.
Additionally, superparamagnetic iron oxide core of individual NPs becomes more efficient at dephasing the spins of surrounding water protons, enhancing spin−spin relaxation times (T2 relaxation times) so that the NPs act as magnetic relaxation switches (MRS) . Based on this phenomenon, Perez and colleagues  have developed biocompatible magnetic nanosensors that act as MRS to detect molecular interactions in the reversible self-assembly of disperse magnetic particles into stable nanoassemblies recently. MRS technology can be used to detect different types of molecular interactions (DNA-DNA, protein-protein, protein-small molecule, and enzyme reactions) with high efficiency and sensitivity using magnetic relaxation measurements MRI. Furthermore, the magnetic changes are detectable in turbid media and in whole-cell lysates without protein purification. The developed magnetic nanosensors can be used in a variety of biological applications such as in homogenous assays, as reagents in miniaturized microfluidic systems, as affinity ligands for rapid and high-throughput magnetic readouts of arrays, as probes for magnetic force microscopy, and potentially for in vivo imaging. For instance, oligonucleotides functionalized iron oxide NPs aggregate in the presence of target oligonucleotides (20 pM limit), resulting in a measurable increase (30 ms) in the T2 relaxation times of the surrounding water. It was further discovered that base pair insertions in the target strand resulted in only 2–5 ms increases in the relaxation times, while single base pair mismatches resulted in 1–21 ms increases in T2, indicating that these systems could potentially be used to selectively detect DNA mutations.
Although there have been many significant progresses in the synthesis of organic materials functionalized iron oxide NPs, simultaneous control of their shape, stability, biocompatibility, surface structure, and magnetic properties is still a challenge. As an alternative, inorganic compound functionalized iron oxide NPs can greatly enhance the antioxidation properties for naked iron oxide NPs, and its corresponding scope of application has been greatly extended. Moreover, inorganic compounds functionalized iron oxide NPs are very promising for application in catalysis, biolabeling, and bioseparation. The applied coating inorganic materials include silica, metal, nonmetal, metal oxides, and sulfides. Composite NPs can roughly be divided into two major parts: preserved the magnetic property of iron oxides and preserved the other properties of inorganic materials.
This section, the interest arises from the possibility of combining the magnetic and the other properties by entrapping magnetic iron oxide NPs in the other inorganic compound layers, or by connecting magnetic iron oxide NPs with the other inorganic materials. We enumerate some typical and recent examples for the discussions of each feasible method and the corresponding properties and application of composite NPs.
Silica is the most common compound for preparing the functionalized iron oxide NPs, silica-coated iron oxide NPs have several advantages as follows: (a) this coating provides not only the stability to the iron oxide NPs in solution, but also avoids the interparticle interactions and prevent agglomeration generating, (b) this composite NPs possess a good biocompatibility, hydrophilicity and stability, and (c) the technology of preparation for size tunable composite NPs is already mature, and its variation of the shell thickness is relatively easy to control. In addition, silica-coating helps in binding the various biological or the other ligands at the NPs surface for various applications. For instance, Ashtari et al.  have reported an effective method for recovery of target ssDNA based on amino-modified silica-coated Fe3O4 NPs.
At present, the Stöber methods, sol–gel process, and aerosol pyrolysis are the prevailing choices for coating iron oxide NPs with silica. In general, silica coating will increase the size of particles and the magnetic properties of composite NPs also will change. It is noteworthy that silica thickness from 5 to 200 nm can be tuned by varying the concentration of ammonia and the ratio of tetraethoxysilane (TEOS) to water, moreover, silica coating was easily preformed on the iron oxide NPs’ surface through hydroxyl groups in the aqueous environment, especially using the Stöber method and sol–gel process. This resulted in better dispersion and less aggregation of the magnetic particles. The current research focus is further extended the function of silica functionalized iron oxide NPs, and obtains the magnetic composites with tunable structure and good dimension stability.
For obtaining the magnetic composites with tunable structure and good dimension stability still remains challenges, many skillful approaches have successfully been employed. Lu et al.  reported a sol–gel procedure that leads to uniform silica-coated iron oxide NPs, and their shell thickness can be adjusted by controlling the amount of precursors (TEOS) added to the 2-propanol solution. Fluorescent dyes have also been incorporated into the silica shells by covalently coupling these organic compounds with the sol–gel precursor. These multifunctional NPs are potentially useful in a number of areas because they can be simultaneously manipulated with an externally applied magnetic field and characterized in situ using conventional fluorescence microscopy. An alternative method to prepare these NPs with uniform silica shells and tailored thickness is to use microemulsion method, also known as the water-in-oil (W/O) microemulsion process, which has three primary components: water, oil, and surfactant . Homogeneous SiO2-coated Fe2O3 core-shell NPs with controlled silica shell thickness from 1.8 to 30 nm had been synthesized by reverse microemulsion .
The aerosol pyrolysis method has recently arisen as a facile, rapid method to obtain NPs with relevant properties. Especially, by taking advantage of the subtle interplay between the parameters controlling NPs formation in aerosol process, it is possible to obtain either a continuous, three-dimensional network of particles (present a matrix structure) or a hollow structure. Moreover, aerosol pyrolysis has also been used for silica coating, but the structure of composite NPs commonly is the mosaic type, such as hollow silica spheres with iron oxide shells. Taetaj et al. [117, 118] described this method for the synthesis of superparamagnetic hollow silica spheres and the shell containing γ-Fe2O3 nanocrystals with the size range from 4 to 10 nm. The spherical composites were prepared by aerosol pyrolysis of a methanol solution containing tetraethoxysilane and iron nitrate and further annealing in a conventional furnace. And it was observed that the blocking temperature (T B) strongly depends on nanocomposite size, the enhancement of the effective magnetic anisotropy with respect to the bulk γ-Fe2O3 can be considered as coming fundamentally from surface anisotropy .
From the above examples, it can be seen that silica functionalized iron oxide NPs is a facile process. In this case, great progress in the field of silica-coated iron oxide NPs have been made, some research results have also being transformed into commercial application [120, 121].
Another facile route to protect the iron oxide NPs is to induce a controlled oxidation of a pure single-metal or nonmetal shell, such as gold, silver, platinum, palladium, iron, carbon etc. The control of the single-metal or nonmetal layer has a tremendous impact on the scope of iron oxides’ application, particularly to expand its scope of biomedical and catalyst application. For instance, gold is often employed to passivate the surface of magnetite NPs to avoid oxidation. We need to notice that the gold, silver, and carbon single-metal functionalization will conduce the descend of the iron oxide NPs’ saturation magnetization (M s) value, but the result of cobalt, platinum, copper, palladium single-metal functionalization may be opposite, depending on the mass magnetic susceptibility (χ) value of the used materials. In addition, the diameter of metallic or nonmetallic functionalized iron oxide NPs is prone to tailoring, and the necessary diameter can be obtained by controlling the reduction and repeat times.
In general, there are two ways for preparing the metal functionalized iron oxide NPs, one is direct reduction of the single-metal ions on the surface of iron oxide NPs. Mandal et al.  have reported that the Fe3O4 NPs were separated, coated with noble metal gold and silver by directly reducing the Au+ and Ag+, respectively, to achieve stability of the magnetic NPs for a long time, this route yielded structures of size from 18 to 30 nm, although the author claims that the NPs possess a well-defined core-shell structure, the TEM micrograph of samples cannot directly reflect. Data also showed that the saturation magnetization (M s) of gold-coated is 38 emu g−1 (T = 10 K) and it is reduced by 57.6% from the bulk Fe3O4 NPs (92 emu g−1 T = 10 K). Generally, this method often applies to prepare the core-shell type composite NPs, but it is prone to maintain the magnetic properties of naked iron oxides.
Taking into account the application prospects of magnetic record and magnetic ink materials recently, most studies have focused on the development of carbon-coated iron oxide magnetic NPs (such as carbon-encapsulated magnetic NPs), the carbon shell not only protected the iron oxide NPs from rapidly degraded by environment, but it also prevented the NPs’ agglomeration caused by van der Waals attraction. Though carbon-coated will cause the reduction of saturation magnetization, the other magnetic properties will change little. Moreover, carbon functionalized iron oxide NPs have many advantages over the other materials, such as much higher chemical and thermal stability as well as biocompatibility. Recent methods offer new alternatives for the controlled synthesis of novel, stable, and functional iron oxides/C NPs. Wang et al.  reported the preparation of Fe3O4/C nanocomposition by heating the aqueous solution of glucose and oleic acid-stabilized magnetite NPs. Dantas et al.  reported the synthesis of iron oxides/C composites, and it can be used in the treatment of textile waste water as heterogeneous catalysts in the Fenton reaction. Though carbon-coated iron oxide NPs have many advantageous properties, the synthesis of monodispersed composite NPs in isolated from is currency one of challenges in this field.
Furthermore, single-metal functionalized iron oxide NPs (especially noble metal functionalized iron oxide NPs, and mostly take the direct method by reducing the single-metal ions on the surface of iron oxide NPs) also used as catalysts, such as Au/Fe2O3 catalyst for CO oxidation [129, 130], Au/α-Fe2O3 catalyst for water-gas shift reaction [131, 132], Fe3O4/Pd nanoparticle-based catalyst for the cross-coupling of acrylic acid with iodobenzene  and decarboxylative coupling reaction in aqueous media , Ag-Fe3O4 catalyst for epoxidation of styrene , etc. These heterogeneous catalysts with a matrix structure generally as the magnetically recyclable catalysts (MRCs) are developed in recent years and can be very useful to assist an effective separation and recovery in a liquid-phase reaction by a magnet, especially when the catalysts are in the nanometer-sized range and possess higher activities than their pure and bulk single-metal or nonmetal counterparts [136, 137]. Therefore, the development of the facile and rapid methods for the preparation of efficient MRCs is still a challenge.
There have been abundant researches concerning the metal oxides or metal sulfides functionalized iron oxide NPs, mainly because of its importance of unique physical or chemical properties. In general, researches primarily concentrate on common materials (ZnO, MgO, CaO, SnO2, Al2O3 etc.) [141–144], magnetic materials (iron oxides, CoO, NiO, CoFe2O4, etc.) , optical and electrical functional materials (TiO2, ZnS, Y2O3, etc.) [146–148].
Recently common materials coated on the surface of iron oxide NPs are receiving more attention, because it usually imports metal oxides’ special properties. Li et al.  reported a chemical displacement procedure that leads to air-stable Fe3O4@Al2O3 core-shell NPs. The NPs are rather uniform and they claim that it with captured phosphopeptides were directly deposited on the MALDI (matrix-assisted laser desorption/ionization) target for analysis due to its high magnetic response. Hong et al.  reported ZnO-coated magnetite core-shell NPs were obtained by coating the Fe3O4 NPs with direct precipitation using zinc acetate and ammonium carbonate. They claim that the functionalized NPs’ antioxidation ability is much better than the naked Fe3O4 NPs. However, the particles obtained are not very uniform and its saturation magnetization (M s) decrease from 67.78 to 20.33 emu/g.
Magnetic materials coated on the iron oxide NPs usually have a dramatic influence on the magnetic properties. The combination of two different magnetic phases will lead to new functionalized iron oxide NPs, with many possible applications. Cheon et al. [6, 151] reported the fabrication of highly ordered binary Fe3O4@CoFe2O4 NPs by superlattices transition; the preparation process shows a unique ferrimagnetic phase transformation behavior through nanoscale redox chemical reactions, the particles’ saturation magnetization have been greatly enhanced, and its coercivity (H C) increased from 580 to 15,000 Oe.
Although in this review there are various strategies for obtaining the functionalized iron oxide NPs, the results have shown that three major effectivenesses as follows: (a) Improves the biocompatibility and chemical stability, and tailors the dispersibility and water solubility; (b) Endows the iron oxide new physico-chemical properties, such as magnet-optical properties, magnetic-electrical properties, magnetic-thermal properties, etc.; (c) Provides the iron oxide new functional endgroups for the subsequent functionalized procedures or the subsequent applications, such as conjugation with the DNA, antibody, protein, etc.
In the coming years, despite all the recent progresses made, it is still a challenge to be faced that synthesis of high-quality functionalized magnetic iron oxide NPs with a tunable sizes and shapes in a controlled manner. Moreover, synthesis and surface engineering of iron oxide NPs involves complex chemical, physical, and physicochemical multiple interactions, it is the another challenge to understand the synthetic mechanisms detailedly. However, the magnetic properties and function of naked or surface functionalized iron oxide NPs depend upon their physical properties: the size and shape, their microstructure, and the chemical phase in which they are present . Luckily, several physicochemical techniques have been developted to determine these parameters.
Therefore, how to improve the stability and availability of functionalized iron oxide NPs in extreme environmental conditions, how to develop an efficient and orderly magnetic micro- or nano-assembly structures, and how to realize large-scale or industrial synthesis, these problems are urgent to be solved for obtaining a ideal functionalized iron oxide materials.
For all that, we still believe the surface functionalization and modification of magnetic iron oxide NPs to introduce additional functionality will attract more and more attention. Furthermore, multifunctional magnetic iron oxide composite nanoparticle systems with designed active sites will promise for a various applications, such as catalysts, magnetic recording, bioseparation, biodetection, etc. The future work in this area must be focused on the research of the toxicity and degradability of naked or surface functionalized iron oxide NPs, and preparing it via green chemistry for reducing the environmental pollution as much as possible. Successful development in this area will aid the growth of the various scientific researches or industrial applications as well as improving the quality of life in the population.
W. Wu thanks all the colleagues during past collaborations at the HUT who have contributed to the work described here: Lei Zeng, Jingke Huang, Rong Hu and Professors Jianxin Tang and Hong Chen. This review is a dedication to all of them.