For macromolecular agents, due to their complex structure with numerous functional groups, the two approaches, ligand exchange and ligand adsorption are usually applied together to form a more stable structure. By ligand exchange or ligand adsorption, polymers with multiple functional groups can be expediently combined with MNPs. Because of the same reaction process, polymer coating usually needs the help of active terminal groups. Various monomeric species, such as bisphosphonates, DMSA and alkoxysilanes, have been evaluated to facilitate attachment of polymer coatings on MNPs.^{[19, 38]} In polymer coatings, polymers form a barrier among MNPs to avoid agglomeration and provide varieties of surface properties. Most biocompatible MNPs developed for in vivo applications need to be stabilized and functionalized with coating materials. The coating moieties can affect the relaxation of water molecules in various forms, such as diffusion, hydration and hydrogen binding.^[5] In the research, these coatings also serve to link MNPs with biomolecules or to change the surface charge or chemical environment. Moreover, polymer coatings improve the colloidal stability of NPs.^[39] Due to the complex structures of polymers, there are many aspects that affect the surface performance of MNPs (for example, the molecular weight, the properties of terminal groups and the conformation of the polymers).

Quite a few natural and synthetic polymers have been demonstrated in polymer coating of MNPs.^{[2, 23, 40, 41]} The glycans such as dextran or chitosan are widely used in polymer coatings.^{[42, 43]} Chitosan, a biodegradable natural polymer, is derived by deacetylation of chitin obtained from the shells of crustaceans. It has many biological applications because of its biological activities, biocompatibility, high charge density, low toxicity toward mammalian cells and ability to improve dissolution. Weissleder and his group research dextran coated iron oxide nanoparticles and derivative magnetic nanoparticles. Their work on monocrystalline iron oxide nanoparticles (MION)^[44] and cross-linked iron oxide (CLIO) nanoparticles^[45] found that dextran-coated superparamagnetic iron oxide nanoparticles were a very suitable platform for the synthesis of multifunctional imaging agents.^[46] Hyeon et al. developed chitosan oligosaccharide-stabilized ferrimagnetic iron oxide nanocubes (Chito-FIONs) as an effective heat nanomediator for cancer hyperthermia.^[47] The Chito-FIONs' magnetic heating ability is superior to that of commercial superparamagnetic iron oxide nanoparticles, enabling eradication of cancer cells through caspase-mediated apoptosis.

Another frequently-used polymer is polyethylene glycol (PEG).^{[48– 50]} PEG is a flexible water-soluble polymer. The high hydrophilicity of PEG chains can render the MNP core soluble and stabilized in aqueous media. PEG has been demonstrated to reduce uptake by macrophages^[31] sharply, so as to increase the blood circulation time in vivo. By changing the molecular weight of PEG, the thickness of the coating can be controlled.^{[49, 51]} PEG-derivative modified MNPs were prepared by post-synthesis coating. With increasing molecular weight, the number of branched chains and functionalities, higher stability and better dispersion can be attained. Sun et al.synthesized heterobifunctional PEG ligands using 3-(3, 4-dihydroxyphenyl) propanoic acid and PEG as reactants (Fig. 4).^[52] They successfully modified porous hollow NPs (PHNPs) of Fe₃O₄ via this ligand and achieved targeted delivery and controlled release of the cancer chemotherapeutic drug cisplatin. However, a PEG shell is unfavorable for uptake of MNPs by most cells. To solve this problem, these MNPs can be modified by hyaluronic acid (HA), a targeting moiety, for uptake by stem cells.^[53] A recent study reported that different terminal groups partly affected the MRI images of MNPs.^[54]

Other polymers such as cellulose, poly (ethylene oxide) (PEO), poly (vinyl alcohol) (PVA), poly(acrylic acid) (PAA) and poly (lactide-co-glycolide) (PLGA) are also used for polymer coatings of MNPs. PLGA and cellulose are Food and Drug Administration (FDA) approved for a variety of uses in humans and commonly employed for drug delivery and oral formulations. Xu et al. used a single emulsion method to obtain oleic acid-stabilized iron oxide NPs (10 nm core size) encapsulated in PLGA.^[55] The PLGA coating gave the NPs a much higher r₂ relaxivity than normal SPIO nanoparticles. Hong et al. synthesized novel polymeric nanoparticles (YCC-DOX) composed of poly (ethylene oxide)-trimellitic anhydride chloride-folate (PEO-TMA-FA), doxorubicin (DOX) and superparamagnetic iron oxide.^[56] These NPs show unusually high MRI sensitivity, comparable to a conventional MRI contrast agent, despite their lower iron content. Lin et al. prepared PAA modified GdVO₄ NPs by filling PAA hydrogel into GdVO₄ hollow spheres. The PAA@ GdVO₄ NPs can act as a dual mode agent for MRI and up-conversion imaging and be applied for pH-dependent drug release due to their hollow structure.^[57]

Fig. 4.

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	Fig. 4. Schematic of surface modification of hollow NPs with heterobifunctional PEG ligands.[52] Reproduced with permission from Ref. [52]. Copyright 2009 American Chemical Society.

To gain specificity and reduce side effects and toxicity, biomarker targeted functional proteins or peptide fragments, such as RGD targeting α _vβ ₃ integrin, HER2/neu antibodies, urokinase type plasminogen activator (uPA) amino-terminal fragments (ATF), and single chain anti-epidermal growth factor receptor (EGFR) antibodies, have been conjugated on the surface of MNPs, so that the nanoprobes would be recognized and internalized by tumor cells expressing a specific receptor.

Fig. 5.

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	Fig. 5. Schematic illustration of the encapsulation process for DOX-SPIO.[50] Reproduced with permission from Ref. [50]. Copyright 2008 Elsevier Ltd.

Other applications in polymer coatings are also beneficial. To simplify the coating procedures, researchers have developed “ one-pot” methods, a series of copolymers can now be used to accomplish in situ coating of MNPs.^[58] Nevertheless, the growth of nanocrystals can be influenced as a result of the presence of polymers, leading to abnormal structures and surfaces of MNPs (Fig. 5).^[59] Polymers or macromolecules such as peptides or PEG have the conformation to form a monolayer by self-assembly; ^[60] consequently polymer coatings can be formed by self-assembly on the surface of MNPs.^{[59, 61– 64]} Polymer coatings’ effects on NP magnetic properties is also a research field.^{[43, 65, 66]} Gao et al. reported novel multifunctional polymeric micelles composed of a chemotherapeutic agent doxorubicin (DOXO) and a cRGD ligand.^[65] They demonstrated that each micelle loaded a cluster of superparamagnetic iron oxide (SPIO) nanoparticles inside, allowing the micelles to be tracked by ultrasensitive MRI detection of the MNPs.

As one of the earliest tools for drug delivery in nanomedical practice, liposome techniques have been developing for a long time. Liposome are composed of a lamellar phase lipid bilayer, so they are usually biocompatible. Having a bilayer structure, amphipathic liposomes can encapsulate MNPs and can have diameters ranging from 100 nm to 5 μ m. Thus, another advantage of liposome encapsulation is to gather a certain number of MNPs for collective delivery to the target. For these reasons, liposome complexes are an ideal platform for delivery of contrast agents in MRI.^{[67, 68]}

Polymeric micelles offer the advantage of multifunctional carriers that can serve as delivery vehicles carrying nanoparticles, hydrophobic chemotherapeutics and other functional materials and molecules. Stimuli-responsive polymers are especially attractive since their properties can be modulated in a controlled manner. Due to its large encapsulation range, molecules, proteins, DNA and MNPs can all be encapsulated by liposome as one unit.^[69]

Coating MNPs with inorganic agents is generally accomplished by chemical reaction. Silica is most widely used for surface modification via an inorganic coating. Silica-coated MNPs always form core-shell structures. Silica has many advantages over organic coatings. Silica-coated NPs are robust, water-soluble, colloidally stable and photostable.^{[70, 71]} Serving as protective coatings, silica shells are easy to synthesize with controlled size. The general method to produce silica coating can be divided into two types: classical Stober method^{[72– 74]} (in aqueous phase) and sol-gel method^{[75– 77]} (in both aqueous and oleic phase).

The functionalization of silica shells is similar to ligand adsorption. This inevitably makes the diameter of the modified MNPs too large, which affects the biocompatibility, fluidity, stability and magnetic performance of the MNPs. To control the thickness of the silica shell, researchers have utilized tetraethoxysilane (TEOS) as the source of silica, controlled reaction conditions very carefully, and finally obtained diameters from 10 nm to 1 μ m.^{[77– 79]} Zhang et al. studied the regulation of the controlled synthesis of Fe₃O₄@SiO₂ core-shell nanoparticles via a reverse microemulsion method.^[80] They found that the thickness of the silica shell increased with the size of the aqueous domain. This result can guide us to avoid the formation of core-free silica particles (Fig. 6).

Fig. 6.

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	Fig. 6. The coating mechanism of SiO2 on the surface of Fe3O4NPs.[80] Reproduced with permission from Ref. [80]. Copyright 2012 American Chemical Society.

With controlled size, silica shells are appropriate for encapsulation of NPs and organic molecules like dyes or drugs. Salgueirino-Maceira et al. encapsulated Fe₃O₄ NPs and CdTe quantum dots within composite silica spheres.^[81] These silica spheres can serve as both luminescent and magnetic nanomaterial. Zhu et al. accomplished the same function by embedding a dye molecule inside the silica shell.^[82] Researchers also focus on the synthesis of various other core-shell structures. Deng et al. synthesized superparamagnetic microspheres with an Fe₃O₄@SiO₂ core and a perpendicularly aligned mesoporous SiO₂ shell (Fig. 7).^[83] The microspheres possess very high magnetization, large surface area, large pore volume, and uniform, accessible mesopores. Wu et al. reported a silica nanoshuttle as a drug delivery system with a nanoscale PEGylated-phospholipid coating and a 13-(chlorodimethylsilylmethyl)heptacosane-derived mesoporous silica NP.^[84] The therapeutic and imaging agents were trapped and ligand-assisted targeted delivery was achieved through surface functionalization of the phospholipids. Recently, silica shells with foamed or porous structures have received more attention do to the convenience of loading and releasing drugs.^{[85, 86]}

Fig. 7.

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	Fig. 7. Synthesis route of Fe3O4@nSiO2@mSiO2.[83] Reproduced with permission from Ref. [83]. Copyright 2008 American Chemical Society.

A robust core-shell structure, silica coated MNPs can be functionalized with various biomolecules. The silica shell tends to adsorb molecules, but silane coupling agents can significantly inhibit this process.^{[87, 88]} These agents always consist of siloxy (linking with silica shells) at one side and biocompatible groups like amino, sulfydryl and so on (linking with biomolecules) or even biomolecules themselves that already incorporate a silane group at another side. Biomolecules can easily be added to the outer shells by using alkoxysilanes with active groups, such as aminopropylsilane (APS) or mercaptopropylsilane (MPS).^{[89– 92]}

The metallic elements used for surface modification are relatively inert in order to act as a protective layer. The coating metal and MNPs are tightly coupled through a chemical reaction process. The metal coating is more easily bio-functionalized than the bare surface of MNPs.

Gold is the major element among noble metal coatings. Due to strong conjugation with sulfur, gold offers remarkable advantages in sulfydryl-containing surface coatings.^{[93, 94]} Because of the chemical inertness of gold, forming gold shells is difficult, so gold coated MNPs are completely stable. Zhong et al. produced gold-coated iron oxide nanoparticles via a reduction of gold precursors on iron oxide nanoparticles of selected sizes as seeds.^[94] Williams et al. synthesized gold-coated iron oxide NPs via iterative hydroxylamine seeding. The gold-coated particles exhibit a surface plasmon resonance peak that blue-shifts from 570 to 525 nm with increasing Au deposition and the magnetic properties of NPs are largely independent of Au addition. In addition to core-shell structures, Au-coated MNPs with heterostructures are widely used in medical practice (Fig. 8).^{[95, 96]} Gold also has a good photothermal property. Kim et al. fabricated a new gold nanorod (GNR) conjugated with MNP composite.^[97] The GNR-MNP performed very efficiently as a photothermal agent for repeated cycles of photothermal ablation of bacteria.

Fig. 8.

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	Fig. 8. Synthesis process of Au-Fe3O4 nanoparticles.[95] Gold nanoparticles are attached to the surface of Fe3O4 nanoparticles. Reproduced with permission from Ref. [95]. Copyright 2007 American Chemical Society.

Silver is another element among noble metal coatings. Silver coating makes MNPs germicidal, ^[98] because silver has very strong sterilization ability. The study of silver coating is very similar to that of gold. Silver can also form both core-shell structures and heterostructures.^{[99, 100]} Chen et al.synthesized Fe₃O₄@C@Ag hybrid nanoparticles.^[101] Owing to the carbon and silver on its surface, this nanoprobe, synergistically combining NIR-controlled drug release and the two imaging modes of MRI and two-photon fluorescence (TPF) imaging, could lead to a multifunctional system for medical diagnosis and therapy. Sometimes researchers utilize gold and silver together, looking for better biomedical properties.^[102]

Some rare earth elements can be also be used in surface modification via the formation of core-shell structures. For example, an Fe₃O₄@NaLuF₄:Yb, Er/Tm core-shell nanostructure with multifunctional properties was developed by step-wise synthesis (Fig. 9).^[103] Comprising an Fe₃O₄ core and a NaLuF₄ shell, this class of nanoprobes combines the merits of three imaging modes, upconversion luminescence (UCL), MR and computed tomography (CT), and is suitable for various applications requiring different spatial resolutions and imaging depths.

Fig. 9.

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	Fig. 9. Synthesis process of Fe3O4@NaLuF4 nanoparticles.[103] Reproduced with permission from Ref. [103]. Copyright 2012 Elsevier Ltd.