Magnetic nanoparticles have been widely used in a variety of applications, especially in biomedical fields such as magnetic resonance imaging (MRI), ^{[1– 5]} magnetic separation, ^{[6– 10]} magnetic hyperthermia therapy, ^{[11– 16]} and drug delivery.^{[17– 20]} With the growing concern for the prevention and treatment of cancer, research into MRI diagnosis and magnetic hyperthermia therapy, which are commonly referred to as “ theranostics, ” ^[15] has accelerated. One key issue is to improve the magnetic properties of theranostic agents to achieve early detection and efficient treatment for cancer.^[21] Already, superparamagnetic nanoparticles (SPIOs) have been widely investigated as theranostic agents, and some have been commercially available for many years.^{[22– 25]} It is widely accepted in this field that a stable suspension for biomedical applications can be achieved only by using SPIOs. The non-superparamagnetic nanoparticles possess remanance which may lead to undesired agglomeration. Unfortunately, small SPIOs with low saturation magnetization have limits in theranostic applications. Designing and optimizing the size, composition, shape, and surface of magnetic nanoparticle coatings is reported to improve the performance of theranostic agents.^{[4, 26– 37]} However, in the development of these theranostic agents, their efficiency has reached its limit, because their saturation magnetization is comparable to that of bulk materials.^{[38, 39]} In addition, introducing other magnetic elements (such as Co and Mn) to increase the magnetic moment may raise concerns about toxicity. Seeking a new class of theranostic agents to replace SPIOs might be an alternative way to solve this problem, but such research encountered a bottleneck in the past. Thus, finding a new approach to design and develop magnetic nanoparticles with good suspension and improved magnetic properties as well as significantly enhanced theranostic performance is becoming important and urgent.

At nanoscale, size and shape effects play important roles in the magnetic properties of nanostructures.^{[40– 42]} The size effect results in single-domain ferromagnetic/ferrimagnetic and superparamagnetic nanoparticles, which have attracted intense interest due to their extraordinary potential for biomedical applications. When shape changes at a nanoscale, new magnetization configurations appear. Different shapes prefer different magnetic domain structures for energy minimization, leading to tremendous variation in magnetic properties. To fully exploit the size and shape effects at nanoscale and realize optimum properties for targeted applications, the understanding of nanomagnetism, control of magnetic properties and development of related synthetic methods are of great importance.

The discovery of magnetic vortex-domain nanorings/nanodiscs has brought a novel approach for forming a good suspension and improving magnetic properties. To achieve a stable vortex-domain structure, the dimensions of the nanorings/nanodiscs must be carefully manipulated. For example, outer diameter, height and inner-to-outer diameter ratio are the key parameters for nanorings to be located in the exact region of the stable vortex area.^[43] In particular, this unique magnetic structure endows nanorings/nanodiscs with negligible or decreased remanence and coercivity — greatly reducing dipole– dipole interactions and enabling good colloidal stability — but with much higher saturation magnetization and larger hysteresis loops than SPIOs. Under an external field, nanorings/nanodiscs undergo magnetic moment reversal processes and move along the field direction rapidly. Therefore, nanorings/nanodiscs with magnetic vortex-domain structure have emerged as a new material for theranostic applications.

In this review, we aim to provide an overview of recent developments in the chemical synthesis of magnetic vortexdomain nanorings/nanodiscs and developments in their applications. We first introduce the general principles of nanomagnetism and magnetic vortex-domain. We then discuss chemical synthesis of magnetic vortex-domain nanorings/nanodiscs. Toward the end, the potential applications of the nanorings/nanodiscs in biomedicine are highlighted.

Characterization of magnetic nanoparticles might address many magnetic properties. The basic properties are the types of response to a magnetic field (including ferromagnetic/ferrimagnetic/superparamagnetic, paramagnetic and antiferromagnetic).^{[44, 45]} The magnetization curve characterizes this magnetic behavior of magnetic nanoparticles. For ferromagnetic/ferrimagnetic materials, the magnetic properties are typically of interest, such as saturation magnetization (M_s), remanence magnetization (M_r) and coercivity (H_c) can be obtained from the hysteresis loop (Fig.  1(a) and Fig.  1(d)). Figure  1(b) illustrates the dependence of coercivity on particle size. To minimize its magnetostatic energy, a ferromagnetic/ferrimagnetic particle needs to possess multiple magnetic domain structures. For particles smaller than a certain critical value, the energy required to create a domain wall is greater than the demagnetizing energy, enforcing a single-domain state. In this state, coercivity reaches a maximum at critical size, associated with the transition from multi-domain to the single domain. Further decreasing particle size results in a steep decrease of the H_c due to the assistance of thermal energy k_BT (k_B and T are the Boltzmann constant and temperature) in the switching process.^[42] When particle size is reduced to a level where the magnetic anisotropy energy (KV) (K and V are the effective anisotropy constant and the nanoparticle volume) is much smaller than k_BT, the spins rotate freely, without any external field. Such a nanoparticle is said to be superparamagnetic. As shown in Fig.  1(c), the M– H curve of SPIOs shows no hysteresis. The forward and backward magnetization curves coincide completely and the area is almost negligible, indicating the anhysteretic nature. Magnetic nanoparticles in a superparamagnetic state do not tend to agglomerate, enabling suspension of the particles. Most experimental work in this field to date has used SPIOs. However, SPIOs’ weak magnetic interaction offsets their M_s.^[30] Moreover, the usefulness of SPIOs suffers from surface effects, due to their high specific surface, which also offsets M_s, because of surface spin disorder in this case.^[46] In addition, due to the decreased saturation magnetization, high magnetic fields, which may harm the human body, are required to manipulate these nanoparticles. Conversely, if magnetic particles with high saturation magnetization are fabricated, agglomeration may occur, owing to the large M_r. As shown in Figs.  1(c) and 1(d), under an applied magnetic field, the magnetic moment of the domains of ferromagnetic/ferrimagnetic particles and single-domain superparamagnetic particles are aligned. After removal of the applied magnetic field, ferromagnetic/ferrimagnetic particles maintain a net magnetization.

Fig.  1.

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Fig.  1. (a) A typical hysteresis loop of a ferromagnetic/ferrimagnetic material. (b) Schematic illustration of the dependence of coercivity on particle size. (c) and (d) Typical hysteresis loops of a superparamagnetic nanomaterial and a ferromagnetic/ferrimagnetic nanomaterial. Under a magnetic field, the magnetic moments of the domains of ferromagnetic particles and single-domain superparamagnetic particles are aligned. After removal of the magnetic field, ferromagnetic particles maintain a net magnetization.

Magnetic vortex structures offer a new opportunity to achieve stable suspension and high saturation magnetization simultaneously. The hysteresis loop of a magnetic vortex nanoring is shown in Fig.  2(d). Due to the enclosed domain without stray fields, the M_r and H_c of magnetic vortex nanorings are close to zero. At the same time, in comparison with SPIOs, the magnetic vortex nanoring, larger in size, has a much higher M_s. This makes magnetic vortex nanostructures a promising candidate for diverse biomedical applications.

Fig.  2.

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Fig.  2. (a)– (c) Observed remanence states of the magnetite nanorings within the vortex region of the ground state phase diagram at β = (a) 0.4, (b) 0.6, (c) 0.8.[43] Reprinted with permission from Ref.  [43]; Copyright 2012, AIP Publishing, LLC. (d)– (e) Magnetic states during switching when field is parallel to nanorings[43] and nanodisc[59] The cartoons are schematic diagrams of the corresponding domain structures. The unit 1  Oe = 79.5775  A/m. Reprinted with permission from Ref.  [43], copyright 2012, AIP Publishing, LLC. Reprinted with permission from Ref.  [59], © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The flux-closure vortex domain structure, where the spins align circularly, is a common magnetic state in magnetic nanorings/nanodiscs and has been intensively studied.^{[47– 60]} In particular, the vortex-domain structure is sensitive to nanoring dimensions.^[43] Our group has performed three-dimensional (3D) Landau– Liftshitz– Gilbert (LLG) micromagnetic simulations for magnetite nanorings. Figures  2(a)– 2(c) illustrate the observed remanence states of the magnetite nanorings within the vortex region of the ground state phase diagram at β = 0.4, 0.6 and 0.8 (β = D_in/D_out) with the applied magnetic field along the x direction. The symbols represent computed points. We concluded that only the few areas highlighted by dashed lines were stable vortex areas.

Under an external magnetic field, the magnetic vortex state transforms into another state, which is closely related to the geometric shape of the nanomaterials.^{[47, 48]} Figures  2(d) and 2(e) provide examples of reversal processes in magnetic nanorings and nanodiscs, simulated by Yang et al. For magnetic vortex-domain nanorings, the hysteresis loop is typically of a two-step magnetization reversal process involving an onion-to-vortex transition and then a transition from vortex to the reverse onion state.^{[43, 61, 62]} As illustrated in Fig.  2(d), at H = 0 (vortex state), the magnetization circulates around the ring without stray field. As H increases, a new magnetic domain with opposite chirality nucleates. When H is larger than the switching field H_s, the onion state appears with two opposite head-to-head domain walls. Figure  2(e) presents a domain evaluation of a nanodisc. Obviously, at H = 0, the transition occurs from saturation state (i) to the c-state (ii). As H increases, a vortex core moves in from the edge of the nanodisc and forms a vortex state (iii). When H further increases, the vortex core moves gradually toward the opposite edge. The nanodisc is saturated until the vortex core disappears (iv). In contrast to magnetic vortex-domain nanodiscs with high energy vortex core, the vortex state in rings is a stable magnetic configuration. Based on the theory simulation of magnetic vortex-domain colloid, Fan et al. were first to propose a colloid of magnetic vortex nanorings for biomedical applications.^{[43, 63, 64]} The M– H curve (Fig.  2(d)) reveals there is no remanence for magnetic vortex nanorings. For fields sweeping from positive to negative saturation, the onion state maintains at remanence and the transition from onion to vortex state occurs abruptly at a certain field. The vortex state leads to weak magnetic interactions of nanorings that can be utilized to facilitate a magnetic nanoring suspension. The unique vortex structure and high saturation magnetization can provide strong local field inhomogeneity and large hysteresis, resulting in an extremely large relaxivity in MRI and extremely large specific absorption rate (SAR) in magnetic hyperthermia, respectively. In addition, a dispersion consisting of vortex nanorings can provide a fast, strong response under relatively small external field to meet the increasing demands of biological applications.

Controllable synthesis of magnetic nanorings/discs is a key for forming a stable vortex-domain structure and pursuing its biomedical applications. The prevailing strategy for preparing magnetic nanorings/discs is the solvothermal method.^{[54, 65– 68]}

Fig.  3.

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Fig.  3. (a) (top) Typical synthesis of magnetic nanorings; (bottom) SEM image and HRTEM of prepared Fe3O4 nanorings; inset is a selected area electron diffraction (SAED) image[64] Reprinted with permission from Ref.  [64], © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. (b) (top) Schematic illustration for the synthesis of Fe3O4 nanodiscs; [59] (bottom) SEM image and HRTEM of prepared Fe3O4 nanodiscs; inset is an SAED image[59] Reprinted with permission from Ref.  [59], © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Single-crystalline magnetic nanorings were fabricated by hydrothermal growth of hematite (α -Fe₂O₃) nanorings and post reduction. Fan et al.^{[65, 66]} reported that α -Fe₂O₃ nanorings could be formed through hydrothermal treatment of FeCl₃ in the presence of NH₄H₂PO₄. In this case, NH₄H₂PO₄ could covalently adsorb onto α -Fe₂O₃ crystal planes parallel to the c axis and react with α -Fe₂O₃ to form a dissolvable complex in solution, which can serve as either a surfactant to induce anisotropic growth or an etching agent. As a result, hollow nanorings can be obtained during this coordination-assisted dissolution process. By varying the concentration of FeCl₃ and NH₄H₂PO₄, the size of hematite nanorings can be modulated. Figure  3(a) shows the overall scheme for the synthesis of spinel MFe₂O₄ nanorings. The insets are optical images of Fe₃O₄ and α -Fe₂O₃ nanorings. The obtained α -Fe₂O₃ nanorings can be further transformed into cubic spinel magnetite Fe₃O₄, maghemite γ -Fe₂O₃ or ferrite MFe₂O₄ (M = Co, Mn, Ni, Cu) by using a thermal transformation process, without changing their size and shape. Both the scanning electron microscope (SEM) and high-resolution transmission electron microscope (HRTEM) analysis reveal that the as-prepared Fe₃O₄ nanorings have uniform size and shape and a single crystal nature.

High quality Fe₃O₄ nanodiscs are fabricated by a twostep chemical synthesis, as shown in Fig.  3(b). Chen et al.^[68] were first to report an alcohol-thermal reaction for the fabrication of uniform α -Fe₂O₃ nanodiscs. Hexagonal α -Fe₂O₃ nanodiscs have been successfully grown via a simple ethanolthermal route in the presence of ethanol with the addition of acetate sodium. Acetate anions in acetate sodium can covalently adsorb onto α -Fe₂O₃ (0001) surfaces and control the growth along the specific direction. The size can be finely tuned by the selective use of alcohol solvent with an increasing presence of carbon atoms in the linear alkyl chain. α -Fe₂O₃ nanodiscs are successfully converted into Fe₃O₄ nanodiscs by a hydrogen-wet reduction method. Using this method, high quality Fe₃O₄ nanodiscs are fabricated as shown in Fig.  3(b) (bottom).

Exceptional progress has been achieved in synthesis, vortex-domain structure control, and biomedical applications of magnetic vortex nanorings/nanodiscs, as described in this review. Magnetic vortex nanorings/nanodiscs are new platforms for theranostic applications. Chemical synthesis of magnetic nanorings/nanodiscs with vortex domain structure has progressed enormously. Both in vitro and in vivo studies have demonstrated their potential as diagnostic and therapeutic agents. However, several problems still require considerable work to be solved before magnetic vortex nanorings/nanodiscs are fully established for clinical translation. For example, synthesis of magnetic vortex nanorings/nanodiscs with very small size (10  nm– 50  nm) is still challenging. Producing different shapes of nanostructures with vortex-domain magnetic structure is a big problem that needs to be solved. Magnetic vortex domain nanostructure is expected to be functionalized with targeting ligands so that the cellular uptake is more targetable and controllable. The biodistribution, targeting efficiency, toxicity, biodegradability and clearance of magnetic vortex domain nanostructures also need to be studied further. In depth understanding of the magnetic vortex domain will provide a guideline to produce magnetic vortex nanostructures for other applications, such as thermosensitive drug release for cancer treatment. It is expected that magnetic vortex domain structure will be widely applied in magnetic, biomedical and nanotechnology fields.