Nano‐Metamaterial: A State‐of‐the‐Art Material for Magnetic Resonance Imaging

Metamaterials are artificially designed materials with multilevel‐ordered microarchitectures, which exhibit extraordinary properties not occurring in nature, and their applications have been widely exploited in various research fields. However, the progress of metamaterials for biomedical applications is relatively slow, largely due to the limitations in the size tailoring. When reducing the maximum size of metamaterials to nanometer scale, their multilevel‐ordered microarchitectures are expected to obtain superior functions beyond conventional nanomaterials with single‐level microarchitectures, which will be a prospective candidate for the next‐generation diagnostic and/or therapeutic agents. Here, a forward‐looking discussion on the superiority of nano‐metamaterials for magnetic resonance imaging (MRI) according to the imaging principles, which is attributed to the unique periodic arrangement of internal multilevel structural units in nano‐metamaterials, is presented. Moreover, recent advances in the development of nano‐metamaterials for high‐performance MRI are introduced. Finally, the challenges and future perspectives of nano‐metamaterials as promising MRI contrast agents for biomedical applications are briefly commented.

DOI: 10.1002/smsc.202300015 Metamaterials are artificially designed materials with multilevel-ordered microarchitectures, which exhibit extraordinary properties not occurring in nature, and their applications have been widely exploited in various research fields. However, the progress of metamaterials for biomedical applications is relatively slow, largely due to the limitations in the size tailoring. When reducing the maximum size of metamaterials to nanometer scale, their multilevelordered microarchitectures are expected to obtain superior functions beyond conventional nanomaterials with single-level microarchitectures, which will be a prospective candidate for the next-generation diagnostic and/or therapeutic agents. Here, a forward-looking discussion on the superiority of nano-metamaterials for magnetic resonance imaging (MRI) according to the imaging principles, which is attributed to the unique periodic arrangement of internal multilevel structural units in nano-metamaterials, is presented. Moreover, recent advances in the development of nano-metamaterials for high-performance MRI are introduced. Finally, the challenges and future perspectives of nano-metamaterials as promising MRI contrast agents for biomedical applications are briefly commented. magnetic resonance imaging (MRI), etc.) have played an important role in preclinical and clinical research. [12][13][14][15][16] Among these, MRI is a noninvasive and radiation-free imaging technique with excellent soft tissue resolution, which is widely applied in clinical diagnosis, such as various malignant lesions, tissue necrosis, and local ischemia. [17] The utilization of MRI contrast agents can accelerate the longitudinal (T 1 ) or transverse (T 2 ) relaxation of surrounding water protons, thus improving the signal-to-noise ratio and imaging contrast. [18] The structure of contrast agents determines the imaging capability, [19] and thus the development of high-performance MRI contrast agents via exquisite structural regulation is helpful to achieve accurate diagnosis of major diseases even at the early stage. [20] Compared with conventional contrast agents, including paramagnetic small-molecule complexes and simple magnetic nanoparticles with single-level microarchitectures, [21] the magnetic nano-metamaterials exhibit unique structural properties of ordered multilevel multiscale periodically arranged microarchitectures, which necessarily possess extraordinary imaging performance and could carve out a new horizon in the field of MRI ( Figure 2). In this Perspective, the unique advantages of nano-metamaterials for MRI are discussed, as well as their recent advances and future developments are commented.

Superiority of Nano-Metamaterial for MRI
Most clinically available MRI contrast agents are paramagnetic gadolinium ionic (Gd 3þ ) complexes, which produce positive T 1 contrast and brighten the area of the target. [22] However, their usage is limited by fast excretion and undesirable side effects. [23] Therefore, a wide range of research has been focused on the investigation of nanoparticle-based MRI contrast agents. [24,25] Compared with conventional molecular coordination complexes, nanoscale contrast agents show several outstanding advantages, including markedly improved contrast effect, long blood  [2] Copyright 2016, Springer Nature. b) Schematic illustration of a ferroelectric nano-metamaterial with a 2D Archimedean lattice structure. Reproduced under the terms of the CC-BY Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0). [11] Copyright 2015, The Authors, published by Springer Nature.
In contrast to conventional nanoparticulate contrast agents with single-level microarchitectures, the unique multilevel microarchitecture of nano-metamaterials can alter a variety of imagingrelated parameters, thus inducing a coordinative effect to improve the MRI performance ( Figure 3). In this regard, we present a detailed description of the superiority of nano-metamaterials for MRI according to the imaging principles. Typically, based on the classical Solomon-Bloembergen-Morgan (SBM) theory, the longitudinal relaxivity (r 1 ) of T 1 contrast agents can be modeled as following [45] As shown in Equation (1), the r 1 value of T 1 contrast agents consists of three portions, including inner sphere relaxivity (r 1 IS ), second sphere relaxivity (r 1 SS ), and outer sphere relaxivity (r 1 OS ), among which, the r 1 IS that arises from the water protons directly binding to the paramagnetic ions of T 1 contrast agents is the most important contributor for r 1 value. [46] In Equation (2)-(4), q is the number of water molecules in the inner sphere; T 1m and τ m are the T 1 relaxation times and residency times of water protons in the inner sphere; τ C is the correlation time for describing the fluctuating magnetic dipole; τ R represents the rotational correlation times of T 1 contrast agents; r CH is the distance between the metal ions and water molecules; T 1e describes the electronic T 1 relaxation process; μ 0 , γ H , g e , μ B , S, and ω H are constants that represent the permeability of the vacuum, the gyromagnetic ratio of the proton, the electric g-factor, the Bohr magneton, the total electron spin of the paramagnetic ions and the proton Larmor frequency, respectively.
The T 1 contrast effects of conventional nanoparticle-based contrast agents are mainly attributed to the interactions between paramagnetic ions (e.g., Fe 3þ , Gd 3þ , Mn 2þ , etc.) on nanoparticle surfaces and surrounding water molecules. [41] In contrast, nanometamaterials with dense multilevel periodic structures can facilitate the access of water molecules to their internal paramagnetic ions and trap water molecules in the interstices of their complicated microarchitectures, endowing them with larger q and longer τ m than that of conventional nanoparticulate contrast agents. Moreover, the immobilization of paramagnetic ions in nanometamaterials extremely limits their free rotation, leading to an increase in the τ R . According to Equation (1)-(4), with large q as well as long τ m and τ R , nano-metamaterials can significantly accelerate the T 1 relaxation times of water protons, thereby, exhibiting an appreciable T 1 contrast effect. In contrast, the development of superparamagnetic nano-metamaterials is also desirable for T 2 -weighted MRI. Benefiting from their dense multilevel-ordered periodic arrangement of the substructure, the overall crystallinity, rigidity, and magnetism, nano-metamaterials are expected to exhibit a remarkable contrast enhancement compared with previously reported nanosized contrast agents with single-level microarchitectures, which can intensify the perturbation of nuclear spin relaxation of surrounding water protons under an applied magnetic field, [47] thus achieving significantly enhanced T 2 contrast effect.  Apparently, the complex microhierarchical structure of nano-metamaterials greatly contributes to their MR contrast capability, which can be readily modulated to obtain high-performance MRI contrast agents. The cutting-edge nano-metamaterials with outstanding imaging performance have a broad application prospect in the monitoring of previously undetectable biological entities in living systems.

MRI Application of Nano-Metamaterials
Metamaterials with multilayered and multilevel microstructures exhibit distinctive properties that are progressively applied in biomedical fields, including wearable stretchable sensors, [48] and transdermal drug delivery systems. [49] However, the synthetic limitations, such as size control, remain significant challenges for the development of well-defined nano-metamaterials as cutting-edge imaging probes for biomedical imaging applications. As a result, despite nano-metamaterial is theoretically a highly promising candidate for MRI, practical MRI applications using nano-metamaterial are extremely scarce. Indeed, conventional nanomaterials with single-level microarchitectures follow the law of minimum energy, [50] while the construction of hierarchical nano-metamaterials is relatively challenging from the point of thermodynamics. A system in thermodynamic equilibrium has a constant frequency-dependent effective temperature (T eff (ω)), where deviation from the T eff (ω) will lead to the generation of a new structure with a new equilibrium state. [51] However, the thermodynamic process only depends on the T eff (ω), which limits the freedom degrees of architectural regulation. [52] In contrast, the time-dependent dynamic pathway owns multiple variable parameters, providing opportunities for creating various nonequilibrium structures under a T eff (ω)-constant system. [53] Accordingly, Ling, Wang, and co-workers [52] proposed a pioneering dual-kinetic control strategy to fabricate multilevel multiscale nano-metamaterials by manipulating dynamic processes in a thermodynamically constant system, where the two independent kinetic pathways, nonsolvent-induced block copolymer (BCP) self-assembly and osmotically driven self-emulsification could be simultaneously regulated (Figure 4a). Utilizing this strategy, multilevel multiscale Fe 3þ -"onion-like core porous crown" nanoparticles (Fe 3þ -OCPCs), which consist of two substructures: 1) an onion-like core; and 2) a hierarchical porous corona, were successfully prepared (Figure 4b,c). Notably, the number and size of the pores in the hierarchical microarchitectures of Fe 3þ -OCPCs can be precisely controlled by changing the concentration of Fe 3þ (Figure 4d). Moreover, as shown in Figure 4e, the Fe 0.02 3þ -OCPCs and Fe 0.06 3þ -OCPCs exhibited an excellent T 1 contrast effect with r 1 values of 10.48 and 13.39 mM À1 s À1 , respectively, which were 2.5-and 3.4-fold higher than that of homogeneous Fe 0.06 3þ -poly(2-vinylpyridine) (P2VP) nanoparticles (4.21 mM À1 s À1 , 3.0 T), primarily attributed to the distinctive hierarchically ordered multilevel structure of Fe 3þ -OCPCs. On one hand, the hierarchical porous corona facilitates the sufficient contact between paramagnetic Fe 3þ and surrounding water protons, which is conducive to promoting the T 1 relaxation of water protons. On the other hand, the onion-like core accommodated multilayers of block polymer can increase the magnetic dipolar interaction and local viscosity of Fe 3þ , thus prolonging the τ m of Fe 3þ -OCPCs by limiting the mobility of water molecules nearby paramagnetic Fe 3þ (Figure 4f ). Accordingly, compared with homogeneous Fe 3þ -P2VP, Fe 3þ -OCPCs exhibited superior T 1 contrast enhancement effect in vivo and effectively light up tumors 30 min after injection (Figure 4g). Therefore, such a dual-kinetic control strategy with two independent dynamic processes represents an effective strategy for constructing well-defined nano-metamaterials, which serves as a proof-of-concept to demonstrate that the architectural regulation of nanoparticles is important for MRI performance. Nevertheless, the colloid stability of current nano-metamaterials in biological environments needs to be further improved. . Schematic illustration of the mechanism for the enhanced T 2 and T 1 relaxation of water protons in magnetic nano-metamaterials. Regarding T 2 relaxation rates, the dense multilevel periodically arranged microarchitectures of nano-metamaterials contribute to a significant enhancement of the overall magnetization, and thus affecting the diffusion rate of water protons. Besides, the unique structural features of nano-metamaterials can promote the interaction of water molecules with the internal paramagnetic ions, and trap water molecules in the interstices of their complicated microarchitectures, which lead to larger q, longer τ m ; and τ R than those of conventional nanoparticulate contrast agents, thus accelerating the T 1 relaxation of water protons.
www.advancedsciencenews.com www.small-science-journal.com Moreover, the precise size control of nano-metamaterials is imperative for broader MRI applications in living systems.

Future Perspective
Owing to the multilevel-ordered microarchitectures, nanometamaterials hold great potential in developing next-generation high-performance MRI contrast agents, which is attributed to their capability to enhance the important parameters affecting the relaxation times of water protons, such as hydration number, rotational correlation times, water residence times, magnetic perturbation, and potential others. However, one should be aware that the development of nano-metamaterials as MRI contrast agents is still in the proof-of-concept stage, and several challenges remain to be addressed before further expanding their biomedical imaging applications.
First, the precise control and regulation of the size, multilevel microarchitecture, and magnetic property of nano-metamaterials are urgently needed to ensure the tunable MRI performance. Especially, controllable large-scale production of nanometamaterials with a maximum size down to <100 nm is necessary for in vivo delivery and imaging. Therefore, more efforts should be devoted to optimizing nano-metamaterials based on the dual-kinetic strategy via adjusting reaction conditions, such as T eff (ω), solvents, and reactants. Besides, the further development of other advanced synthetic approaches for the controllable fabrication of nano-metamaterials is highly desired. Second, the surface ligands of nano-metamaterials can directly influence their microarchitectures, colloidal stability, and  disease-targeting capability. Since the complex biological environments would greatly affect the biological fates of nanometamaterials, the increasing understanding of nano-bio interactions and the optimization of the surface modification are extremely helpful to obtain highly efficient nano-metamaterials for in vivo imaging. Third, to develop a new class of diagnostic agents based on nano-metamaterials with multilevel multiscale microarchitectures, the relationship among the synthesis parameters, microarchitectures, and biological properties of nanometamaterials has to be comprehensively and systematically studied, which is expected to provide a valuable theoretical basis for extensive biomedical applications. Additionally, the ultimate goal of biomedical imaging is to provide guidance for further disease treatment. Accordingly, various therapeutic agents, such as functional nanoparticles, molecular drugs, and bioactive proteins, can be introduced into the layered microstructure of nano-metamaterials to construct multifunctional systems with integrated imaging and therapeutic functions, for highperformance imaging-guided therapy of major diseases, including malignant tumors, cardiovascular diseases, and neurodegenerative diseases. All in all, the multilevel, multiscale, and complexity exhibited by the microarchitecture of nano-metamaterials endow them with significant superiority as next-generation MRI contrast agents. We anticipate the ingeniously designed highperformance nano-metamaterials shall greatly promote groundbreaking medical diagnosis research and elucidate unknown life phenomena, spearheading the new era of 21st-century precision medicine.