Research Progress | APM Advances Ultrasensitive Molecular Magnetic Resonance Imaging with Multivariate Metal-Organic Frameworks

    Recently, the research group led by Prof. Xin Zhou at the Innovation Academy for Precision Measurement Science and Technology, CAS, developed a multiligand engineering strategy to construct multivariate metal-organic frameworks (MTV-MOFs) for ultrasensitive magnetic resonance molecular imaging. Building on the physical signal amplification provided by hyperpolarized ₁₂₉Xe, the team precisely tailored the pore microenvironment of metal-organic frameworks (MOFs) to modulate their interactions with ₁₂₉Xe. By integrating this approach with hyperpolarized ₁₂₉Xe chemical exchange saturation transfer (Hyper-CEST), the researchers achieved a six-order-of-magnitude enhancement of the hyperpolarized ₁₂₉Xe magnetic resonance signal through a chemical–physical cascade amplification process. This advance promotes the application of MOFs in ultrasensitive magnetic resonance molecular imaging and expands their potential in biomedicine. The findings were recently published in the Journal of the American Chemical Society, titled “Engineered multivariate metal-organic frameworks for magnetic resonance molecular imaging signal enhancement”.

    Hyperpolarized ₁₂₉Xe MRI is a highly sensitive, background-free imaging technique that has been applied to the detection of major pulmonary diseases. Using the advanced hyperpolarization technology, the Ultrasensitive Magnetic Resonance Research Team led by Prof. Xin Zhou has achieved more than 100,000-fold enhancement of the signal and successfully developed the world's first human lung gas MRI system. The system has obtained a Class III innovative medical device registration certificate in China and has been clinically applied at more than ten top-tier hospitals across China, providing a world-leading technological solution for the early screening and noninvasive assessment of diseases such as chronic obstructive pulmonary disease and lung cancer. Encapsulation and enrichment of hyperpolarized ₁₂₉Xe within molecular cages, coupled with Hyper-CEST, offer a promising approach to further improving detection sensitivity and enabling the ultrasensitive detection of trace analytes. However, the performance of currently available ₁₂₉Xe molecular cages remains limited by inefficient ₁₂₉Xe capture and weak entrapped ₁₂₉Xe signals. Therefore, developing new ₁₂₉Xe molecular cages and enhancing the intensity of the entrapped ₁₂₉Xe signal are important for advancing ultrasensitive magnetic resonance molecular imaging toward clinical applications.

    In 2025, the Nobel Prize in Chemistry was awarded to Prof. Omar M. Yaghi for his pioneering contributions to the field of MOFs. MOFs have attracted considerable interest for their potential biomedical applications, including drug delivery, biosensing, and medical imaging. Zhou’s team previously demonstrated the strong affinity of ZIF-8 for ₁₂₉Xe (PNAS, 2020). In a subsequent study, the team introduced multiple metal species into the framework to modulate ₁₂₉Xe-MOF interactions and enhance the ₁₂₉Xe signal (Nature Communications, 2025). However, tuning the metal centers alone offers limited control over the local electronic environment surrounding ₁₂₉Xe.

    In this study, Zhou’s team developed a multiligand engineering strategy to fine-tune pore polarity and hydrogen-bonding networks at the atomic scale, thereby precisely tuning ₁₂₉Xe–MOF interactions and enhancing the ₁₂₉Xe signal. Using the water-stable MOF CAU-1 as the parent framework, the team incorporated 2-hydroxyterephthalic acid and 2-aminoterephthalic acid ligands into the same MOF lattice to obtain a series of multivariate MOFs, CAU-1-(OH)^x-(NH²)^1−x. By varying the molar ratio of the two ligands, the researchers established a synergistic hydrogen-bonding network within the pores, enabling continuous modulation of the pore microenvironment and the host-guest interactions between ₁₂₉Xe and the MOF.

    The results showed that CAU-1-(OH)^0.5-(NH²)^0.5, containing equal molar proportions of the hydroxy and amino linkers, exhibited the greatest signal enhancement. Its maximum Hyper-CEST signal reached 65 times that of single-component CAU-1, demonstrating a synergistic “1+1> 2” enhancement effect. Multiple characterization techniques and theoretical calculations revealed that the synergistic hydrogen-bonding network formed through multiligand engineering partially restricted the entry of water molecules into the pores, creating a favorable pore environment for ₁₂₉Xe binding. This pore environment helped balance ₁₂₉Xe adsorption and chemical exchange, ultimately enhancing the magnetic resonance signal.

    Cellular experiments showed that CAU-1-(OH)^0.5-(NH²)^0.5 was internalized by A549 lung cancer cells and retained a strong ₁₂₉Xe capture capacity, enabling Hyper-CEST molecular imaging in living cells. Cellular MRI further demonstrated the ability of CAU-1-(OH)^0.5-(NH²)^0.5 to generate an enhanced ₁₂₉Xe MRI signal in a cellular environment, highlighting the potential of multiligand engineering to tailor MOF pore environments for ₁₂₉Xe capture in biological systems. These findings underscore the potential of multivariate MOFs for biomedical applications.

    This work represents the first application of multiligand engineering to the construction of ₁₂₉Xe molecular cages, establishing a new approach distinct from the previously developed metal-site doping strategy. By engineering the organic ligands, the study enables precise regulation of the chemical environment within MOF pores at the atomic scale and provides theoretical guidance for the rational design of high-performance ₁₂₉Xe molecular cages. Looking ahead, the complementary development of metal-site doping and multiligand engineering is expected to further advance ₁₂₉Xe MRI-based molecular imaging toward in vivo, noninvasive, and target-specific detection.

    PhD student Zhen Wang and Associate Professor Qingbin Zeng are co-first authors. Professor Xin Zhou and Qianni Guo are co-corresponding authors. This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Sciences, and others.

Figure 1. (a) Synthesis process and schematic illustration of CAU-1-(OH)^x-(NH2)^1-x。(b) Comparation of Hyper-CEST performance of single-component MOF and MTV-MOF. (c) Quantification of Hyper-CEST signal enhancement. (d) Hyper-CEST MR images of CAU-1-(OH)^0.5-(NH²)^0.5 in aqueous solution. (e) Hyper-CEST MRI of CAU-1-NH² and CAU-1-(OH)^0.5-(NH²)^0.5 in A549 cells. (f) TEM images of the distribution of CAU-1-NH² and CAU-1-(OH)^0.5-(NH²)^0.5 in A549 cells, scale bar = 1 μm.