Nature Communications | Researchers from the Ultrasensitive Magnetic Resonance Research Group Propose a ‘Color-Magnetic’ Encoded Method for Color MRI in Lungs

    Recently, the research team led by Professor Xin Zhou at the Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences (CAS), published a research brief in Nature Communications, titled “Multivariate metal-organic frameworks enable chemical shift-encoded MRI with femtomolar sensitivity for biological systems”. This study introduces a “color-magnetic” encoded method enables non-invasive color MRI in vivo.

    Fluorescent molecules are varied and play a critical role in fields such as protein labeling, fluorescence tracing, and immunofluorescence. Substrates can be labeled with various colors according to the emission wavelength of fluorescent molecules, enabling the simultaneous detection of multiple targets. After functional modification, these molecules can be used for multi-target color-encoded imaging of cells and tissues. However, the penetration depth of fluorescence is limited, restricting its application in in vivo. In contrast, MRI has no such penetration depth limitations and is widely used in clinical disease detection. Chemical shifts, an important MR parameter, play a key role in molecular structure identification and substrate detection in MRI. Similar to fluorescent emission wavelengths correspond to different colors, magnetic resonance probes can be contrasted as "color-magnetic" markers to encode targets based on their chemical shifts. This allows for in vivo color MRI analysis of different targets. However, traditional proton probes have a limited chemical shift range, are susceptible to background signal interference, and exhibit low detection sensitivity.

    The research team led by Professor Xin Zhou has developed hyperpolarization technology that enhances the inert gas ₁₂₉Xe magnetic resonance signals by more than 100,000 times. The team's self-developed ‘Human Lung Gas MRI System’ has received approval for a Class III innovative medical device registration. This system enables ‘structure-function coupling synchronous imaging’ of the human body and has been widely applied in clinical settings across more than ten top-tier hospitals in China. It provides cutting-edge, non-invasive technology for the evaluation of major pulmonary diseases, such as COPD and lung cancer. ₁₂₉Xe is highly sensitive to its chemical environment, with a wide range of chemical shift changes, making it an ideal probe for chemical shift analysis. After inhaling hyperpolarized ₁₂₉Xe gas, which undergoes gas-blood exchange in the lungs, different forms of ₁₂₉Xe—gaseous ₁₂₉Xe (₁₂₉Xe@gas), dissolved ₁₂₉Xe in lung tissues (₁₂₉Xe@TP), and ₁₂₉Xe bound to hemoglobin (₁₂₉Xe@RBC)—exhibit distinct chemical shifts. When ₁₂₉Xe is combined with functionalized ‘molecular cages’ acting as ‘color-magnetic’ markers, new specific chemical shifts are generated within the ‘cage’. By using MRI to perform ‘color-magnetic’ encoding of these different chemical shifts, it is possible to achieve color MRI of multiple lung targets, providing a non-invasive, in vivo diagnostic tool for precise pulmonary disease subtyping. However, previously developed ₁₂₉Xe signals within the ‘molecular cage’ were weak, making it challenging to simultaneously label signals of different chemical shifts in vivo. This limitation significantly restricted the application of hyperpolarized ₁₂₉Xe chemical shift-based molecular imaging in living organisms. Therefore, constructing a ‘molecular cage’ capable of binding hyperpolarized ₁₂₉Xe gas and enhancing the ₁₂₉Xe signal within the ‘cage’ is crucial for achieving in vivo color MRI.

    In previous work, Professor Xin Zhou’s team discovered that the MOF material ZIF-8 has a high affinity for Xe and can be used to capture Xe atoms for hyperpolarized ₁₂₉Xe MRI (PNAS, 2020). Building on this foundation, the team introduces a multivariate MOF construction strategy into the field of hyperpolarized ₁₂₉Xe MRI for the first time. By incorporating various metals into the ZIF-8 framework and modulating the interaction between the ZIF-8 pores and Xe, they effectively enhance the signal intensity of ₁₂₉Xe within the MOF cage in aqueous solutions. Using this strategy, the NiZn-ZIF-8 framework was constructed, leading to a more than 210-fold enhancement of the entrapped ₁₂₉Xe signal compared to dissolved ₁₂₉Xe. When injected into the lungs of rats as a "color-magnetic" marker, strong ₁₂₉Xe signals from the NiZn-ZIF-8 cage (₁₂₉Xe@NiZn-ZIF-8) were obtained. By encoding four distinct chemical shifts of ₁₂₉Xe in the rat lungs (₁₂₉Xe@gas, ₁₂₉Xe@TP, ₁₂₉Xe@RBC, and ₁₂₉Xe@NiZn-ZIF-8, as shown in Figure 1), images of ₁₂₉Xe in four chemical environments were captured. These signals from different chemical shifts were effectively differentiated without interference, achieving in vivo multi-chemical shift color MRI. This MOF-based ‘color-magnetic’ marker functions similarly to fluorescent markers and can be further functionalized to meet specific needs. It enables ultrasensitive, multitarget color MRI for various biological markers.

Dr. Qingbin Zeng (Associate Professor) and Dr. Quer Yue from the Innovation Academy for Precision Measurement Science and Technology, CAS, are co-first authors of the paper, with Professor Xin Zhou and Professor Qianni Guo serving as the corresponding authors. This work was supported by the National Natural Science Foundation of China, the Chinese Academy of Sciences, and others.

Figure 1. The imaging effect of the NiZn-ZIF-8 ‘color-magnetic’ marker was evaluated both in solution and in vivo. In vivo, the marker clearly encodes gas-phase ₁₂₉Xe@gas, tissue-dissolved ₁₂₉Xe@TP, hemoglobin-bound ₁₂₉Xe@RBC, and cage-bound ₁₂₉Xe@NiZn-ZIF-8. This enables in vivo color MRI of rat lungs, achieving multi-chemical shift imaging with distinct chemical environments.