Abstract Trapping Xe atoms within MOFs represents a promising strategy for hyperpolarized 129Xe MRI, owing to their structural tunability and ultrahigh porosity. Enhancing the entrapped 129Xe NMR signal is critical to overcoming current limitations of 129Xe MRI in biomedical applications. Although metal-centered doping has been explored to boost 129Xe signals, ligand-centered precise engineering to optimize the entrapped 129Xe NMR signal in MOFs remains largely underexplored. Herein, we present, for the first time, a ligand-based multivariate engineering approach to enhance the entrapped 129Xe NMR signal of water-stable CAU-1-derived MTV-MOFs. By finely tuning the molar ratio of −OH and −NH2 functionalized linkers, the pore microenvironment and Xe-framework interactions are continuously modulated. The MTV-MOF with the optimal ligand composition exhibits a remarkable 65-fold enhancement in 129Xe NMR signal compared to the single-component MOF. Furthermore, this material demonstrates excellent 129Xe MRI performance in living cells, highlighting its potential for biomedical imaging. This ligand-engineered multivariate approach establishes a versatile platform for tailoring Xe-host interactions in MOFs, offering a promising pathway to develop high-performance Xe molecular cages and expand the frontier of MOF-based molecular imaging technologies.

Fluorescent molecules with specific target moieties are essential for histopathological analysis, but their limited tissue penetration depth makes in vivo, in situ color encoding analysis challenging. Magnetic resonance imaging (MRI) offers deep tissue penetration. When combined with chemical shift-encoded MRI reporters, it enables in vivo chemical shift encoding for biotarget imaging and analysis. These reporters require both strong signal intensity and large chemical shift window. However, conventional proton MRI reporters, with low sensitivity and a small chemical shift window, limit their in vivo applications. Here, we describe a chemical shift-encoded hyperpolarized 129Xe MRI reporter based on the multivariate metal-organic framework, NiZn-ZIF-8, to overcome these challenges. The proposed NiZn-ZIF-8 gives distinct chemical shifts for dissolved and entrapped 129Xe without signal interference, enhancing the 129Xe NMR signal by 210 times compared to dissolved 129Xe in water and biological media. This enables detection threshold at ≈ 4 fM concentrations, setting a record for the lowest concentration of xenon hosts detected in nanomaterials. Additionally, NiZn-ZIF-8 exhibits good in vivo MRI performance, allowing xenon encoding and distinction in rat lungs. NiZn-ZIF-8 represents a versatile and powerful platform for advanced molecular imaging and in vivo biomedical diagnostics.

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is a powerful tool for detecting respiratory system diseases. However, 129Xe is an inert gas and lacks specific detection capability. Entrapping xenon within molecular cages to enable specific detection is a challenging task, and numerous molecular cages have been developed and evaluated to address this challenge. Herein, we report that the aluminum-based metal-organic framework, CAU-1, can effectively entrap xenon for hyperpolarized 129Xe MRI in aqueous solutions. This platform exhibits high water stability and good dispersibility, and shows excellent xenon entrapment capability, even at a concentration as low as 50 µg/mL. Importantly, it is responsive to pH changes across a range from 6.6 to 5.0, making it promising for monitoring the weakly acidic environment in tumors or metabolic abnormality. Furthermore, the scalable and cost-effective production of this molecular cage will facilitate future advancements in molecular imaging and chemical sensing applications.

Magnetic resonance imaging (MRI) is a cornerstone technology in clinical diagnostics and in vivo research, offering unparalleled visualization capabilities. Despite significant advancements in the past century, traditional 1H MRI still faces sensitivity limitations that hinder its further development. To overcome this challenge, hyperpolarization methods have been introduced, disrupting the thermal equilibrium of nuclear spins and leading to an increased proportion of hyperpolarized spins, thereby enhancing sensitivity by hundreds to tens of thousands of times. Among these methods, hyperpolarized (HP) 129Xe MRI, also known as ultrasensitive 129Xe MRI, stands out for achieving the highest polarization enhancement and has recently received clinical approval. It effectively tackles the challenge of weak MRI signals from low proton density in the lungs. HP 129Xe MRI is valuable for assessing structural and functional changes in lung physiology during pulmonary disease progression, tracking cells, and detecting target molecules at pico-molar concentrations. This review summarizes recent developments in HP 129Xe MRI, including its physical principles, manufacturing methods, in vivo characteristics, and diverse applications in biomedical, chemical, and material sciences. In addition, it carefully discusses potential technical improvements and future prospects for enhancing its utility in these fields, further establishing HP 129Xe MRI's importance in advancing medical imaging and research.

We report a dual-signal chemical exchange saturation transfer (Dusi-CEST) strategy for drug delivery and detection in living cells. The two signals can be detected by operators in complex environments. This strategy is demonstrated on a cucurbit[6]uril (CB[6]) nanoparticle probe, as an example. The CB[6] probe is equipped with two kinds of hydrophobic cavities: one is found inside CB[6] itself, whereas the other exists inside the nanoparticle. When the probe is dispersed in aqueous solution as part of a hyperpolarized 129Xe NMR experiment, two signals appear at two different chemical shifts (100 and 200 ppm). These two resonances correspond to the NMR signals of 129Xe in the two different cavities. Upon loading with hydrophobic drugs, such as paclitaxel, for intracellular drug delivery, the two resonances undergo significant changes upon drug loading and cargo release, giving rise to a metric enabling the assessment of drug delivery success. The simultaneous change of Dusi-CEST likes a mobile phone that can receive both LTE and Wi-Fi signals, which can help reduce the occurrence of false positives and false negatives in complex biological environments and help improve the accuracy and sensitivity of single-shot detection.

Nature often provides invaluable insights into technological innovation and the construction of nanomaterials. Inspired by the pitaya fruit's strategy of wrapping seeds within its pulp to enhance seed survival, a unique nanocomposite based on metal-organic framework (MOF)-encapsulated CuS nanoparticles (NPs) is developed. This design effectively addresses the challenge of short retention time afforded by CuS NPs for therapeutic and imaging purposes. The MOF acts as the “pitaya pulp” protecting the internal CuS NPs (“pitaya seeds”), thereby increasing their retention time in vivo. This system exhibits triple-enzyme-mimicking activities and is proposed for application in photoacoustic and magnetic resonance imaging-guided therapies, including chemodynamic therapy, photothermal therapy, and cuproptosis-related therapy. The exceptional enzyme-mimicking activities of superoxide dismutase, catalase, and peroxidase not only produce oxygen to alleviate hypoxia but also generate a reactive oxygen species (ROS) storm for effective tumor destruction. By combining these multienzymatic properties, superior photothermal performance, and Cu-induced cuproptosis, nanozyme-treated mice exhibited an 84% inhibition of tumor growth—approximately double the effect observed in mice treated with CuS NPs alone. This study presents a smart strategy for integrating imaging with therapeutic modalities, achieving exceptional outcomes for precise imaging-guided tumor therapy.

Assessing the effectiveness of nanomedicines involves evaluating the drug content at the target site. Currently, most research focuses on monitoring the signal responses from loaded drugs, neglecting the changes caused by the nanohosts. Here, we propose a strategy to quantitatively evaluate the content of loaded drugs by detecting the signal variations resulting from the alterations in the microenvironment of the nanohosts. Specifically, hyperpolarized (HP) 129Xe atoms are employed as probes to sense the nanohosts' environment and generate a specific magnetic resonance (MR) signal that indicates their accessibility. The introduction of drugs reduces the available space in the nanohosts, leading to a crowded microenvironment that hinders the access of the 129Xe atoms. By employing 129Xe atoms as a signal source to detect the alterations in the microenvironment, we constructed a three-dimensional (3D) map that indicated the concentration of the nanohosts and established a linear relationship to quantitatively measure the drug content within the nanohosts based on the corresponding MR signals. Using the developed strategy, we successfully quantified the uptake of the nanohosts and drugs in living cells through HP 129Xe MR imaging. Overall, the proposed HP 129Xe atom-sensing approach can be used to monitor alterations in the microenvironment of nanohosts induced by loaded drugs and provides a new perspective for the quantitative evaluation of drug presence in various nanomedicines.

影像技术的迅速发展使科学家和临床医生能够准确地了解疾病的发病机制和病理过程,并根据患者的情况制订个性化的治疗策略.将各种成像手段与造影剂相结合,可实现对疾病的精准诊断.金属有机骨架(MOFs)具有孔隙率高、孔径可调、易于后修饰等特点,在生物医学影像领域中得到了广泛的研究.本文选取了 MOFs 中较为经典的材料ZIF-8,从其高负载率与易修饰等角度出发,重点介绍了ZIF-8 与多种分子影像造影剂相结合所形成 ZIF-8 复合造影剂在光学成像、光声成像、磁共振成像、计算机断层扫描成像(CT)等不同医学成像平台的巨大应用价值,此外还阐述了 ZIF-8 应用于生物医学影像所面临的重大挑战,并对该领域未来的研究方向进行了展望.

Due to limited detection sensitivity and contrast limitation, imaging substrates with 129Xe MRI in living cells is still a challenge. Here, we present an effective protocol to detect and image substrates in human lung cancer cells A549 with hyperpolarized 129Xe MRI. This protocol was optimized for a cryptophane-based probe sensitive to biothiols and can be expanded to other Xe-based probes to detect potential biomarkers in other mammalian cells. For complete details on the use and execution of this protocol, please refer to Zeng et al. (2021).

Metal organic frameworks with tunable pore structures are able to provide varied chemical environments for hyperpolarized129Xe atom hosting, which results in distinguishing magnetic resonance signals, and stains ultra-sensitive magnetic resonance imaging (MRI) with diverse colors.

Magnetic resonance imaging (MRI) provides structural and functional information, but it did not probe chemistry. Chemical information could help improve specificity of detection. Herein, we introduce a general method based on a modular design to construct a molecular building block Xe probe to help image intracellular biothiols (glutathione (GSH), cysteine (Cys) and homocysteine (Hcy)), the abnormal content of which is related to various diseases. This molecular building block possesses a high signal-to-noise ratio and no background signal effects. Its detection threshold was 100 pM, which enabled detection of intracellular biothiols in live cells. The construction strategy can be easily extended to the detection of any other biomolecule or biomarker. This modular design strategy promotes efficiency of development of low-cost multifunctional probes that can be combined with other readout parameters, such as optical readouts, to complement 129Xe MRI to usher in new capabilities for molecular imaging.

Functionalized hyperpolarized xenon "cage" molecules have often been used for ultrasensitive detection of biomolecules and microenvironment properties. However, the rapid and accurate measurement of molecule concentration is still a challenge. Here, we report a molecule concentration measurement method using long-interval chemical exchange inversion transfer (CEIT) NMR spectroscopy. The molecule concentration can be quantitatively measured with only 2 scans, which shortens the acquisition time by about 10 times compared to conventional Hyper-CEST (chemical exchange saturation transfer) z-spectrum method. Moreover, we found that the accuracy of concentration determination would be the best when the CEIT effect is 1-1/e or close to it, and a relative deviation of CrA-(COOH)6 less than ±1% has been achieved by only a one-step optimization of the number of cycles. The proposed method enables efficient and accurate determination of molecule concentration, which provides a potential way for rapid quantitative molecular imaging applications.

Riboflavin and its derivatives are the most important coenzymes in vivo metabolism, and are closely related to life activities. In this paper, the first photolysis 129Xe biosensor was developed by combining cryptophane-A with riboflavin moiety, which showed photosensitivity recorded by hyperpolarized 129Xe NMR/MRI technology with an obvious chemical shift change of 5.3 ppm in aqueous solution. Cellular fluorescence imaging confirmed that the biosensor could be enriched in MCF-7 cells, and MTT assays confirmed that the cytotoxicity was enhanced after irradiation. Findings suggested that the biosensor has a potential application in tumor targeting and the inhibition of tumor cell proliferation after photodegradation.

Significance Hyperpolarized 129 Xe NMR/MRI is a useful method for diagnosis of diseases of the respiratory system. However, the sensitive detection of specific compounds in blood remains a challenge because of the weak 129 Xe signal in aqueous solution. We developed a way, Hyper-SAME, to promote the 129 Xe signal in aqueous solution. The 129 Xe signal intensity is four times beyond that of free 129 Xe in water and 200 times better than the benchmark molecular cage, cryptophane-A, in its saturated aqueous solution. Additionally, the hyperpolarized 129 Xe signal can be amplified further by combining Hyper-SAME with hyperpolarized 129 Xe chemical exchange saturation transfer.

Yaping Yuan,ab‡ Qianni Guo, ab‡ Xiaoxiao Zhang, a‡ Weiping Jiang, ab Chaohui Ye ab and Xin Zhou *ab a. Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy of Precision Measurement Science and Technology, Chinese Academy of Sciences-Wuhan National Laboratory for Optoelectronics, Wuhan 430071, P.R. China. E-mail: xinzhou@wipm.ac.cn b. University of Chinese Academy of Sciences, Beijing, 100049, P.R. China

A smart multitool platform for theranostics would be useful for monitoring the administration of therapies in vivo. However, the integration of multiple functions into a single small-molecule platform remains a challenge. In this study, we developed a multifunctional probe based on a small-molecule platform. The properties of this probe were investigated via hyperpolarized 129Xe NMR/MRI, fluorescence imaging in cells and in vivo, and photodynamic therapy (PDT) in tumor mouse models. This multifunctional probe shows good pH response across a broad range of pH values. It also exhibits excellent fluorescence in vivo for mapping its biodistribution. Additionally, it produces enough 1O2 radicals for in vivo PDT. The combination of these functionalities into a single small-molecule platform, rather than a bulky nanoconstruct, offers unique possibilities for molecular imaging and therapy.

MRI with hyperpolarized 129Xe can achieve low-concentration detection.

Hyperpolarized 129Xe NMR has a detection sensitivity up to 10 000 times higher than that in the conventional 1H NMR. Hyperpolarized 129Xe gas has only one NMR signal, but can produce multiple signals when combined with molecular cages, providing the chances to develop targeted molecular probes. In this paper, water-soluble cucurbit[6]uril nanoparticles were used for loading hyperpolarized 129Xe gas to construct targeted molecular probes. It was observed that such molecular probes had double "cage" signals and the potential to be developed into multi-functional probes.