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Hyperpolarization stands out as a technique capable of significantly enhancing the sensitivity of nuclear magnetic resonance (NMR) and magnetic resonance imaging (MRI). Dynamic nuclear polarization (DNP), among various hyperpolarization methods, has gained prominence for its efficacy in real-time monitoring of metabolism and physiology. By administering a hyperpolarized substrate through dissolution DNP (dDNP), the biodistribution and metabolic changes of the DNP agent can be visualized spatiotemporally. This approach proves to be a distinctive and invaluable tool for non-invasively studying cellular metabolism in vivo, particularly in animal models. Biomarkers play a pivotal role in influencing the growth and metastasis of tumor cells by closely interacting with them, and accordingly detecting pathological alterations of these biomarkers is crucial for disease diagnosis and therapy. In recent years, a range of hyperpolarized DNP molecular bioresponsive agents utilizing various nuclei, such as 13C, 15N, 31P, 89Y, etc., have been developed. In this context, we explore how these magnetic resonance signals of nuclear spins enhanced by DNP respond to biomarkers, including pH, metal ions, enzymes, or redox processes. This review aims to offer insights into the design principles of responsive DNP agents, target selection, and the mechanisms of action for imaging. Such discussions aim to propel the future development and application of DNP-based biomedical imaging agents.

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BACKGROUND: Deciphering the molecular dynamics (MD) of rotaxanes is crucial for designing and refining their applications in molecular devices. This study employed fluorine-19 nuclear magnetic resonance (19F NMR) and magnetic resonance imaging (MRI) to unveil the interplay between mechanical bonds and steric hindrance in a series of fluorinated rotaxanes. RESULTS: 1H/19F NMR revealed stable "Z"-shaped wheel conformations minimizing steric clashes and favoring π-π interactions with the axle. Utilizing fluorines and axle protons as reporters, 1H/19F relaxation rates and solid-state 19F NMR studies demonstrated that mechanical bond primarily governs wheel motion, while steric hindrance dictates axle movement. Intriguingly, mechanical bond mainly affects local axle groups, leaving distant ones minimally impacted. MD simulations corroborated these findings. Temperature-dependent 19F NMR indicated that energy input enhances rotational motion and wheel conformational transitions. Furthermore, the drastic increase in 19F relaxation rates upon mechanical bond formation and steric hindrance enables sensitive and selective 19F MRI visualization of MD changes. SIGNIFICANCE: This study, by elucidating the roles of internal and external factors on rotaxane molecular dynamics using 19F NMR/MRI, offers valuable insights that can advance the field of rotaxane-based molecular devices.

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The advent of drones has revolutionized various aspects of our lives, and in the realm of biological systems, molecular drones hold immense promise as "magic bullets" for major diseases. Herein, we introduce a unique class of fluorinated macromolecular amphiphiles, designed in the shape of jellyfish, serving as exemplary molecular drones for fluorine-19 MRI (19F MRI) and fluorescence imaging (FLI)-guided drug delivery, status reporting, and targeted cancer therapy. Functioning akin to their mechanical counterparts, these biocompatible molecular drones autonomously assemble with hydrophobic drugs to form uniform nanoparticles, facilitating efficient drug delivery into cells. The status of drug delivery can be tracked through aggregation-induced emission (AIE) of FLI and 19F MRI. Furthermore, when loaded with a heptamethine cyanine fluorescent dye IR-780, these molecular drones enable near-infrared (NIR) FL detection of tumors and precise delivery of the photosensitizer. Similarly, when loaded with doxorubicin (DOX), they enable targeted chemotherapy with fluorescence resonance energy transfer (FRET) FL for real-time status updates, resulting in enhanced therapeutic efficacy. Compared to conventional drug delivery systems, molecular drones stand out for their simplicity, precise structure, versatility, and ability to provide instantaneous status updates. This study presents prototype molecular drones capable of executing fundamental drone functions, laying the groundwork for the development of more sophisticated molecular machines with significant biomedical implications.

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Using molecular imaging techniques to monitor biomarkers and drug release profiles simultaneously is highly advantageous for cancer diagnosis and treatment. However, achieving the accurate quantification of both biomarkers and drug release with a single imaging modality is challenging. This study presents the development of a glutathione (GSH)-responsive polymer-based micelle, PEG-SS-FCy7/PEG-SS-GEM (PSFG), which can precisely localize the tumor using bimodal imaging and prevent drug leakage. These PSFG micelles exhibit a small particle size of 106.3 ± 12.7 nm with a uniform size distribution, and the drug loading efficiency can also be easily controlled by changing the PEG-SS-FCy7 (PSF) and PEG-SS-GEM (PSG) feeding ratio. The PSFG micelles display weak fluorescence emission and minimal drug release under physiological conditions but collapse in the presence of GSH to trigger near-infrared fluorescence and the 19F magnetic resonance imaging signal, allowing for real-time monitoring of intracellular GSH levels and drug release. GSH could synergistically promote the disassembly of the micellar structure, resulting in accelerated probe and drug release of up to about 93.1% after 24 h. These prodrug micelles exhibit high in vitro and in vivo antitumor abilities with minimal side effects. The GSH-responsive drug delivery system with dual-modal imaging capability provides a promising imaging-guided chemotherapeutic platform to probe the tumor microenvironment and quantify real-time drug release profiles with minimal side effects.

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The immune checkpoint blockade strategy has improved the survival rate of late-stage lung cancer patients. However, the low immune response rate limits the immunotherapy efficiency. Here, we report a ROS-responsive Fe3O4-based nanoparticle that undergoes charge reversal and disassembly in the tumor microenvironment, enhancing the uptake of Fe3O4 by tumor cells and triggering a more severe ferroptosis. In the tumor microenvironment, the nanoparticle rapidly disassembles and releases the loaded GOx and the immune-activating peptide Tuftsin under overexpressed H2O2. GOx can consume the glucose of tumor cells and generate more H2O2, promoting the disassembly of the nanoparticle and drug release, thereby enhancing the therapeutic effect of ferroptosis. Combined with Tuftsin, it can more effectively reverse the immune-suppressive microenvironment and promote the recruitment of effector T cells in tumor tissues. Ultimately, in combination with α-PD-L1, there is significant inhibition of the growth of lung metastases. Additionally, the hyperpolarized 129Xe method has been used to evaluate the Fe3O4 nanoparticle-mediated immunotherapy, where the ventilation defects in lung metastases have been significantly improved with complete lung structure and function recovered. The ferroptosis-enhanced immunotherapy combined with non-radiation evaluation methodology paves a new way for designing novel theranostic agents for cancer therapy.

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In standard quantum weak measurements, preselection and postselection of quantum states are implemented in the same photon. Here we go beyond this restrictive setting and demonstrate that the preselection and postselection can be performed in two different photons, if the two photons are polarization entangled. The Pancharatnam-Berry phase metasurface is incorporated in the weak measurement system to perform weak coupling between probe wave function and spin observable. By introducing nonlocal weak measurement into the microscopy imaging system, it allows us to remotely switch different microscopy imaging modes of pure-phase objects, including bright-field, differential, and phase reconstruction. Furthermore, we demonstrate that the nonlocal weak-measurement scheme can prevent almost all environmental noise photons from detection and thus achieves a higher image contrast than the standard scheme at a low photon level. Our results provide the possibility to develop a quantum nonlocal weak-measurement microscope for label-free imaging of transparent biological samples.

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Smart lipids with fluorescence emission, thermal response, and polyethylene glycolation (PEGylation) functions can be highly valuable for formulation, image-traceable delivery, and targeted release of payloads. Herein, a series of jellyfish-shaped amphiphiles with a tetraphenylethene (TPE) core and four symmetrical amphiphilic side chains were conveniently synthesized and systematically investigated as smart lipids. Compared with regular amphiphilic TPE lipids and phospholipids, the unprecedented jellyfish-shaped molecular geometry was found to enable a series of valuable capabilities, including sensitive and responsive aggregation-induced emission of fluorescence (AIE FL) and real-time FL monitoring of drug uptake. Furthermore, the jellyfish-shaped geometry facilitated the concentration-dependent aggregation from unimolecular micelles at low concentrations to "side-by-side" spherical aggregates at high concentrations and a unique mode of AIE. In addition, the size and the arrangement of the amphiphilic side chains were found to dominate the aggregate stability, cell uptake, and thus the cytotoxicity of the amphiphiles. This study has unprecedentedly developed versatile smart TPE lipids with precise structures, and unique physicochemical and biological properties while the peculiar structure-property relationship may shed new light on the design and application of AIE fluorophores and functional lipids in biomedicine and materials science.

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The BET family member BRD4 is a bromodomain-containing protein that plays a vital role in driving oncogene expression. Given their pivotal role in regulating oncogenic networks in various cancer types, BET inhibitors (BETi) have been developed, but the clinical application has been impeded by dose-limiting toxicity and resistance. Understanding the mechanisms of BRD4 activity and identifying predictive biomarkers could facilitate the successful clinical use of BETis. Herein, we show that KDM5C and BRD4 cooperate to sustain tumor cell growth. Mechanistically, KDM5C interacted with BRD4 and stimulated BRD4 enhancer recruitment. Moreover, binding of the BRD4 C-terminus to KDM5C stimulated the H3K4 demethylase activity of KDM5C. The abundance of both KDM5C-associated BRD4 and H3K4me1/3 determined the transcriptional activation of many oncogenes. Notably, depletion or pharmacologic degradation of KDM5C dramatically reduced BRD4 chromatin enrichment and significantly increased BETi efficacy across multiple cancer types in both tumor cell lines and patient-derived organoid models. Furthermore, targeting KDM5C in combination with BETi suppressed tumor growth in vivo in a xenograft mouse model. Collectively, this work reveals a KDM5C-mediated mechanism by which BRD4 regulates transcription, providing a rationale for incorporating BETi into combination therapies with KDM5C inhibitors to enhance treatment efficacy. SIGNIFICANCE: BRD4 is recruited to enhancers in a bromodomain-independent manner by binding KDM5C and stimulates KDM5C H3K4 demethylase activity, leading to synergistic effects of BET and KDM5C inhibitor combinations in cancer.

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Magnetic coupling between paramagnetic centers is a crucial phenomenon in the design of efficient MRI contrast agents. In this study, we investigate the paraCEST properties and magnetic coupling effects of a novel homodinuclear Ni(ii) complex, 1, containing a Robson type macrocyclic ligand. A thorough analysis of the complex's electronic and magnetic properties revealed that the magnetic coupling effect reduces the transverse relaxation rate and enhances the sharpness of the proton resonances, leading to enhanced CEST efficiency. This novel mechanism, which we coined "magnetic-coupling induced line sharpening" (MILS), can be crucial for optimizing the performance of paramagnetic metal complexes in paraCEST imaging. Moreover, magnetic coupling plays a critical role in the relaxation properties of homodinuclear complexes. Our study not only paves the way for the creation of advanced paraCEST agents with enhanced CEST capabilities and sensitivity but also provides valuable guidance for the design of other MRI contrast agents utilizing dinuclear metal complexes.

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Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.

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Despite its remarkable clinical breakthroughs, immune checkpoint blockade (ICB) therapy remains limited by the insufficient immune response in the "cold" tumor. Nanozyme-based antitumor catalysis is associated with precise immune activation in the tumor microenvironment (TME). In this study, a cascade-augmented nanoimmunomodulator (CMZM) with multienzyme-like activities, which includes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and glutathione oxidase (GSHOx), that dissociates under an acidic and abundant GSH TME, is proposed for multimodal imaging-guided chemodynamic therapy (CDT)/photodynamic therapy (PDT) enhanced immunotherapy. Vigorous multienzyme-like activities can not only produce O2 to alleviate hypoxia and promote the polarization of M2 to M1 macrophages, but also generate ROS (•OH and 1 O2 ) and deplete GSH in the TME to expose necrotic cell fragments and reverse immunosuppressive TME by eliciting the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes (CTLs) in tumors. Therefore, inhibitory effects on both primary and distant tumors are achieved through synergy with an α-PD-L1 blocking antibody. This cascade multienzyme-based nanoplatform provides a smart strategy for highly efficient ICB immunotherapy against "cold" tumors by revising immunosuppressive TME.

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In this Letter, we propose a multifunctional imaging system enabled by a single geometric-phase-based liquid crystal (LC) element, which integrates chiral polarization and edge enhancement imaging. The element is located at the frequency domain plane in a 4F imaging system, and the phase profile of the element consists of a fork grating in the x direction and a grating in the y direction, which provide edge enhancement and chiral polarization imaging capabilities. Benefiting from the tunable property of the LC, the system can be switched from a polarization and edge imaging mode to the normal conventional imaging mode which is capable of conveniently acquiring the needed image information. Experiments demonstrate that the system can easily achieve multifunctional and switchable imaging, which agrees well with our design, and our LC element can work in the broadband spectrum because of the geometric phase modulation. The multifunctional strategy used here can effectively avoid the need to increase the size of the original microscopic system and the need for additional mechanical rotation of components. We believe that the proposed system with the additional advantages of electric control and tunability can find applications in biological imaging, medical detection, and optical computing.

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To realize sensing and labeling biomarkers is quite challenging in terms of designing multimodal imaging probes. In this study, we developed a novel ß-galactosidase (ß-gal) activated bimodal imaging probe that combines near-infrared (NIR) fluorescence and magnetic resonance imaging (MRI) to enable real-time visualization of activity in living organisms. Upon ß-gal activation, Gal-Cy-Gd-1 exhibits a remarkable 42-fold increase in NIR fluorescence intensity at 717 nm, allowing covalent labeling of adjacent target enzymes or proteins and avoiding molecular escape to promote probe accumulation at the tumor site. This fluorescence reaction enhances the longitudinal relaxivity by approximately 1.9 times, facilitating high-resolution MRI. The unique features of Gal-Cy-Gd-1 enable real-time and precise visualization of ß-gal activity in live tumor cells and mice. The probe's utilization aids in identifying in situ ovarian tumors, offering valuable assistance in the precise removal of tumor tissue during surgical procedures in mice. The fusion of NIR fluorescence and MRI activation through self-immobilizing target enzymes or proteins provides a robust approach for visualizing ß-gal activity. Moreover, this approach sets the groundwork for developing other activatable bimodal probes, allowing real-time in vivo imaging of enzyme activity and localization.

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Identification of mucin modulators is of remarkable significance to facilitate mucin-based antineoplastic therapy. However, little is known about circular RNAs (circRNAs) on regulating mucins. Dysregulated mucins and circRNAs were identified via high-throughput sequencing and their relationships with lung cancer survival were analyzed in tumor samples of 141 patients. The biological functions of circRABL2B were determined via gain- and loss-of-function experiments and exosome-packaged circRABL2B treatment in cells, patient-derived lung cancer organoids and nude mice. We identified that circRABL2B was negatively correlated with MUC5AC. Patients with low circRABL2B and high MUC5AC displayed the poorest survival (HR=2.00; 95% CI=1.12-3.57). Overexpressed circRABL2B significantly inhibited cell malignant phenotypes, while it knock-down exerted opposite effects. CircRABL2B interacted with YBX1 to inhibit MUC5AC, and subsequently suppressed integrin ß4/pSrc/p53 signaling and impoverished cell stemness, and promoted erlotinib sensitivity. Exosome-packaged circRABL2B exerted significant anti-cancer actions in cells, patient-derived lung cancer organoids and nude mice. Meanwhile, circRABL2B in plasma exosomes could distinguish early-stage lung cancer patients from healthy controls. Finally, we found circRABL2B was downregulated at the transcriptional level, and EIF4a3 involved the formation of circRABL2B. In conclusion, our data suggest that circRABL2B counteracts lung cancer progression via MUC5AC/integrin ß4/pSrc/p53 axis, which provides a rationale to enhance the efficacy of anti-MUCs treatment in lung cancer.

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Developing a theranostic system that integrates multimodal imaging, synergistic therapeutic, and formulation entities is a promising strategy for efficient cancer treatment. However, the complexity and safety concerns of multiple functional entities hinder their clinical translation. Herein, versatile "all-in-one" heptamethine cyanine amphiphiles (PEG-Cy-Fs) with multiple favorable capabilities, including fluorine-19 magnetic resonance imaging (19 F MRI), near-infrared fluorescence imaging (NIR FLI), photodynamic therapy (PDT), photothermal therapy (PTT), polyethylene glycolation (PEGylation) and high biocompatibility, are developed for the convenient construction of theranostic platforms. Amphiphiles PEG-Cy-Fs are synthesized on a multi-hundred-milligram scale with high efficacy, which self-assembled with a chemotherapy drug tamoxifen (TAM) into monodisperse and stable nanoparticles (SoFoTm/PEG-Cy-F18 ) with "turned on" FLI, sensitive 19 F MRI, mitochondria-targeting ability, high PDT and PTT efficacy, and PEGylation-optimized pharmacokinetics. The selective accumulation of SoFoTm/PEG-Cy-F18 in xenograft MCF-7 tumor with a long retention time (>10 days) enabled 19 F MRI-NIR FLI-guided chemo-photodynamic-photothermal therapy (chemo-PDT-PTT) of breast cancer with high therapeutical index in mice. The "all-in-one" heptamethine cyanine amphiphile may facilitate the convenient and standardized preparation of high-performance theranostics systems for clinical translation.

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The one-pot nucleophilic ring-opening reaction of oligoethylene glycol macrocyclic sulfates provides an efficient strategy for the monofunctionalization of oligoethylene glycols without protecting or activating group manipulation. In this strategy, the hydrolysis process is generally promoted by sulfuric acid, which is hazardous, difficult to handle, environmentally unfriendly, and unfit for industrial operation. Here, we explored a convenient handling solid acid, Amberlyst-15, as a replacement for sulfuric acid to accomplish the hydrolysis of sulfate salt intermediates. With this method, 18 valuable oligoethylene glycol derivatives were prepared with high efficiency, and gram-scale applicability of this method has been successfully demonstrated to afford a clickable oligoethylene glycol derivative 1b and a valuable building block 1g for F-19 magnetic resonance imaging traceable biomaterial construction.

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Hyperviscosity syndrome (HVS) is a combination of clinical signs and symptoms related to increased blood viscosity. HVS can increase the thrombotic risk by causing a major disturbance to the blood flow, which is usually found in the advanced stages of the tumor. Moreover, some of the drugs used in chemotherapy, such as 5-fluorouracil and erythropoietin, are also capable of causing HVS through their respective pathways. Clinically, the viscosity of a patient's blood sample is measured by a rotary rheometer to estimate the risk of hyperviscosity syndrome. However, the measurement of blood viscosity in vitro is easily affected by storage time, storage environment, and anticoagulants. In addition, the fluid conditions in the rheometer are quite different from those in natural blood vessels, making this method inappropriate for evaluating blood viscosity and its effects in vivo under physiological condition. Herein, we presented a novel magnetic resonance imaging method called local-saturation-and-delay imaging (LSDI). The radial distributions of flow velocity measured by LSDI are consistent with the Ultrasonic (US) method (Spearman correlation coefficient r = 0.990). But the result of LSDI is more stable than US (p < 0.0001). With the LSDI method, we can directly measure the radial distribution of diastolic flow velocity, and further use these data to calculate the whole blood relative viscosity (WBRV) and erythrocyte aggregation trend. It was a strong correlation between the results measured by LSDI and rotary rheometer in the group of rats given erythropoietin. Furthermore, experimental results in glioma rats indicate that LSDI is equivalent to a rheometer as a method for predicting the risk of hyperviscosity syndrome. Therefore, LSDI, as a non-invasive method, can effectively follow the changes in WBRV in rats and avoid the effect of blood sampling during the experiment on the results. In conclusion, LSDI is expected to become a novel method for real-time in vivo recognition of the cancer progression and the influence of drugs on blood viscosity and RBC aggregation.

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Although albumin has been extensively used in nanomedicine, it is still challenging to fluorinate albumin into fluorine-19 magnetic resonance imaging (19F MRI)-traceable theranostics because existing strategies lead to severe 19F signal splitting, line broadening, and low 19F MRI sensitivity. To this end, 34-cysteine-selectively fluorinated bovine serum albumins (BSAs) with a sharp singlet 19F peak have been developed as 19F MRI-sensitive and self-assembled frameworks for cancer theranostics. It was found that fluorinated albumin with a non-binding fluorocarbon and a long linker is crucial for avoiding 19F signal splitting and line broadening. With the fluorinated BSAs, paclitaxel (PTX) and IR-780 were self-assembled into stable, monodisperse, and multifunctional nanoparticles in a framework-promoted self-emulsion way. The high tumor accumulation, efficient cancer cell uptake, and laser-triggered PTX sharp release of the BSA nanoparticles enabled 19F MRI-near infrared fluorescence imaging (NIR FLI)-guided synergistic chemotherapy (Chemo), photothermal and photodynamic therapy of xenograft MCF-7 cancer with a high therapeutical index in mice. This study developed a rational synthesis of 19F MRI-sensitive albumin and a framework-promoted self-emulsion of multifunctional BSA nanoparticles, which would promote the development of protein-based high-performance biomaterials for imaging, diagnosis, therapy, and beyond.

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