Metasurface-Assisted Quantum Nonlocal Weak-Measurement Microscopy.

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.

Monitoring ROS Responsive Fe3O4-based Nanoparticle Mediated Ferroptosis and Immunotherapy via 129Xe MRI.

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.

Simultaneous chiral polarization and edge enhancement imaging enabled by a single geometric-phase-based element.

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.

An NIR Fluorescence Turn-on and MRl Bimodal Probe for Concurrent Real-time in vivo Sensing and Labeling of ß-Galactosidase.

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.

Photoactivated Nanohybrid for Dual-Nuclei MR/US/PA Multimodal-Guided Photothermal Therapy.

Nanohybrids have gained immense popularity for the diagnosis and chemotherapy of lung cancer for their excellent biocompatibility, biodegradability, and targeting ability. However, most of them suffer from limited imaging information, low tumor-to-background ratios, and multidrug resistance, limiting their potential clinical application. Herein, we engineered a photoresponsive nanohybrid by assembling polypyrrole@bovine serum albumin (PPy@BSA) encapsulating perfluoropentane (PFP)/129Xe for selective magnetic resonance (MR)/ultrasonic (US)/photoacoustic (PA) trimodal imaging and photothermal therapy of lung cancer, overcoming these drawbacks of single imaging modality and chemotherapy. The nanohybrid exhibited superior US, PA, and MR multimodal imaging performance for lung cancer detection. The high sensitivity of the nanohybrid to near-infrared light (NIR) resulted in a rapid increase in temperature in a low-intensity laser state, which initiated the phase transition of liquid PFP into the gas. The ultrasound signal inside the tumor, which is almost zero initially, is dramatically increased. Beyond this, it led to the complete depression of 19F/129Xe Hyper-CEST (chemical exchange saturation transfer) MRI during laser irradiation, which can precisely locate lung cancer. In vitro and in vivo results of the nanohybrid exhibited a successful therapeutic effect on lung cancer. Under the guidance of imaging results, a sound effect of photothermal therapy (PTT) for lung cancer was achieved. We expect this nanohybrid and photosensitive behavior will be helpful as fundamental tools to decipher lung cancer in an earlier stage through trimodality imaging methods.

Examining the optical model of graphene via the photonic spin Hall effect.

In modern optics, there are two general models to describe the behavior of light in graphene: the zero-thickness model and the slab model. The difference in physical phenomena predicted by the two models is very small, which is hardly distinguished by traditional measurement methods. Therefore, which model can describe the light-matter interaction in graphene more exactly is still a challenging issue. In this work, based on the sensitive optical phenomenon called the photonic spin Hall effect, the small difference can be magnified to a detectable level by the weak-value amplification. The experimental results show that the zero-thickness model can more accurately describe the interaction between light and monolayer or bilayer graphene, while the case of more than two layers, which can no longer be regarded as two-dimensional thickness, should be described by the slab model. Our results may provide information on light interacting with graphene for future investigation in photonics and optoelectronics.

Realization of all-optical higher-order spatial differentiators based on cascaded operations.

Cascaded operations play an important role in traditional electronic computing systems for the realization of advanced strategies. Here, we introduce the idea of cascaded operations into all-optical spatial analog computing. The single function of the first-order operation has difficulty meeting the requirements of practical applications in image recognition. The all-optical second-order spatial differentiators are implemented by cascading two first-order differential operation units, and the image edge detection of amplitude and phase objects are demonstrated. Our scheme provides a possible pathway toward the development of compact multifunctional differentiators and advanced optical analog computing networks.

Realization of tunable edge-enhanced images based on computing metasurfaces.

Bright-field imaging and edge imaging can extract different characteristics from objects, and therefore play important roles in image processing and pattern recognition. Here, we propose a fast, convenient, and electrically driven adjustable scheme to achieve tunable edge-enhanced images based on computing metasurfaces. The computing metasurface can perform spatial differential operation as optical waves propagate through it. This optical differential operation is polarization-dependent, thus any desirable contrast can be realized by the interplay between two orthogonal polarization components. By regulating the external voltages applied on the liquid-crystal phase plate, different phase retardances between two orthogonal polarization components are introduced; this allows us to quickly switch between the bright-field image and the edge image.

Intrinsic Optical Spatial Differentiation Enabled Quantum Dark-Field Microscopy.

By solving the Maxwell's equations in Fourier space, we find that the cross-polarized component of the dipole scattering field can be written as the second-order spatial differentiation of the copolarized component. This differential operation can be regarded as intrinsic which naturally arises as consequence of the transversality of electromagnetic fields. By introducing the intrinsic spatial differentiation into heralded single-photon microscopy imaging technique, it makes the structure of pure-phase object clearly visible at low photon level, avoiding any biophysical damages to living cells. Based on the polarization entanglement, the switch between dark-field imaging and bright-field imaging is remotely controlled in the heralding arm. This research enriches both fields of optical analog computing and quantum microscopy, opening a promising route toward a nondestructive imaging of living biological systems.

Synthesis of symmetrical secondary oligoethylene glycolated amines from diethanolamine.

Monodisperse oligoethylene glycols (M-OEGs)-containing symmetrical secondary amines are highly valuable synthetic intermediates in drug development and materials sciences. Scalable three-step synthesis of M-OEGs secondary amines with flexible M-OEGs and/or alkyl chains is described herein. Through reduction amination of diethanolamine, Williamson ether synthesis, and subsequent deprotection, a series of M-OEGs secondary amines with diverse and fine-tunable chemical structures were conveniently prepared. The presented strategy is attractive with readily available starting materials, simple catalytic systems, scalable synthesis, and avoids the use of explosive sodium azide.

Synthesis of trifluoromethylated aza-BODIPYs as fluorescence-19F MRI dual imaging and photodynamic agents.

Dual-imaging agents with highly sensitive fluorescence (FL) imaging and highly selective fluorine-19 magnetic resonance imaging (19F MRI) are valuable for biomedical research. At the same time, photosensitizers with a high reactive oxygen species (ROS) generating capability are crucial for photodynamic therapy (PDT) of cancer. Herein, a series of tetra-trifluoromethylated aza-boron dipyrromethenes (aza-BODIPYs) were conveniently synthesized from readily available building blocks and their physicochemical properties, including ultraviolet-visible (UV-Vis) absorption, FL emission, photothermal efficacy, ROS generating efficacy, and 19F MRI sensitivity, were systematically investigated. An aza-BODIPY with 12 symmetrical fluorines was identified as a potent FL-19F MRI dual-imaging traceable photodynamic agent. It was found that the selective introduction of trifluoromethyl (CF3) groups into aza-BODIPYs may considerably improve their UV absorption, FL emission, photothermal efficacy, and ROS generating properties, which lays the foundation for the rational design of trifluoromethylated aza-BODIPYs in biomedical applications.

Hydrofluorocarbon nanoparticles for 19F MRI-fluorescence dual imaging and chemo-photodynamic therapy.

The synergistic chemotherapy and photodynamic therapy (PDT) may significantly improve the cancer therapeutic efficacy, in which fluorinated nanoemulsions are highly advantageous for their ability to deliver oxygen to hypoxic tumors and provide fluorine-19 magnetic resonance imaging (19F MRI). The low solubility of chemotherapy drugs and photosensitizers in current perfluorocarbon (PFC)-based 19F MRI agents usually leads to complicated formulations or chemical modifications and low nanoemulsion stability and performance. Herein, we employ readily available partially fluorinated ethyl 2-(3,5-bis(trifluoromethyl)phenyl)acetate as the 19F MRI agent and the solvent to dissolve the cancer stem cell inhibitor salinomycin and the photosensitizer ICG for the convenient preparation of 19F MRI-fluorescence dual imaging and synergistic chemotherapy, photothermal and photodynamic therapy nanoemulsions. The chemotherapy drug salinomycin has a high solubility in the partially fluorinated reagent, facilitating its high loading and efficient delivery. Paramagnetic iron(III) (Fe3+) is incorporated into the nanoemulsion through the dissolved chelator to significantly improve the 19F MRI sensitivity. Furthermore, the dissolved fluorinated 2-pyridone enables the efficient capture and sustained release of singlet oxygen in the dark for high PDT efficacy. The multifunctional nanoemulsions show sensitive 19F MRI and fluorescence dual imaging capability and high synergistic chemotherapy, photothermal and photodynamic therapy efficacy in cancer cells, which may be valuable oxygen delivery, sustained ROS generating and release, dual imaging and multimodal therapy agents for hypoxic tumors. This study provided a convenient co-solubilization strategy for the rapid construction of multifunctional theranostics for hypoxic tumors.

In Vivo Nitroreductase Imaging via Fluorescence and Chemical Shift Dependent 19 F NMR.

Nitroreductase (NTR) is an important biomarker widely used to evaluate the degree of tumor hypoxia. Although a few optical methods have been reported for detecting nitroreductase at low concentration ranges, an effective strategy for nitroreductase monitoring in vivo without limits to the imaging depth is still lacking. Herein, a novel dual-mode NIR fluorescence and 19 F MRI agent, FCy7-NO2 , is proposed for imaging tumor hypoxia. We show that FCy7-NO2 serves as not only a rapid NIR fluorescence enhanced probe for monitoring and bioimaging of nitroreductase in tumors, but also a novel 19 F MR chemical shift-sensitive contrast agent for selectively detecting nitroreductase catalyzed reduction. Notably, integrating two complementary imaging technologies into FCy7-NO2 enables sensitive detection of nitroreductase in a broad concentration range without tissue-depth limit. In general, this agent has a remarkable response to nitroreductase, which provides a promising method for understanding tumor evolution and its physiological role in the hypoxic microenvironment.

Discovery of a novel linc01125 isoform in serum exosomes as a promising biomarker for NSCLC diagnosis and survival assessment.

A non-invasive method to distinguish potential lung cancer patients would improve lung cancer prevention. We employed the RNA-sequencing analysis to profile serum exosomal long non-coding RNAs (lncRNAs) from non-small cell lung cancer (NSCLC) patients and pneumonia controls, and then determined the diagnostic and prognostic value of a promising lncRNA in four datasets. We identified 90 dysregulated lncRNAs for NSCLC and found the most significant lncRNA was a novel isoform of linc01125. Serum exosomal linc01125 could distinguish NSCLC cases from disease-free and tuberculosis controls, with the area under the curve values as 0.662 [95% confidence interval (CI) = 0.614-0.711] and 0.624 (95% CI = 0.522-0.725), respectively. High expression of exosomal linc01125 was also correlated with an unfavorable overall survival of NSCLC (hazard ratio = 1.48, 95% CI = 1.05-2.08). Clinic treatment decreased serum exosomal linc01125 in NSCLC patients (P = 0.036). Linc01125 functions to inhibit cancer growth and metastasis via acting as a competing endogenous RNA to up-regulate tumor necrosis factor alpha-induced protein 3 (TNFAIP3) expression by sponging miR-19b-3p. Notably, the oncogenic transformation of 16HBE led to decreased linc01125 in cells but increased linc01125 in cell-derived exosomes. The expression of linc01125 in total exosomes was highly correlated with that in tumor-associated exosomes in serum. Moreover, lung cancer cells were capable of releasing linc01125 into exosomes in vitro and in vivo. Our analyses suggest serum exosomal linc01125 as a promising biomarker for non-invasively diagnosing NSCLC and predicting the prognosis of NSCLC.

Optical analog computing of two-dimensional spatial differentiation based on the Brewster effect.

Optical analog computing has attracted widespread attention in recent decades due to its advantages of lower consumption, higher efficiency, and real-time imaging in image processing. Here, we propose a two-dimensional optical analog computing scheme based on the Brewster effect. We experimentally demonstrate two-dimensional edge detection with high efficiency. By combining microscopy, our approach may develop some significant applications in cellular and molecular imaging.

Spatial differential operation and edge detection based on the geometric spin Hall effect of light.

Unlike the conventional spin Hall effect of light (SHEL) originating from the light-matter interaction, the spin-dependent splitting in the geometric SHEL is purely a geometric effect and independent from the properties of matter. Here it is shown that the geometric SHEL is not only of fundamental theoretical interest in understanding the spin-orbit interaction of light, but also sheds light on important technological applications. This Letter describes the theoretical foundation and experimental realization of optical differential operation and one-dimensional edge detection based on the geometric SHEL.

Quantitatively Fine-Tuning the Physicochemical and Biological Properties of Peptidic Polymers through Monodisperse PEGylation.

In biomedicine, PEGylation is one of the most successful strategies to modify the physicochemical and biological properties of peptides, proteins, and other biomacromolecules. Because of the polydisperse nature of regular PEGs and limited PEGylation strategies, it is challenging to quantitatively fine-tune and accurately predict the properties of biomacromolecules after PEGylation. However, such fine-tuning and prediction may be crucial for their biomedical applications. Herein, some monodisperse PEGylation strategies, including backbone PEGylation, side-chain PEGylation, and highly branched PEGylation, have been developed. In a comparative fashion, the impact of PEGylation strategies and monodisperse PEG sizes on the physicochemical and biological properties, including lipophilicity, thermosensitivity, biocompatibility, plasma stability, and drug delivery capability, of peptidic polymers has been quantitatively studied. It was found that the physicochemical and biological properties of PEGylated peptidic polymers can be quantitatively fine-tuned and accurately predicted through these monodisperse PEGylation strategies. After the comparative study, a side-chain monodisperse PEGylated peptidic polymer was chosen as fluorine-19 magnetic resonance and fluorescence dual-imaging traceable drug delivery vehicle. Our study may not only promote the transformation of PEGylation from an empirical technology to a quantitative science but also shed light on the rational design of PEGylated biomaterials and pharmaceutics.

Synthesis of Branched Monodisperse Oligoethylene Glycols and 19F MRI-Traceable Biomaterials through Reductive Dimerization of Azides.

Multifunctionalized and branched M-OEGs represent valuable PEGylation agents, linkers, and scaffolds in biomedicine. However, the tedious synthesis limited their availability and application. We herein present an azide reductive dimerization method for the convenient synthesis of aza-M-OEGs and derivatives, which provides easy access to a variety of multifunctionalized and branched M-OEGs in one step. With this method, hexa-arm M-OEGs with 54 symmetrical fluorines were synthesized in two steps as a water-soluble, self-assemble, 19F MRI sensitive, and biocompatible dendritic biomaterial.

Engineered Paramagnetic Graphene Quantum Dots with Enhanced Relaxivity for Tumor Imaging.

Nano contrast agents (Nano CA) are nanomaterials used to increase contrast in the medical magnetic resonance imaging (MRI). However, the related relaxation mechanism of the Nano CA is not clear yet and little significant breakthrough in relaxivity enhancement has been achieved. Herein, a new hydrophilic Gd-DOTA complex functionalized with different chain length of PEG was synthesized and incorporated into graphene quantum dots (GQD) to obtain paramagnetic graphene quantum dots (PGQD). We performed a variable-temperature and variable-field intensity NMR study in aqueous solution on the water exchange and rotational dynamics of three different chain lengths of PGQD. The optimal GQD with paramagnetic chain length shows a great improvement in performance on 1H NMR relaxometric studies. In vitro results demonstrated that the relaxivity of the designed PGQD could be controlled by regulating the PEG length, and its relaxivity was ∼16 times higher than that of current commercial MRI contrast agents (e.g., Gd-DTPA), on a "per Gd" basis. The relaxivity of the Nano CA can be rationally tuned to obtain unmatched potentials in MR imaging, exemplified by preparation of the paramagnetic GQD with the enhanced T1 relaxivity. The fabricated PGQDs with suitable PEG length got the best relaxivity at 1.5 T. After intravenous injection, its feeding process by solid tumor could even be monitored by clinically used 1.5 T MRI scanners. This research will also provide an excellent platform for the design and synthesis of highly effective MR contrast agents.

Peptidic Monodisperse PEG "combs" with Fine-Tunable LCST and Multiple Imaging Modalities.

Thermosensitive and imaging-traceable materials with fine-tunable lower critical solution temperature (LCST) around body temperature are highly valuable in biomedicine. However, such materials are rare because it is challenging to fine-tune the LCST and incorporate suitable imaging modalities. Herein, peptidic monodisperse polyethylene glycol (M-PEG) "combs" with fine-tunable LCST, "hot spot" fluorine-19 magnetic resonance imaging (19F MRI), thermoresponsive fluorescent imaging, and drug loading ability were developed through accurately programming their structures during solid phase peptide synthesis (SPPS). The easy availability, structural accuracy, biocompatibility, and versatility provide the M-PEG "combs" with promising prospects as thermoresponsive and imaging-traceable biomaterials for controlled drug delivery.