High-resolution X-ray luminescence extension imaging.

Current X-ray imaging technologies involving flat-panel detectors have difficulty in imaging three-dimensional objects because fabrication of large-area, flexible, silicon-based photodetectors on highly curved surfaces remains a challenge1-3. Here we demonstrate ultralong-lived X-ray trapping for flat-panel-free, high-resolution, three-dimensional imaging using a series of solution-processable, lanthanide-doped nanoscintillators. Corroborated by quantum mechanical simulations of defect formation and electronic structures, our experimental characterizations reveal that slow hopping of trapped electrons due to radiation-triggered anionic migration in host lattices can induce more than 30 days of persistent radioluminescence. We further demonstrate X-ray luminescence extension imaging with resolution greater than 20 line pairs per millimetre and optical memory longer than 15 days. These findings provide insight into mechanisms underlying X-ray energy conversion through enduring electron trapping and offer a paradigm to motivate future research in wearable X-ray detectors for patient-centred radiography and mammography, imaging-guided therapeutics, high-energy physics and deep learning in radiology.

Advancing X-ray Luminescence for Imaging, Biosensing, and Theragnostics.

X-ray luminescence is an optical phenomenon in which chemical compounds known as scintillators can emit short-wavelength light upon the excitation of X-ray photons. Since X-rays exhibit well-recognized advantages of deep penetration toward tissues and a minimal autofluorescence background in biological samples, X-ray luminescence has been increasingly becoming a promising optical tool for tackling the challenges in the fields of imaging, biosensing, and theragnostics. In recent years, the emergence of nanocrystal scintillators have further expanded the application scenarios of X-ray luminescence, such as high-resolution X-ray imaging, autofluorescence-free detection of biomarkers, and noninvasive phototherapy in deep tissues. Meanwhile, X-ray luminescence holds great promise in breaking the depth dependency of deep-seated lesion treatment and achieving synergistic radiotherapy with phototherapy.In this Account, we provide an overview of recent advances in developing advanced X-ray luminescence for applications in imaging, biosensing, theragnostics, and optogenetics neuromodulation. We first introduce solution-processed lead halide all-inorganic perovskite nanocrystal scintillators that are able to convert X-ray photons to multicolor X-ray luminescence. We have developed a perovskite nanoscintillator-based X-ray detector for high-resolution X-ray imaging of the internal structure of electronic circuits and biological samples. We further advanced the development of flexible X-ray luminescence imaging using solution-processable lanthanide-doped nanoscintillators featuring long-lived X-ray luminescence to image three-dimensional irregularly shaped objects. We also outline the general principles of high-contrast in vivo X-ray luminescence imaging which combines nanoscintillators with functional biomolecules such as aptamers, peptides, and antibodies. High-quality X-ray luminescence nanoprobes were engineered to achieve the high-sensitivity detection of various biomarkers, which enabled the avoidance of interference from the biological matrix autofluorescence and photon scattering. By marrying X-ray luminescence probes with stimuli-responsive materials, multifunctional theragnostic nanosystems were constructed for on-demand synergistic gas radiotherapy with excellent therapeutic effects. By taking advantage of the capability of X-rays to penetrate the skull, we also demonstrated the development of controllable, wireless optogenetic neuromodulation using X-ray luminescence probes while obviating damage from traditional optical fibers. Furthermore, we discussed in detail some challenges and future development of X-ray luminescence in terms of scintillator synthesis and surface modification, mechanism studies, and their other potential applications to provide useful guidance for further advancing the development of X-ray luminescence.

Passivation of Organic-Inorganic Hybrid Perovskite with Poly(lactic Acid) to Achieve Stable Red-Light Flexible Films.

Low-dimensional organic-inorganic hybrid perovskites (OIHPs) have shown significant potential in the optoelectronic field due to their adjustable structure and properties. However, the poor air stability and flexibility of the OIHP crystals limit their further development. Herein, three OIHP crystals have been synthesized using cadmium chloride and the isomer of phenylenediamine as raw materials. Mn2+ doping turns on the red-light emission of Cd-based OIHPs at around 625 nm. Interestingly, the organic ligands with different steric hindrance can induce a transition of the OIHP structure from two dimensions (2D) to one dimension (1D), thereby regulating the quantum yield of red luminescence in the range of 38.4% to nearly 100%. It is found that the surface-exposed amino groups are easy to oxidize, resulting in the instability of these OIHP crystals. Therefore, poly(lactic acid) (PLA) is selected to passivate OIHPs through hydrogen bonding between C═O of PLA and -NH2 on the surface of OIHPs. As a result, the production of OIHP-based flexible films with highly efficient and stable red emission can be obtained after being encapsulated by PLA. They demonstrate enormous application potential in flexible X-ray imaging. This study not only realizes stable perovskite films but also provides an effective design idea for red flexible scintillators.

All-inorganic perovskite nanocrystal scintillators.

The rising demand for radiation detection materials in many applications has led to extensive research on scintillators1-3. The ability of a scintillator to absorb high-energy (kiloelectronvolt-scale) X-ray photons and convert the absorbed energy into low-energy visible photons is critical for applications in radiation exposure monitoring, security inspection, X-ray astronomy and medical radiography4,5. However, conventional scintillators are generally synthesized by crystallization at a high temperature and their radioluminescence is difficult to tune across the visible spectrum. Here we describe experimental investigations of a series of all-inorganic perovskite nanocrystals comprising caesium and lead atoms and their response to X-ray irradiation. These nanocrystal scintillators exhibit strong X-ray absorption and intense radioluminescence at visible wavelengths. Unlike bulk inorganic scintillators, these perovskite nanomaterials are solution-processable at a relatively low temperature and can generate X-ray-induced emissions that are easily tunable across the visible spectrum by tailoring the anionic component of colloidal precursors during their synthesis. These features allow the fabrication of flexible and highly sensitive X-ray detectors with a detection limit of 13 nanograys per second, which is about 400 times lower than typical medical imaging doses. We show that these colour-tunable perovskite nanocrystal scintillators can provide a convenient visualization tool for X-ray radiography, as the associated image can be directly recorded by standard digital cameras. We also demonstrate their direct integration with commercial flat-panel imagers and their utility in examining electronic circuit boards under low-dose X-ray illumination.

Wide-Range Color-Tunable Organic Scintillators for X-Ray Imaging Through Host-Guest Doping.

With the increasing demands of X-ray detection and medical diagnosis, organic scintillators with intense and tunable X-ray excited emission have been becoming important. To guarantee the X-ray absorption, heavy atoms were widely added in reported organic scintillators, which led to emission quenching. In this work, we propose a new strategy to realize organic scintillators through the host-guest doping strategy. Then the X-ray absorption centers (host) and emission centers (guest) are separated. Under X-ray excitation, these materials displayed intense and readily tunable emissions ranging from green (520 nm) to near infrared (NIR) regions (682 nm). Besides, the relationship between the X-ray absorption and spatial arrangement of the heavy atoms in the host matrix was also revealed. The potential application of these wide-range color tunable organic host-guest scintillators in X-ray imaging were demonstrated. This work provides a new feasible strategy for constructing high-performance organic scintillators with tunable luminescence properties.

Probing Energy-Funneling Kinetics in Nanocrystal Sublattices for Superior X-Ray Imaging.

Long-lasting radioluminescence scintillators have recently attracted substantial attention from both research and industrial communities, primarily due to their distinctive capabilities of converting and storing X-ray energy. However, determination of energy-conversion kinetics in these nanocrystals remains unexplored. Here we present a strategy to probe and unveil energy-funneling kinetics in NaLuF4:Mn2+/Gd3+ nanocrystal sublattices through Gd3+-driven microenvironment engineering and Mn2+-mediated radioluminescence profiling. Our photophysical studies reveal effective control of energy-funneling kinetics and demonstrate the tunability of electron trap depth ranging from 0.66 to 0.96 eV, with the corresponding trap density varying between 2.38×105 and 1.34×107 cm-3. This enables controlled release of captured electrons over durations spanning from seconds to 30 days. It allows tailorable emission wavelength within the range of 520-580 nm and fine-tuning of thermally-stimulated temperature between 313-403 K. We further utilize these scintillators to fabricate high-density, large-area scintillation screens that exhibit a 6-fold improvement in X-ray sensitivity, 22 lp/mm high-resolution X-ray imaging, and a 30-day-long optical memory. This enables high-contrast imaging of injured mice through fast thermally-stimulated radioluminescence readout. These findings offer new insights into the correlation of radioluminescence dynamics with energy-funneling kinetics, thereby contributing to the advancement of high-energy nanophotonic applications.

A Lanthanide Upconversion Nanothermometer for Precise Temperature Mapping on Immune Cell Membrane.

Cell temperature monitoring is of great importance to uncover temperature-dependent intracellular events and regulate cellular functions. However, it remains a great challenge to precisely probe the localized temperature status in living cells. Herein, we report a strategy for in situ temperature mapping on an immune cell membrane for the first time, which was achieved by using the lanthanide-doped upconversion nanoparticles. The nanothermometer was designed to label the cell membrane by combining metabolic labeling and click chemistry and can leverage ratiometric upconversion luminescence signals to in situ sensitively monitor temperature variation (1.4% K-1). Moreover, a purpose-built upconversion hyperspectral microscope was utilized to synchronously map temperature changes on T cell membrane and visualize intracellular Ca2+ influx. This strategy was able to identify a suitable temperature status for facilitating thermally stimulated calcium influx in T cells, thus enabling high-efficiency activation of immune cells. Such findings might advance understandings on thermally dependent biological processes and their regulation methodology.

Near-Infrared II Gold Nanocluster Assemblies with Improved Luminescence and Biofate for In Vivo Ratiometric Imaging of H2S.

Ultrasmall gold nanoclusters (AuNCs) are emerging as promising luminescent nanoprobes for bioimaging due to their fantastic photoluminescence (PL) and renal-clearable ability. However, it remains a great challenge to design them for in vivo sensitive molecular imaging in desired tissues. Herein, we have developed a strategy to tailor the PL and biofate of near-infrared II (NIR-II)-emitting AuNCs via ligand anchoring for improved bioimaging. By optimizing the ligand types in AuNCs and using Er3+-doped lanthanide (Ln) nanoparticles as models, core-satellite Ln@AuNCs assemblies were rationally constructed, which enabled 2.5-fold PL enhancement of AuNCs at 1100 nm and prolonged blood circulation compared to AuNCs. Significantly, Ln@AuNCs with dual intense NIR-II PL (from AuNCs and Er3+) can effectively accumulate in the liver for ratiometric NIR-II imaging of H2S, facilitated by H2S-mediated selective PL quenching of AuNCs. We have then demonstrated the real-time imaging evaluation of liver delivery efficacy and dynamics of two H2S prodrugs. This shows a paradigm to visualize liver H2S delivery and its prodrug screening in vivo. Note that Ln@AuNCs are body-clearable via the hepatobiliary excretion pathway, thus reducing potential long-term toxicity. Such findings may propel the engineering of AuNC nanoprobes for advancing in vivo bioimaging analysis.

Lanthanide-Activated Nanoparticles: A Toolbox for Bioimaging, Therapeutics, and Neuromodulation.

Owing to their unique features, the past decade has witnessed rapid developments of lanthanide-activated nanoparticles for biological applications. These include highly tunable upconverting and downshifting photoluminescence when illuminated in deep tissue, excellent photostability against blinking and bleaching effects, biocompatibility through versatile surface modification, and ease of achieving multifunctionality, as well as satisfactory signal output. These attributes make lanthanide-doped nanoparticles an ideal toolbox for advanced bioimaging and next-generation therapeutics.The interest in lanthanide-doped nanoparticles for biomedical research arises from their unique optical properties in response to deep-tissue-penetrable light sources. Upon near-infrared irradiation, these nanoparticles with properly doped emitters display photon upconversion with large anti-Stokes shifts and broad-spectrum tunability from the ultraviolet to the visible. It is also possible to achieve orthogonal photoluminescence with variations in wavelength and lifetime. Coupled with surface ligands, dyes, biomolecules, or other types of functional nanomaterials, lanthanide-doped nanoparticles offer new opportunities for applications in bioimaging, advanced oncotherapy, and neuromodulation. Given the possibility of locating downshifting luminescence at "biological transmission windows", exquisite design of lanthanide-doped nanoparticles also enables deep-tissue imaging with high spatial resolution. In addition, these nanoparticles can respond to high-energy photons, such as X-rays, to trigger nonradioactive and radiative pathways, making it possible to develop high-sensitivity X-ray detectors. Precise control of paramagnetic lanthanide ions in nanocrystal lattices also provides advanced materials for high-performance magnetic resonance imaging in medical diagnostics and biomedical research. Full consideration of fundamental attributes of lanthanide-doped nanoparticles will facilitate the design of multifunctional and sensitive probes and improve diagnostic and therapeutic outcomes.In this Account, we categorize various lanthanide-activation strategies into three modes: near-infrared excitation, X-ray irradiation, and magnetic field stimulation. We introduce energy manipulations in upconverting, downshifting, and persistence luminescence in spectral and time domains and discuss how they can be applied in biological practices. We assess general design principles for lanthanide-activated nanosystems with multiple modalities of bioimaging, oncotherapy, and neuromodulation. We also review the current state-of-the-art in the field of lanthanide-based theranostic nanoplatforms, with particular emphasis on energy conversion and nano-/biointerfacing as well as emerging bioapplications. In this context, we also highlight recent advances in controlling optical properties of nanoplatforms for single- or multimodal bioimaging, stimulus-responsive phototherapy, and optogenetics. Finally, we discuss future opportunities and challenges of this exciting research field.

Singlet Oxygen Generation in Dark-Hypoxia by Catalytic Microenvironment-Tailored Nanoreactors for NIR-II Fluorescence-Monitored Chemodynamic Therapy.

Singlet oxygen (1 O2 ) has a potent anticancer effect, but photosensitized generation of 1 O2 is inhibited by tumor hypoxia and limited light penetration depth. Despite the potential of chemodynamic therapy (CDT) to circumvent these issues by exploration of 1 O2 -producing catalysts, engineering efficient CDT agents is still a formidable challenge since most catalysts require specific pH to function and become inactivated upon chelation by glutathione (GSH). Herein, we present a catalytic microenvironment-tailored nanoreactor (CMTN), constructed by encapsulating MoO42- catalyst and alkaline sodium carbonate within liposomes, which offers a favorable pH condition for MoO42- -catalyzed generation of 1 O2 from H2 O2 and protects MoO42- from GSH chelation owing to the impermeability of liposomal lipid membrane to ions and GSH. H2 O2 and 1 O2 can freely cross the liposomal membrane, allowing CMTN with a built-in NIR-II ratiometric fluorescent 1 O2 sensor to achieve monitored tumor CDT.

Influence of Isomerism on Radioluminescence of Purely Organic Phosphorescence Scintillators.

There are few reports about purely organic phosphorescence scintillators, and the relationship between molecular structures and radioluminescence in organic scintillators is still unclear. Here, we presented isomerism strategy to study the effect of molecular structures on radioluminescence. The isomers can achieve phosphorescence efficiency of up to 22.8 % by ultraviolet irradiation. Under X-ray irradiation, both m-BA and p-BA show excellent radioluminescence, while o-BA has almost no radioluminescence. Through experimental and theoretical investigation, we found that radioluminescence was not only affected by non-radiation in emissive process, but also highly depended on the material conductivity caused by the different molecular packing. This study not only allows us to clearly understand the relationship between the molecular structures and radioluminescence, but also provides a guidance to rationally design new organic scintillators.

Microfluidic technologies in cell isolation and analysis for biomedical applications.

Efficient platforms for cell isolation and analysis play an important role in applied and fundamental biomedical studies. As cells commonly have a size of around 10 microns, conventional handling approaches at a large scale are still challenged in precise control and efficient recognition of cells for further performance of isolation and analysis. Microfluidic technologies have become more prominent in highly efficient cell isolation for circulating tumor cells (CTCs) detection, single-cell analysis and stem cell separation, since microfabricated devices allow for the spatial and temporal control of complex biochemistries and geometries by matching cell morphology and hydrodynamic traps in a fluidic network, as well as enabling specific recognition with functional biomolecules in the microchannels. In addition, the fabrication of nano-interfaces in the microchannels has been increasingly emerging as a very powerful strategy for enhancing the capability of cell capture by improving cell-interface interactions. In this review, we focus on highlighting recent advances in microfluidic technologies for cell isolation and analysis. We also describe the general biomedical applications of microfluidic cell isolation and analysis, and finally make a prospective for future studies.

Confining Excitation Energy in Er3+ -Sensitized Upconversion Nanocrystals through Tm3+ -Mediated Transient Energy Trapping.

A new class of lanthanide-doped upconversion nanoparticles are presented that are without Yb3+ or Nd3+ sensitizers in the host lattice. In erbium-enriched core-shell NaErF4 :Tm (0.5 mol %)@NaYF4 nanoparticles, a high degree of energy migration between Er3+ ions occurs to suppress the effect of concentration quenching upon surface coating. Unlike the conventional Yb3+ -Er3+ system, the Er3+ ion can serve as both the sensitizer and activator to enable an effective upconversion process. Importantly, an appropriate doping of Tm3+ has been demonstrated to further enhance upconversion luminescence through energy trapping. This endows the resultant nanoparticles with bright red (about 700-fold enhancement) and near-infrared luminescence that is achievable under multiple excitation wavelengths. This is a fundamental new pathway to mitigate the concentration quenching effect, thus offering a convenient method for red-emitting upconversion nanoprobes for biological applications.

Online multi-channel microfluidic chip-mass spectrometry and its application for quantifying noncovalent protein-protein interactions.

To establish an automatic and online microfluidic chip-mass spectrometry (chip-MS) system, a device was designed and fabricated for microsampling by a hybrid capillary. The movement of the capillary was programmed by a computer to aspirate samples from different microfluidic channels in the form of microdroplets (typically tens of nanoliters in volume), which were separated by air plugs. The droplets were then directly analyzed by MS via paper spray ionization without any pretreatment. The feasibility and performance were demonstrated by a concentration gradient experiment. Furthermore, after eliminating the effect of nonuniform response factors by an internal standard method, determination of the association constant within a noncovalent protein-protein complex was successfully accomplished with the MS-based titration indicating the versatility and the potential of this novel platform for widespread applications.

Recent Advances in Photosensitizer Materials for Light-Mediated Tumor Therapy.

Photodynamic therapy (PDT) as an emerging therapeutic method has drawn much attention in the treatment field for cancer. Photosensitizer, which can convert photon energy into cytotoxic species under light irradiation, is the core component in PDT. The design of photosensitizers still faces problems of light absorption, targeting, penetration and oxygen dependence. With the rapid progress of material science, various photosensitizers have been developed to produce cytotoxic species for treatment of tumor with high selectivity, safety, and noninvasiveness. Besides, the applications of photosensitizers have been expanded to diverse cancer treatments such as drug release, optogenetics and immune checkpoint blockade. In this review, we summarize the recent advances of photosensitizers in various therapeutic methods for cancer. Prevailing challenges and further prospects associated with photosensitizers are also discussed.

Metal-Halide Perovskite Nanocrystal Superlattice: Self-Assembly and Optical Fingerprints.

Self-assembly of nanocrystals into superlattices is a fascinating process that not only changes geometric morphology, but also creates unique properties that considerably enrich the material toolbox for new applications. Numerous studies have driven the blossoming of superlattices from various aspects. These include precise control of size and morphology, enhancement of properties, exploitation of functions, and integration of the material into miniature devices. The effective synthesis of metal-halide perovskite nanocrystals has advanced research on self-assembly of building blocks into micrometer-sized superlattices. More importantly, these materials exhibit abundant optical features, including highly coherent superfluorescence, amplified spontaneous laser emission, and adjustable spectral redshift, facilitating basic research and state-of-the-art applications. This review summarizes recent advances in the field of metal-halide perovskite superlattices. It begins with basic packing models and introduces various stacking configurations of superlattices. The potential of multiple capping ligands is also discussed and their crucial role in superlattice growth is highlighted, followed by detailed reviews of synthesis and characterization methods. How these optical features can be distinguished and present contemporary applications is then considered. This review concludes with a list of unanswered questions and an outlook on their potential use in quantum computing and quantum communications to stimulate further research in this area.

Transcranial deep-tissue phototherapy for Alzheimer's disease using low-dose X-ray-activated long-afterglow scintillators.

Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-ß (Aß) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aß oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Here, we report an Aß targeted, low-dose X-ray-excitable long-afterglow scintillator (ScNPs@RB/Ab) for efficient deep-brain phototherapy. We demonstrate that the as-synthesized ScNPs@RB/Ab is capable of converting X-rays into visible light to activate the photosensitizers of rose bengal (RB) for Aß oxygenation through the scalp and skull. We show that the ScNPs@RB/Ab persistently emitting visible luminescence can substantially minimize the risk of excessive X-ray exposure dosage. Importantly, peptide KLVFFAED-functionalized ScNPs@RB/Ab shows a blood-brain barrier permeability. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aß burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects. Our study paves a new pathway to develop high-efficiency transcranial AD phototherapy. STATEMENT OF SIGNIFICANCE: Non-invasive phototherapy has been emerging as an ambitious tactic for suppression of amyloid-ß (Aß) self-assembly against Alzheimer's disease (AD). However, it remains a daunting challenge to develop efficient photosensitizers for Aß oxygenation that are activatable in a deep brain tissue through the scalp and skull, while reducing side effects on normal tissues. Herein, we report an Aß targeted, low-dose X-ray-excitable long-afterglow scintillators (ScNPs@RB/Ab) for efficient deep-brain phototherapy. In vivo experimental results validated that ScNPs@RB/Ab alleviated Aß burden and slowed cognitive decline in triple-transgenic AD model mice at extremely low X-ray doses without side effects.

Intramolecular charge transfer enables highly-efficient X-ray luminescence in cluster scintillators.

Luminescence clusters composed of organic ligands and metals have gained significant interests as scintillators owing to their great potential in high X-ray absorption, customizable radioluminescence, and solution processability at low temperatures. However, X-ray luminescence efficiency in clusters is primarily governed by the competition between radiative states from organic ligands and nonradiative cluster-centered charge transfer. Here we report that a class of Cu4I4 cubes exhibit highly emissive radioluminescence in response to X-ray irradiation through functionalizing biphosphine ligands with acridine. Mechanistic studies show that these clusters can efficiently absorb radiation ionization to generate electron-hole pairs and transfer them to ligands during thermalization for efficient radioluminescence through precise control over intramolecular charge transfer. Our experimental results indicate that copper/iodine-to-ligand and intraligand charge transfer states are predominant in radiative processes. We demonstrate that photoluminescence and electroluminescence quantum efficiencies of the clusters reach 95% and 25.6%, with the assistance of external triplet-to-singlet conversion by a thermally activated delayed fluorescence matrix. We further show the utility of the Cu4I4 scintillators in achieving a lowest X-ray detection limit of 77 nGy s-1 and a high X-ray imaging resolution of 12 line pairs per millimeter. Our study offers insights into universal luminescent mechanism and ligand engineering of cluster scintillators.

Thermally Activated Delayed Fluorescence Coinage Metal Cluster Scintillator.

X-ray scintillators are widely used in medical imaging, industrial flaw detection, security inspection, and space exploration. However, traditional commercial scintillators are usually associated with a high use cost because of their substantial toxicity and easy deliquescence. In this work, an atomically precise Au-Cu cluster scintillator (1) with a thermally activated delayed fluorescence (TADF) property was facilely synthesized, which is environmentally friendly and highly stable to water and oxygen. The TADF property of 1 endows it with an ultrahigh exciton utilization rate. Combined with the effective absorption of X-ray caused by the heavy-atom effect and a limited nonradiative transition caused by close packing in the crystal state, 1 exhibits an excellent radioluminescence property. Moreover, 1 has good processability for fabricating a large, flexible thin-film device (10 cm × 10 cm) for high-resolution X-ray imaging, which can reach 40 µm (12.5 LP mm-1). The properties mentioned earlier make the coinage metal cluster promising for use as a substitute for traditional commercial scintillators.