The hard X-ray nanoprobe beamline at the SSRF

The hard X-ray nanoprobe beamline BL13U is a phase-Ⅱ beamline project at the Shanghai Synchrotron Radiation Facility.The beamline aims to enable comprehensive experiments at high spatial resolutions ranging from 50 to 10 nm. The X-ray energy range of the beamline, 5–25 keV, can detect most elements in the periodic table. Two operating modes were designed to accommodate the experimental requirements of high-energy resolution or high photon flux, respectively. X-ray nanofluorescence, nanodiffraction, and coherent diffraction imaging are developed as the main experimental techniques for BL13U. This paper describes the beamline optics, end station configurations, experimental methods under development, and preliminary test results. This comprehensive overview aims to provide a clear understanding of the beamline capabilities and potential applications.

Electrical characterization of an individual nanowire using flexible nanoprobes fabricated by atomic force microscopy-based manipulation

Nanowires have emerged as promising one-dimensional materials with which to construct various nanocircuits and nanosensors.However,measuring the electrical properties of individual nanowires directly remains challenging because of their small size,thereby hindering the comprehensive understanding of nanowire-based device performance.A crucial factor in achieving reliable electrical characterization is establishing well-determined contact conditions between the nanowire sample and the electrodes,which becomes particularly difficult for soft nanowires.Introduced here is a novel technique for measuring the conductivity of an individual nanowire with the aid of automated nanomanipulation using an atomic force microscope.In this method,two nanowire segments cut from the same silver nanowire are positioned onto a pair of gold electrodes,serving as flexible nanoprobes to establish controllable contact with the sample.By changing the contact points along the nanowire sample,conductivity measurements can be performed on different regions,thereby eliminating the influence of contact resistance by analyzing multiple current–voltage curves.Using this approach,the resistivity of a 100-nm-diameter silver nanowire is determined to be 3.49×10^(−8)Ωm.

Controllable Synthesis of Fluorescent Carbon Dots and Their Detection Application as Nanoprobes

Carbon dots(CDs), as a new member of carbon nanomaterial family, have aroused great interest since their discovery in 2004. Because of their outstanding water solubility, high sensitivity and selectivity to target analytes, low toxicity, favorable biocompatibility, and excellent photostability, researchers from diverse disciplines have come together to further develop the fundamental properties of CDs. Many methods for the production of CDs have been reported, therein, hydrothermal and solvothermal technology needs simple equipments, and microwave synthesis needs less reaction time, hence these methods become current common synthesis methods, in which many precursors have been applied to produce CDs. Due to their excellent fluorescence, CDs have made impressive strides in sensitivity and selectivity to a diverse array of salt ions,organic/biological molecules and target gases. The development of CDs as nanoprobes is still in its infancy, but continued progress may lead to their integration into environmental and biological applications. Hydrothermal,solvothermal, and microwave synthesis of fluorescent carbon dots and their detection applications as nanoprobes in salt ions, organic/biological molecules, and target gases will be reviewed.

Specific Recognition of Breast Cancer Cells In Vitro Using Near Infrared-Emitting Long-Persistence Luminescent Zn_3Ga_2Ge_2O_(10):Cr^(3+)Nanoprobes

In this paper, near-infrared emitting long-persistence luminescent Zn3Ga2Ge2O10:Cr3?(ZGG) nanoparticles with diameters of 30–100 nm and bright luminescence were prepared by a sol–gel synthesis method. After the surface amination, the nanoparticles were further bioconjugated with breast cancer-specific monoclonal antibody(anti-Ep CAM) to form ZGG-Ep CAM nanoprobes which can specifically target breast cancer cell lines(MCF7) in vitro. The results of in vitro images show that the luminescence signals from the cells treated with ZGG-Ep CAM nanoprobes are stronger than those from cells treated with ZGG-unconjugated antibody, indicating that the prepared ZGG-Ep CAM nanoprobes possessed excellent specific recognition capability. Furthermore, due to their long afterglow properties, the imaging could persist more than 1 h. Therefore, these nanoprobes could not only provide a high specificity detection method for cancer cells but also realize the long-time monitoring. Developed near-infrared emitting long-persistence luminescent nanoprobes will be expected to find new perspectives for cell therapy research and diagnosis applications.

Human iPS Cells Loaded with MnO2-Based Nanoprobes for Photodynamic and Simultaneous Enhanced Immunotherapy Against Cancer

How to trigger strong anti-tumor immune responses has become a focus for tumor therapy.Here,we report the human-induced pluripotent stem cells(iPSs)to deliver MnO2@Ce6 nanoprobes into tumors for simultaneous photodynamic therapy(PDT)and enhanced immunotherapy.Ce6 photosensitizer was attached on manganese dioxide(MnO2)nanoparticles,and resultant MnO2@Ce6 nanoprobes were delivered into mitomycin-treated iPSs to form iPS-MnO2@Ce6 nanoprobes.The iPS-MnO2@Ce6 actively targeted in vivo tumors,the acidic microenvironment triggered interaction between MnO2 and H2O2,released large quantities of oxygen,alleviated hypoxia in tumor.Upon PDT,singlet oxygen formed,broken iPSs released tumor-shared antigens,which evoked an intensive innate and adaptive immune response against the tumor,improving dendritic cells matured,effector T cells,and natural killer cells were activated.Meanwhile,regulatory T cells were reduced,and then the immune response induced by iPS-MnO2@Ce6 was markedly stronger than the immune reaction induced by MnO2@Ce6(P<0.05).The iPS-MnO2@Ce6 markedly inhibited tumor growth and metastasis and reduced mortality in mice models with tumor.Human iPS s loaded with MnO2-based nanoprobes are a promising strategy for simultaneous PDT and enhanced immunotherapy against tumor and own clinical translational prospect.

Iron-Imprinted Single-Atomic Site Catalyst-Based Nanoprobe for Detection of Hydrogen Peroxide in Living Cells

Fe-based single-atomic site catalysts(SASCs),with the natural metalloproteases-like active site structure,have attracted widespread attention in biocatalysis and biosensing.Precisely,controlling the isolated single-atom Fe-N-C active site structure is crucial to improve the SASCs’performance.In this work,we use a facile ion-imprinting method(IIM)to synthesize isolated Fe-N-C single-atomic site catalysts(IIM-Fe-SASC).With this method,the ion-imprinting process can precisely control ion at the atomic level and form numerous well-defined single-atomic Fe-N-C sites.The IIM-Fe-SASC shows better peroxidase-like activities than that of non-imprinted references.Due to its excellent properties,IIM-Fe-SASC is an ideal nanoprobe used in the colorimetric biosensing of hydrogen peroxide(H_(2)O_(2)).Using IIM-Fe-SASC as the nanoprobe,in situ detection of H_(2)O_(2)generated from MDA-MB-231 cells has been successfully demonstrated with satisfactory sensitivity and specificity.This work opens a novel and easy route in designing advanced SASC and provides a sensitive tool for intracellular H_(2)O_(2)detection.

A nitroreductase-responsive nanoprobe with homogeneous composition and high loading for preoperative non-invasive tumor imaging and intraoperative guidance

Tumor microenvironment(TME)-activatable probes have been proven to effectively increase signal-tobackground ratios(SBRs)and improve the success rate of complete tumor resection.However,many fluorescence probes have to be loaded into a nanocarrier for tumor targeted delivery,which consequently encounters poor drug loading,heterogeneous composition and non-encapsulated drug aggregates occurred during nanoformulation fabrications.Herein,a nitroreductase(NTR)-activated“OFF-ON”near-infrared fluorescence nanoprobe,named Nano Bodipy,was synthesized by the spontaneous self-assembling of NTRresponsive dye-polyethylene glycol(PEG)amphiphilic polymer in water.The NTR-responsive dye acted as the hydrophobic segment in the amphiphilic polymer,yielding a homogeneous composition and a high loading of 12.2 wt%(according to calculation)in the synthesized Nano Bodipy.The synthesized Nano Bodipy can efficiently accumulate in tumors via the enhanced permeability and retention(EPR)effect,enabling non-invasive tumor-targeted fluorescence imaging and guiding complete tumor resection.Once the synthesized Nano Bodipy entered the tumor cells,they dissociated and were activated by overexpressed NTR.With the real-time fluorescence guide of Nano Bodipy,complete tumor resection surgery was performed successfully.

Rare earth fluorescent nanoprobes with minimal side effects enable tumor microenvironment activation for chemotherapy

Chemotherapy,the use of antitumor drugs to kill cancer cells,is currently one of the most effective treatments for cancer.However,serious toxic side effects caused by long-term drug accumulation can cause significant damage to the body,which limits the clinical application of antitumor drugs.In this study,a novel RENPs@DOX-Fe nanoprobe(NP) was constructed by coating the surface of rare earth nanomaterials(NaLuF_(4):Yb,Er) with a complex formed by doxorubicin(DOX) and iron ion(Ⅲ).Due to the low toxicity of anthracycline-metal complexes,the damage to normal cells is reduced.The unique acidic microenvironment in tumor cells facilitates the decomposition and gradual release of DOX from the DOX-Fe complex.In addition,the DOX-Fe complex can convert near-infrared(NIR) light into heat energy,which promotes the decomposition of the complex,further enhancing the release of DOX in the tumor environment.The change of ratio fluorescence of rare earth nanomaterials at 660 and 1550 nm after DOX release enables visual monitoring of drug release,which can potentially improve the chemotherapeutic effect.In vitro experiments established that RENPs@DOX-Fe NPs with NIR illumination had good therapeutic efficacy in tumors.This work provides new insights into designing tumor microenvironment-responsive nanoprobes for chemotherapy with minimal side effects.

Imaging-guided precision oncotherapy mediated by nanoprobes: From seeing to curing

Malignant tumors are the main diseases threatening human life. Using precise theranostics to diagnose and cure tumors has emerged as a new method to improve patient survival. Based on the current development of precise tumor imaging, image-guided tumor therapy has received widespread attention because it is beneficial for developing precise treatment of tumors, has the potential to improve the efficacy of tumor therapy and reduce the incidence of adverse side effects. Nanoprobes, which are nanomaterial functionalized with specific biomolecules, have intrigued intense interest due to their great potential in monitoring biorecognition and biodetection evens. Benefiting from the unique advantages of nanomaterials, including the easy surface functionalization, the unique imaging performances, and the high drug loading capacity, nanoprobes have become a powerful tool to simultaneously realize tumor precise imaging, diagnosis, and therapy. This review introduces the non-invasive tumor precise imaging and highlights the recent advances of image-guided oncotherapy mediated by nanoprobes in anti-tumor drug delivery, tumor precise surgical navigation, chemodynamic therapy, and phototherapy. Finally, a perspective on the challenge and future direction of nanoprobes in imaging-guided tumor theranostics is also discussed.

Advances in nanoprobes-based immunoassays

Immunoassay is a powerful technique that uses highly specific antigenantibody interactions to detect biochemical targets such as proteins and toxins.As a diagnostic tool,immunoassay is employed in the screening,diagnosis,and prognosis of diseases,which are crucial for the grasp and control of patient conditions in clinical practice.With the rapid development of nanotechnology,immunoassays based on nanoprobes have attracted more and more attention due to the advantages of high sensitivity,specificity,stability,and versatility.These nanoprobes are nanoscale particles that can act as signal carriers or targeting agents for immunoassays.In this paper,we review the recent advances in various types of nanoprobes for immunoassays,such as colloidal gold,quantum dots,magnetic nanoparticles,nanozymes,aggregation-induced emission,and up-conversion nanoparticles.The effect of the nanoprobe construction and synthesis methods on their detection performance deserves to be studied in depth.We also compare their detection ranges and limits in different immunoassay methods,such as lateral flow immunoassays,fluorescent immunoassays,and surface-enhanced Raman scattering immunoassays.Moreover,we discuss the benefits and challenges of nanoprobes in immunoassays and provide insights into their future development.This study aims to offer a comprehensive and critical perspective on the role of nanoprobes in the field of immunoassays.

Dual-ratiometric magnetic resonance tunable nanoprobe with acidic-microenvironment-responsive property to enhance the visualization of early tumor pathological changes

The development of microenvironment-responsive nanoprobes has shown great promise for use in magnetic resonance imaging(MRI),with the advantage of significantly improved specificity and good biocompatibility.However,the clinical application of responsive probes is hampered by a lack of biological sensitivity for early molecular diagnostics and visualizing microenvionment of metabolism reprogramming in tumor progression.Here,we report on a dual-ratiometric magnetic resonance tunable(DMRT)nanoprobe designed by crosslinking different ratios of transferrin chelating gadolinium and superparamagnetic nanoparticles,complexed to a pH responsive biocompatible polymer.This dually activatable nanoprobe enables pH-dependent tumor microenvironment visualization,providing exceptional quantitative pathophysiological information in vitro and in vivo.When used in combination with dual-contrast enhancement triple subtraction imaging technique(DETSI),this smart nanoprobe guarantees the diagnosis of early-stage diseases.We envisage that this novel integrated nanoplatform will provide a new paradigm for the clinical translation of robust DMRT nanoprobes for early disease detection and staging,as well as microenvironment visualization and disease progression monitoring.

Inorganic imaging nanoprobes for breast cancer diagnosis

Breast cancer is one of the most prevalent cancers worldwide,and early diagnosis and screening are vital to its successful treatment.Although medical imaging methods can assist in the early detection of breast cancer,imaging methods that are currently used for clinical diagnosis have drawbacks,such as low sensitivity and accuracy.Contrast agents are often used in diagnostic imaging to address these drawbacks.Nanocontrast agents have attracted considerable attention in recent years due to their unique physicochemical characteristics.Among these agents,inorganic nanoprobes have been substantially developed through improvements in synthesis techniques and pairings with other organic molecules.This paper mainly summarizes the specific applications of inorganic nanoprobes in the magnetic resonance imaging,fluorescence imaging,radionuclide imaging,and bimodal/multimodal imaging of breast cancer.

Recent progress in engineering near-infrared persistent luminescence nanoprobes for time-resolved biosensing/bioimaging

Persistent luminescence nanoprobes (PLNPs) can remain luminescent after ceasing excitation.Due to the ultra-long decay time of persistent luminescence (PersL),autofluorescence interference can be efficiently eliminated by collecting PersL signal after autofluorescence decays completely,thus the imaging contrast and sensing sensitivity can be significantly improved.Since near-infrared (NIR) light shows reduced scattering and absorption coefficient in penetrating biological organs or tissues,near-infrared persistent luminescence nanoprobes (NIR PLNPs) possess deep tissue penetration and offer a bright prospect in the areas of in vivo biosensing/bioimaging.In this review,we firstly summarize the design of different types of NIR PLNPs for biosensing/bioimaging,such as transition metal ions-doped NIR PLNPs,lanthanide ions-doped NIR PLNPs,organic molecules-based NIR PLNPs,and semiconducting polymer self-assembled NIR PLNPs.Notably,organic molecules-based NIR PLNPs and semiconductor self-assembled NIR PLNPs,for the first time,were introduced to the review of PLNPs.Secondly,the effects of different types of charge carriers on NIR PersL and luminescence decay of NIR PLNPs are significantly emphasized so as to build up an in-depth understanding of their luminescence mechanism.It includes the regulation of valence band and conduction band of different host materials,alteration of defect types,depth and concentration changes caused by ion doping,effective radiation transitions and energy transfer generated by different luminescence centers.Given the design and potential of NIR PLNPs as long-lived luminescent materials,the current challenges and future perspective in this rapidly growing field are also discussed.

Synchronous detection of glutathione/hydrogen peroxide for monitoring redox status in vivo with a ratiometric upconverting nanoprobe

Cellular redox status presents broad implications with diverse physiological and pathological processes. Simultaneous detection of both the oxidative and reductive species of redox couples, especially the most representative pair glutathione/hydrogen peroxide (GSH/H2O2), is crucial to accurately map the cellular redox status. However, it still remains challenging to synchronously detect GSH/H2O2 in vivo due to lack of a reliable measuring tool. Herein, a ratiometric nanoprobe (UCNP-TB) possessing simultaneous delectability of GSH/H2O2 is established based on a multi-spectral upconverti ng nano phosphor (UCNP-OA) as the lumin esce nee res onance energy tran sfer (LRET) donor and two dye molecules as the acceptors, including a GSH-sensitive dye (TCG) and a H2O2-sensitive dye (BCH). With the as-prepared UCNP-TB, real-time and synchronous monitoring the variation of GSH and H2O2 in vitro and in living mice can be achieved using the ratio of the upcon versi on lumin esce nee (UCL) at 540 and 650 nm to that at 800 nm as the detecti on sign al, respectively, providi ng highly inhere nt reliability of the sensing results by self-calibrati on. Moreover, the nan oprobe is capable of mappi ng the redox status within the drug-resista nt tumor and the drug-induced hepatotoxic liver via ratiometric UCL imaging. Thus, this nan oprobe would provide a reliable tool to elucidate the redox state in vivo.

Lanthanide-doped near-infrared Ⅱ luminescent nanoprobes for bioapplications

Luminescent biosensing in the second nearinfrared(NIR-II) region is featured with superior spatial resolution and high penetration depth by virtue of the suppressed scattering of long-wavelength photons. Hitherto, the reported NIR-II nanoprobes are mostly based on carbon nanotubes, organic fluorophores or semiconducting quantum dots. As an alternative, trivalent lanthanide ions(Ln3+) doped nanoparticles have been emerging as a novel class of promising nanoprobes. In this review, we highlight the recent progress in the design of highly efficient Ln3+-doped NIR-II nanoparticles towards their emerging bioapplications, with an emphasis on autofluorescence-free bioimaging, sensitive bioassay, and accurate temperature sensing. Moreover, some efforts and challenges towards this rapidly expanding field are envisioned.

A new class of luminescent nanoprobes based on main-group Sb^(3+) emitters

Inorganic luminescent nanocrystals(NCs)doped with main-group ns^(2)-metal ions have evoked tremendous interest in many technological fields owing to their superior optical properties.Herein,we report a new class of luminescent nanoprobes based on 5s2-metal Sb3+-doped CaS NCs that are excitable by using a near ultraviolet light-emitting diode.The optical properties and excited-state dynamics of Sb3+in CaS NCs are comprehensively surveyed through temperature-dependent steady-state and transient photoluminescence(PL)spectroscopies.Owing to the strong electron-phonon coupling of Sb^(3+)in CaS NCs,Sb3+ions experience a dynamic Jahn-Taller distortion on the excited state,which results in bright green PL of Sb3+with a broad emission band,a large Stokes shift,and a high PL quantum yield up to 17.3%.By taking advantage of the intense PL of Sb^(3+),we show in proof-of-concept experiments the application of biotinylated CaS:Sb^(3+)NCs as sensitive luminescent nanoprobes for biotin receptor-targeted cancer cell imaging and zebrafish imaging with a high imaging contrast.These findings provide fundamental insights into the excited-state dynamics of Sb^(3+)in CaS NCs,thus laying a foundation for future design of novel and versatile luminescent nanoprobes via main-group ns2-metal doping.

Tracing of dye molecules in living plants through NaGdF_4:Yb^(3+),Er^(3+)fluorescent nanoprobes

In this paper, we demonstrated trace of dye molecules in living plants. The NaGdF4:Yb^(3+),Er^(3+) nanoparticles probe was used to detect the rhodamine B(RhB) in bean sprout. It is found that the fluorescencedye can be efficiently imbibed during the growing process and the absorbance presented a position dependence effect, which was supported by the upconversion spectra and the fluorescent image characterization. In addition, the concentration of the residual RhB in bean sprout can be efficiently traced by the synthesized probe based on the fluorescent resonant energy transfer. Finally, the relation between the excitation power, concentration and the ratio of yellow to green emission are discussed in detail. These results can be helpful in understanding the RhB dye molecules absorbance process in vegetable growth and provide an efficient way to trace the residual dyes in vivo plant.

Blue-LED-excitable NIR-Ⅱluminescent lanthanide-doped SrS nanoprobes for ratiometric thermal sensing

Lanthanide(Ln^(3+))-doped near infrared(NIR)-II luminescent nanoprobes have shown great promise in many technological fields,but are currently limited by the low absorption efficiency of Ln^(3+)due to the forbidden 4f→4f transition.Herein,we report a novel NIR-II luminescent nanoprobe based on efficient energy transfer from Ce^(3+)to Er^(3+)and Nd^(3+)in sub-10 nm SrS nanocrystals(NCs),which are excitable by using a commercial blue light-emitting diode(LED).Through sensitization by the allowed 4f→5d transition of Ce^(3+),the NCs exhibit strong NIR-II luminescence from Er^(3+)and Nd^(3+)with quantum yields of 2.9%and 2.3%,respectively.Furthermore,by utilizing the intense NIR-II luminescence of Er^(3+)from the thermally coupled Stark sublevels of ^(4)I_(13/2),we demonstrate the application of SrS:Ce^(3+)/Er^(3+)NCs as blue-LED-excitable NIR-II luminescent nanoprobes for ratiometric thermal sensing.These findings reveal the unique advantages of SrS:Ln^(3+)NCs in NIR-II luminescence,which may open up a new avenue for exploring novel and versatile luminescent nanoprobes based on Ln^(3+)-doped sulphide NCs.

Design of SERS nanoprobes for Raman imaging:materials, critical factors and architectures

Raman imaging yields high specificity and sensitivity when compared to other imaging modalities, mainly due to its fingerprint signature. However, intrinsic Raman signals are weak, thus limiting medical applications of Raman imaging. By adsorbing Raman molecules onto specific nanostructures such as noble metals, Raman signals can be significantly enhanced, termed surfaceenhanced Raman scattering(SERS). Recent years have witnessed great interest in the development of SERS nanoprobes for Raman imaging. Rationally designed SERS nanoprobes have greatly enhanced Raman signals by several orders of magnitude, thus showing great potential for biomedical applications.In this review we elaborate on recent progress in design strategies with emphasis on material properties,modifying factors, and structural parameters.

Highly efficient luminescent Ⅰ-Ⅲ-Ⅵ semiconductor nanoprobes based on template-synthesized CuInS2 nanocrystals

CuInS2 semiconductor nanocrystals (NCs) exhibit large absorption coefficient, size-dependent photoluminescence and low toxicity, making them excellent candidates in a variety of bioapplications. However, precise control of both their composition and morphology to improve the luminescent efficiency remains a great challenge via conventional direct synthesis. Herein, we present a novel low-temperature template synthesis of highly efficient luminescent CuInS2 nanoprobes from In2S3 NCs via a facile cation exchange strategy. The proposed strategy enables synthesis of a series of CuInS2 NCs with broad size tunability from 2.2 to 29.6 nm. Through rationally manipulating the stoichiometry of Cu/In, highly efficient luminescence of CuInS2 with the maximum quantum yield of 28.6% has been achieved, which is about one order of magnitude improvement relative to that of directly synthesized NCs. By virtue of the intense emission of CuInS2 nanoprobes, we exemplify their application in sensitive homogeneous biodetection for an important biomolecule of adenosine triphosphate (ATP) with the limit of detection down to 49.3 nM. Moreover, the CuInS2 nanoprobes are explored for ATP-targeted cancer cell imaging, thus revealing their great potentials in the field of cancer diagnosis and prognosis.