Zinc‐Dithizone Complex Engineered Upconverting Nanosensors for the Detection of Hypochlorite in Living Cells

Current chemo/biosensors for hypochlorous acid or hypochlorite detections are usually limited to the submicromolar level because of their insufficient sensitivity, which is a problem because the concentrations in biological matrices is generally on the nanomolar scale or even lower. Developing a probe with a high enough sensitivity remains a challenge. Using the minimal background fluorescence of upconversion nanocrystals to our advantage, we herein report on an energy‐transfer mechanism‐based upconversion luminescent nanosensor for the sensitive and selective detection of hypochlorite in aqueous solution. In this nanosensor water‐dispersible upconversion nanoparticles act as the energy donor and a novel hypochlorite‐responsive coordination complex Zn(DZ)₃ is employed as the energy acceptor. The quenched upconversion luminescence, induced by the Zn(DZ)₃ complex, can be efficiently recovered after addition of hypochlorite through the selective oxidative breakage of the Zn‐S‐C bonds in the Zn(DZ)₃ complex, which was verified by mass spectrometry. The detection limit for hypochlorite of this sensing system is as low as 3 nM. Furthermore, this newly coordination‐complex engineered upconversion nanosensor is successfully applied to image different amounts of exogenous hypochlorite in living HeLa cells.     

Gold and Hairpin DNA Functionalization of Upconversion Nanocrystals for Imaging and In Vivo Drug Delivery

Although multifunctional upconversion imaging probes have recently attracted considerable interest in biomedical research, there are currently few methods for stabilizing these luminescent nanoprobes with oligonucleotides in biological systems. Herein, a method to robustly disperse upconversion nanoprobes in physiological buffers based on rational design and synthesis of nanoconjugates comprising hairpin‐DNA‐modified gold nanoparticles is presented. This approach imparts the upconversion nanoprobes with excellent biocompatibility and circumvents the problem of particle agglomeration. By combining single‐band anti‐Stokes near‐infrared emission and the photothermal effect mediated by the coupling of gold to upconversion nanoparticles, a simple, versatile nanoparticulate system for simultaneous deep‐tissue imaging and drug molecule release in vivo is demonstrated.     

Lighting Up MicroRNA in Living Cells by the Disassembly of Lock‐Like DNA‐Programmed UCNPs‐AuNPs through the Target Cycling Amplification Strategy

Intracellular microRNAs imaging based on upconversion nanoprobes has great potential in cancer diagnostics and treatments. However, the relatively low detection sensitivity limits their application. Herein, a lock‐like DNA (LLD) generated by a hairpin DNA (H1) hybridizing with a bolt DNA (bDNA) sequence is designed, which is used to program upconversion nanoparticles (UCNPs, NaYF₄@NaYF₄:Yb, Er@NaYF₄) and gold nanoparticles (AuNPs). The upconversion emission is quenched through luminescence resonance energy transfer (LRET). The multiple LLD can be repeatedly opened by one copy of target microRNA under the aid of fuel hairpin DNA strands (H2) to trigger disassembly of AuNPs from the UCNP, resulting in the lighting up of UCNPs with a high detection signal gain. This strategy is verified using microRNA‐21 as model. The expression level of microRNA‐21 in various cells lines can be sensitively measured in vitro, meanwhile cancer cells and normal cells can be easily and accurately distinguished by intracellular microRNA‐21 imaging via the nanoprobes. The detection limit is about 1000 times lower than that of the previously reported upconversion nanoprobes without signal amplification. This is the first time a nonenzymatic signal amplification method has been combined with UCNPs for imaging intracellular microRNAs, which has great potential for cancer diagnosis.     

Mesostructured Composite Materials with Electrically Tunable Upconverting Properties

A promising approach of designing mesostructured materials with novel physical behavior is to combine unique optical and electronic properties of solid nanoparticles with long‐range ordering and facile response of soft matter to weak external stimuli. Here, orientationally ordered nematic liquid crystalline dispersions of rod‐like upconversion nanoparticles are designed, practically realized, and characterized. Boundary conditions on particle surfaces, defined through surface functionalization, promote spontaneous unidirectional self‐alignment of the dispersed rod‐like nanoparticles, mechanically coupled to the molecular ordering direction of the thermotropic nematic liquid crystal host. As host is electrically switched at low voltages ≈1 V, nanorods rotate, yielding tunable upconversion and polarized luminescence properties of the composite. Spectral and polarization dependencies are characterized and explained through invoking models of electrical switching of liquid crystals and upconversion dependence on crystalline matrices of nanorods, and their potential practical uses are discussed.     

Activating Antitumor Immunity and Antimetastatic Effect Through Polydopamine‐Encapsulated Core–Shell Upconversion Nanoparticles

Synergistic phototherapy has the potential to conquer the extreme heterogeneity and complexity of difficult tumors and result in better cancer treatment outcomes than monomodal photodynamic therapy (PDT) or photothermal therapy (PTT). However, the previous approaches to combining PDT and PTT are mainly focused on primary tumor obliteration while neglecting tumor metastasis, which is responsible for about 90% of cancer deaths. It is shown that a combined PDT/PTT approach, based on upconversion‐polymer hybrid nanoparticles with surface‐loaded chlorin e6 photosensitizer, can enhance primary tumor elimination and elicit antitumor immunity against disseminated tumors. The specifical arrangement of an external upconversion coating over the polymer core ensures adequate photoabsorption by the upconversion nanoparticles for the generation of reactive oxygen species upon single near‐infrared light irradiation. Furthermore, it is found that synergistic phototherapy can elicit robust systemic and humoral antitumor immune responses. When combined with immune checkpoint blockades, it can inhibit tumor relapse and metastasis as well as prolong the survival of tumor‐bearing mice in two types of tumor metastasis models. This study may establish a new modality for enhancing immunogenic cell death through a synergistic phototherapeutic nanoplatform and extend this strategy to overcome tumor metastasis with an augmented antitumor immune response.     

Ultrafast Single‐Band Upconversion Luminescence in a Liquid‐Quenched Amorphous Matrix

Achieving single‐band upconversion is a challenging but rewarding approach to attain optimal performance in diverse applications, such as multiplexed molecular imaging, security coding, and nonlinear photonic devices. Here, highly efficient single‐band upconversion luminescence in the green spectral regime (16.4 times increase in emission at 525 nm) accomplished by realizing minimal energy loss from two‐photon upconversion in a newly synthesized liquid‐quenched amorphous matrix is reported. In contrast to previously reported single‐band upconversion, this phenomenon originates from the elevated transition probability of the host sensitive transition via changes in the host matrix's microstructure. The elevated transition probability facilitates ultrafast decay of upconversion luminescence with decay times as short as 0.2 µs, the fastest decay ever reported. The material in this study therefore has strong potential for use in photonic devices demanding high upconversion efficiency with a fast response time, which to date has been inaccessible using upconversion materials.     

Photon Upconverted Circularly Polarized Luminescence via Triplet–Triplet Annihilation

Circularly polarized luminescent materials are of increasing attention due to their potential applications in advanced optical technologies, such as chiroptical devices and optical sensing. Recently, in all reported circularly polarized luminescent materials, high‐energy excitation results in low‐energy or downconverted circularly polarized luminescence (CPL) emission. Although photon upconversion—i.e., the conversion of low‐energy light into higher‐energy emission, with a wide variety of applications—has been widely reported, the integration of photon upconversion and CPL in one chiral system to achieve higher‐energy CPL emission has never been reported. Herein, a brief review is provided of recent achievements in photon‐upconverted CPL via the triplet–triplet annihilation mechanism, focusing on the amplified dissymmetry factor g_lum through energy transfer process and dual upconverted and downconverted CPL emission through chirality and energy transfer process.     

Nanodroplet‐Containing Polymers for Efficient Low‐Power Light Upconversion

Sensitized triplet–triplet‐annihilation‐based photon upconversion (TTA‐UC) permits the conversion of light into radiation of higher energy and involves a sequence of photophysical processes between two dyes. In contrast to other upconversion schemes, TTA‐UC allows the frequency shifting of low‐intensity light, which makes it particularly suitable for solar‐energy harvesting technologies. High upconversion yields can be observed for low viscosity solutions of dyes; but, in solid materials, which are better suited for integration in devices, the process is usually less efficient. Here, it is shown that this problem can be solved by using transparent nanodroplet‐containing polymers that consist of a continuous polymer matrix and a dispersed liquid phase containing the upconverting dyes. These materials can be accessed by a simple one‐step procedure that involves the free‐radical polymerization of a microemulsion of hydrophilic monomers, a lipophilic solvent, the upconverting dyes, and a surfactant. Several glassy and rubbery materials are explored and a range of dyes that enable TTA‐UC in different spectral regions are utilized. The materials display upconversion efficiencies of up to ≈15%, approaching the performance of optimized oxygen‐free reference solutions. The data suggest that the matrix not only serves as mechanically coherent carrier for the upconverting liquid phase, but also provides good protection from atmospheric oxygen.     

Theranostic Upconversion Nanobeacons for Tumor mRNA Ratiometric Fluorescence Detection and Imaging‐Monitored Drug Delivery

Remote optical detection and imaging of specific tumor‐related biomarkers and simultaneous activation of therapy according to the expression level of the biomarkers in tumor site with theranostic probes should be an effective modality for treatment of cancers. Herein, an upconversion nanobeacon (UCNPs‐MB/Dox) is proposed as a new theranostic nanoprobe to ratiometrically detect and visualize the thymidine kinase 1 (TK1) mRNA that can simultaneously trigger the Dox release to activate the chemotherapy accordingly. UCNPs‐MB/Dox is constructed with the conjugation of a TK1 mRNA‐specific molecular beacon (MB) bearing a quencher (BHQ‐1) and an alkene handle modified upconversion nanoparticle (UCNP) through click reaction and subsequently loading with a chemotherapy drug (Dox). With this nanobeacon, quantitative ratiometric upconversion detection of the target with high sensitivity and selectivity as well as the target triggered Dox release in vitro is demonstrated. The sensitive and selective ratiometric detection and imaging of TK1 mRNA under the irradiation of near infrared light (980 nm) and the mRNA‐dependent release of Dox for chemotherapy in the tumor MCF‐7 cells and A549 cells are also shown. This work provides a smart and robust platform for gene‐related tumor theranostics.     

Inorganic–Organic Hybrid Nanoprobe for NIR‐Excited Imaging of Hydrogen Sulfide in Cell Cultures and Inflammation in a Mouse Model

Hydrogen sulfide (H₂S) is an important gaseous signaling agent mediated by many physiological processes and diseases. In order to explore its role in biological signaling, much effort has been focused on developing organic fluorescent probes to image H₂S. However, these downconversion H₂S probes are impractical for bio‐imaging beyond a certain depth because of the short tissue penetration of UV/visible light (as an excitation source). In most circumstance, these probes are also not suitable for long‐term assay due to photo‐bleaching. Herein, a new design to detect H₂S based on the coumarin‐hemicyanine (CHC1)‐modified upconversion nanophosphors is reported. This inorganic–organic integrated nanoprobe is demonstrated to display a fast response time with a large ratiometric upconversion luminescence (UCL) enhancement, and extraordinary photo‐stability. CHC1‐UCNPs not only can be used for ratiometric UCL monitoring of pseudo‐enzymatic H₂S production in living cells, but can also be used to identify the risk of endotoxic shock through ratiometric UCL imaging of tissue and measurement of endogenous H₂S levels in plasma. The first ratiometric UCL H₂S nanoprobe reported here may be further developed as the next‐generation diagnostic tool for the detection of inflammatory‐related diseases.     

Hedgehog‐Like Upconversion Crystals: Controlled Growth and Molecular Sensing at Single‐Particle Level

Topological control of nanostructures plays a crucial role in understanding the crystal growth process at the nanometer length scale. Here, the scalable synthesis of upconversion materials with distinct hedgehog‐like morphologies by a seed‐mediated synthetic procedure is reported. It is demonstrated that a close match in the crystal lattice between the core and shell components is essential for synthesizing such hierarchical nanostructures. These optical nanomaterials also enable the development of a single‐particle‐based platform for high‐sensitivity molecular sensing.     

Emerging ≈800 nm Excited Lanthanide‐Doped Upconversion Nanoparticles

Lanthanide‐doped upconversion nanoparticles can tune near‐infrared light to visible or even ultra‐violet light in emissions. Due to their unique photophysical and photochemical properties, as well as their promising bioapplications, there has been a great deal of enthusiastic research performed to study the properties of lanthanide‐doped upconversion nanoparticles in the past few years. Despite the considerable progress in this area, numerous challenges associated with the nanoparticles, such as a low upconversion efficiency, limited host materials, and a confined excitation wavelength, still remain, thus hindering further development with respect to their applications and in fundamental science. Recently, innovative strategies that utilize alternative sensitizers have been designed in order to engineer the excitation wavelengths of upconversion nanoparticles. Here, focusing on the excitation wavelength at ≈800 nm, recent advances in the design, property tuning, and applications of ≈800 nm excited upconversion nanoparticles are summarized. Benefiting from the unique features of ≈800 nm light, including deep tissue penetration depth and low photothermal effect, the ≈800 nm excited upconversion nanoparticles exhibit superior potential for biosensing, bioimaging, drug delivery, therapy, and three dimensional displays. The critical aspects of such emerging nanoparticles with regards to meeting the ever‐changing needs of future development are also discussed.     

Engineering of Lanthanide‐Doped Upconversion Nanoparticles for Optical Encoding

Lanthanide‐doped upconversion nanoparticles (UCNPs) are an emerging class of luminescent materials that emit UV or visible light under near infra‐red (NIR) excitations, thereby possessing a large anti‐Stokes shift property. Due to their sharp excitation and emission bands, excellent photo‐ and chemical stability, low autofluorescence, and high tissue penetration depth of the NIR light used for excitation, UCNPs have surpassed conventional fluorophores in many bioapplications. A better understanding of the mechanism of upconversion, as well as the development of better approaches to preparing UCNPs, have provided more opportunities to explore their use for optical encoding, which has the potential for applications in multiplex detection and imaging. With the current ability to precisely control the microstructure and properties of UCNPs to produce particles of tunable emission, excitation, luminescence lifetime, and size, various strategies for optical encoding based on UCNPs can now be developed. These optical properties of UCNPs (such as emission and excitation wavelengths, ratiometric intensity, luminescence lifetime, and multicolor patterns), and the strategies employed to engineer these properties for optical encoding of UCNPs through homogeneous ion doping, heterogeneous structure fabrication and microbead encapsulation are reviewed. The challenges and potential solutions faced by UCNP optical encoding are also discussed.     

Tuning upconversion through energy migration in core-shell nanoparticles

Photon upconversion is promising for applications such as biological imaging, data storage or solar cells. Here, we have investigated upconversion processes in a broad range of gadolinium-based nanoparticles of varying composition. We show that by rational design of a core-shell structure with a set of lanthanide ions incorporated into separated layers at precisely defined concentrations, efficient upconversion emission can be realized through gadolinium sublattice-mediated energy migration for a wide range of lanthanide activators without long-lived intermediary energy states. Furthermore, the use of the core-shell structure allows the elimination of deleterious cross-relaxation. This effect enables fine-tuning of upconversion emission through trapping of the migrating energy by the activators. Indeed, the findings described here suggest a general approach to constructing a new class of luminescent materials with tunable upconversion emissions by controlled manipulation of energy transfer within a nanoscopic region.     

Thermally Activated Upconversion Near‐Infrared Photoluminescence from Carbon Dots Synthesized via Microwave Assisted Exfoliation

Upconversion near‐infrared (NIR) fluorescent carbon dots (CDs) are important for imaging applications. Herein, thermally activated upconversion photoluminescence (UCPL) in the NIR region, with an emission peak at 784 nm, which appears under 808 nm continuous‐wave laser excitation, are realized in the NIR absorbing/emissive CDs (NIR‐CDs). The NIR‐CDs are synthesized by microwave‐assisted exfoliation of red emissive CDs in dimethylformamide, and feature single or few‐layered graphene‐like cores. This structure provides an enhanced contact area of the graphene‐like plates in the core with the electron‐acceptor carbonyl groups in dimethylformamide, which contributes to the main NIR absorption band peaked at 724 nm and a tail band in 800–850 nm. Temperature‐dependent photoluminescence spectra and transient absorption spectra confirm that the UCPL of NIR‐CDs is due to the thermally activated electron transitions in the excited state, rather than the multiphoton absorption process. Temperature dependent upconversion NIR luminescence imaging is demonstrated for NIR‐CDs embedded in a polyvinyl pyrrolidone film, and the NIR upconversion luminescence imaging in vivo using NIR‐CDs in a mouse model is accomplished.     

Binary Nanoparticle Superlattices for Plasmonically Modulating Upconversion Luminescence

Engineering a facile and controllable approach to modulate the spectral properties of lanthanide‐doped upconversion nanoparticles (UCNPs) is always an ongoing challenge. Herein, long‐range ordered, distinct two‐dimensional (2D) binary nanoparticle superlattices (BNSLs) composed of NaREF₄:Yb/Er (RE = Y and Gd) UCNPs and plasmonic metallic nanoparticles (Au NPs), including AB, AB₃, and AB₁₃ lattices, are fabricated via a slow evaporation‐driven self‐assembly to achieve plasmonic modulation of upconversion luminescence (UCL). Optical measurements reveal that typical red–green UCL from UCNPs can be effectively modulated into reddish output in BNSLs, with a drastically shortened lifetime. Notably, for AB₃‐ and AB₁₃‐type BNSLs with more proximal Au NPs around each UCNP, modified UCL with fine‐structured spectral lineshape is observed. These differences could be interpreted by the interplay of collective plasmon resonance introduced by 2D periodic Au arrays and spectrally selective energy transfer between UCNPs and Au. Thus, fabricating UCNP‐Au BNSLs with desired lattice parameters and NP configurations could be a promising way to tailor the UCL through controlled plasmonic modulation.     

A Novel Theranostic Nanoprobe for In Vivo Singlet Oxygen Detection and Real‐Time Dose–Effect Relationship Monitoring in Photodynamic Therapy

Singlet oxygen, as the main member of reactive oxygen species, plays a significant role in cancer photodynamic therapy. However, the in vivo real‐time detection of singlet oxygen remains challenging. In this work, a Förster resonance energy transfer (FRET)‐based upconversion nanoplatform for monitoring the singlet oxygen in living systems is developed, with the ability to evaluate the in vivo dose–effect relationship between singlet oxygen and photodynamic therapy (PDT) efficacy. In details, this nanoplatform is composed of core–shell upconversion nanoparticles (UCNPs), photosensitizer MC540, NIR dye IR‐820, and poly(acryl amine) PAA‐octylamine, where the UCNPs serve as an energy donor while IR‐820 serves as an energy acceptor. The nanoparticles are found to sensitively reflect the singlet oxygen levels generated in the tumor tissues during PDT, by luminescence intensity changes of UNCPs at 800 nm emission. Furthermore, it could also enable tumor treatment with satisfactory biocompatibility. To the best knowledge, this is the first report of a theranostic nanoplatform with the ability to formulate the in vivo dose–effect relationship between singlet oxygen and PDT efficacy and to achieve tumor treatment at the same time. This work might also provide an executable strategy to evaluate photodynamic therapeutic efficacy based on singlet oxygen pathway.     

Imaging Upconverting Polymersomes in Cancer Cells: Biocompatible Antioxidants Brighten Triplet–Triplet Annihilation Upconversion

Light upconversion is a very powerful tool in bioimaging as it can eliminate autofluorescence, increase imaging contrast, reduce irradiation damage, and increase excitation penetration depth in vivo. In particular, triplet–triplet annihilation upconverting (TTA‐UC) nanoparticles and liposomes offer high upconversion efficiency at low excitation power. However, TTA‐UC is quenched in air by oxygen, which also leads to the formation of toxic singlet oxygen. In this work, polyisobutylene‐monomethyl polyethylene glycol block copolymers are synthesized and used for preparing polymersomes that upconvert red light into blue light in absence of oxygen. In addition, it is demonstrated that biocompatible antioxidants such as l ‐ascorbate, glutathionate, l ‐histidine, sulfite, trolox, or even opti‐MEM medium, can be used to protect the TTA‐UC process in these polymersomes resulting in red‐to‐blue upconversion under aerobic conditions. Most importantly, this approach is also functional in living cells. When A549 lung carcinoma cells are treated with TTA‐UC polymersomes in the presence of 5 × 10^?3 m ascorbate and glutathionate, upconversion in the living cells is one order of magnitude brighter than that observed without antioxidants. These results propose a simple chemical solution to the issue of oxygen sensitivity of TTA‐UC, which is of paramount importance for the technological advancement of this technique in biology.     

Rewritable Optical Memory Through High‐Registry Orthogonal Upconversion

An experimental design, based on a combination of core–shell‐structured upconversion nanoparticles and diarylethene photochromic molecules, for achieving rewritable optical memory is reported. This core–shell design enables the nanoparticles to emit two sets of distinct emission bands with ultrahigh spectral purity through laser excitation at 980 and 1532 nm. Importantly, the ultraviolet emission of the nanoparticles under 980 nm irradiation is used to activate the cyclization reaction of diarylethene through C? C bond formation, while the green emission from the nanoparticles upon 1532 nm excitation leads to the cleavage of the newly formed C? C bond. This pathway offers a convenient and versatile optical method for controlling the process of data writing and erasing with high spatiotemporal resolution.