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Light has profoundly impacted modern medicine and healthcare, with numerous luminescent agents and imaging techniques currently being used to assess health and treat diseases. As an emerging concept in luminescence, aggregation-induced emission (AIE) has shown great potential in biological applications due to its advantages in terms of brightness, biocompatibility, photostability, and positive correlation with concentration. This review provides a comprehensive summary of AIE luminogens applied in imaging of biological structure and dynamic physiological processes, disease diagnosis and treatment, and detection and monitoring of specific analytes, followed by representative works. Discussions on critical issues and perspectives on future directions are also included. This review aims to stimulate the interest of researchers from different fields, including chemistry, biology, materials science, medicine, etc., thus promoting the development of AIE in the fields of life and health.

Development of a practical point-of-care test for urinalysis is crucial for early diagnosis and treatment of chronic kidney disease (CKD). However, the classical gold standard detection method depends on sophisticated instruments and complicated procedures, impeding them from being utilized in resource-limited settings and daily screening. Herein, we report a rapid point-of-care device for the simultaneous quantification of microalbuminuria and leukocyte using one drop of urine. A luminogen (TTVP) with an aggregation-induced emission property can selectively activate its near-infrared fluorescence in the presence of albumin and leukocyte via hydrophobic or electrostatic interactions. The fluorescence signals from urine albumin and leukocyte could be well-separated combined with the coffee-ring effect. Using a smartphone-based detection device, simultaneous quantification of urine albumin and leukocyte was successfully achieved, which only took 20 min and required one drop of urine. The performance of this system is also verified with 120 clinical samples, which might serve as a simple, low-cost, and rapid tool for CKD screening and disease monitoring at the point of care.

Extracellular vesicle-associated miRNAs (EV-miRNAs) are emerging as a new type of noninvasive biomarker for disease diagnosis. Their relatively low abundance, however, makes accurate detection challenging. Here, we designed a DNA nanowire guided-catalyzed hairpin assembly (NgCHA) nanoprobe for profiling EV-miRNAs. NgCHA showed high penetrability to EVs, which allowed rapid delivery of the probes into EVs. In the presence of targeted miRNAs within EVs, a fluorescent signal could be generated and amplified by confining the catalytic hairpin assembly system within the nanowires, thus greatly enhancing the analytical sensitivity. We showed that EV-miRNAs from various cell lines could be accurately quantified by NgCHA in situ . By using a four-EV-miRNA panel, this platform can identify patients with breast cancer at an early stage with 95.2% sensitivity and 86.7% specificity. Its applications for risk assessment as well as cancer type prediction were also successfully demonstrated. This platform is sensitive, low-cost, and simple compared with current methods. It may thus serve as a promising tool for the noninvasive diagnosis and monitoring of cancers and other diseases through EV-miRNA profiling.

The enzyme-linked immunosorbent assay (ELISA) is one of the most commonly used methods for measuring antibodies and antigens in biological samples. However, developing new ELISAs with high detection sensitivity and broad detection dynamic ranges without resorting to complicated signal processing and equipment setups remains a challenge. In this work, we report a strategy to simultaneously improve the detection sensitivity and broaden the dynamic range by replacing the chromogenic reagents used in traditional ELISAs with an aggregation-induced emission luminogen (AIEgen). The developed AIE-ELISA could generate complementary absorbance and fluorescence signals with a linear detection range of 1.6-25,000 pg/mL. The application of this dual-mode AIE-ELISA in the detection of the prostate-specific antigen (PSA) realized a limit of detection of 1.3 pg/mL (3.78 × 10 -14 M) and dynamic range improvement of approximately 2 orders of magnitude compared to a single-mode ELISA, which enabled it to discriminate a minor PSA difference in a patient's serum. The simpler experimental operation, faster enzyme response speed, and better photostability of AIEgen than the traditional chromogenic reagents used in ELISAs showed that our developed AIE-ELISA holds great potential in the fields of immunoassay, immunohistochemistry, and immunocytochemistry.

Dual-modal fluorescence and magnetic resonance imaging (FLI/MRI) is important for the early diagnosis of malignant tumors. However, facile and opportune strategies to synergistically enhance fluorescence intensity and magnetic resonance (MR) contrast have rarely been reported. Herein, we present a facile strategy using albumin aggregates (AAs) to synergistically enhance the fluorescence intensity by aggregation-induced emission (AIE) and MR contrast with prolonged rotational correlation time (τ R ) of Gd(III) chelates and the diffusion correlation time (τ D ) of surrounding water molecules. The amphiphilic dual-modal FLI/MRI probe of NGd was facilely loaded into albumin pockets and then formed AAs to generate a supramolecular structure of NGd-albumin aggregates (NGd-AAs), which show excellent biocompatibility and biosafety, and exhibit superior fluorescence quantum yield and r 1 over NGd with 6- and 8-fold enhancement, respectively. Moreover, compared with the clinical MRI contrast agent Gd-DOTA, r 1 of NGd-AAs showed a 17-fold enhancement. Therefore, NGd-AAs successfully elicited high-performance dual-modal FLI/MRI in vitro and in vivo and high contrast MR signals were observed in the liver and tumor after intravenous injection of NGd-AAs at a dosage of 6 μmol Gd(III)/kg body weight. This generic and feasible strategy successfully realized a synergistic effect for dual-modal FLI/MRI.

Tumor-derived exosomes carrying unique surface proteins have shown great promise as novel biomarkers for liquid biopsies. However, point-of-care analysis for tumor-derived exosomes in the blood with low-cost and easy processing is still challenging. Herein, we develop an integrated approach, homogenous magneto-fluorescent exosome (hMFEX) nanosensor, for rapid and on-site tumor-derived exosomes analysis. Tumor-derived exosomes are captured immunomagnetically, which further initiates the aptamer-triggered assembly of DNA three-way junctions in homogenous solution containing aggregation-induced emission luminogens and graphene oxide, resulting in an amplified fluorescence signal. By integrating magnetic isolation and enhanced fluorescence measurement, the hMFEX nanosensor detects tumor-derived exosomes in the dynamic range spanning 5 orders of magnitude with high specificity, and the limit of detection is 6.56 × 10 4 particles/μL. Analyzing tumor-derived exosomes in limited volume plasma from breast cancer patients demonstrates the excellent clinical diagnostic efficacy of the hMFEX nanosensor. This study provides new insights into the point-of-care testing of tumor-derived exosomes for cancer diagnostics.

The analysis of albumin has clinical significance in diagnostic tests and obvious value to research studies on the albumin-mediated drug delivery and therapeutics. The present immunoassay, instrumental techniques, and colorimetric methods for albumin detection are either expensive, troublesome, or insensitive. Herein, a class of water-soluble tetrazolate-functionalized derivatives with aggregation-induced emission (AIE) characteristics is introduced as novel fluorescent probes for albumin detection. They can be selectively lighted up by site-specific binding with albumin. The resulting albumin fluorescent assay exhibits a low detection limit (0.21 nM), high robustness in aqueous buffer (pH = 6-9), and a broad tunable linear dynamic range (0.02-3000 mg/L) for quantification. The tetrazolate functionality endows the probes with a superior water solubility (>0.01 M) and a high binding affinity to albumin ( K D = 0.25 μM). To explore the detection mechanism, three unique polar binding sites on albumin are computationally identified, where the multivalent tetrazolate-lysine interactions contribute to the tight binding and restriction of the molecular motion of the AIE probes. The key role of lysine residues is verified by the detection of poly-l-lysine. Moreover, we applied the fluorogenic method to quantify urinary albumin in clinical samples and found it a feasible and practical strategy for albumin analysis in complex biological fluids.

Intraarticular injection of hyaluronic acid (HA) for viscosupplementation is a nonsurgical therapy for osteoarthritis (OA). However, HA fails to lubricate under a significant load and tends to be depolymerized by the overproduction of reactive oxygen species (ROS) in inflammation. Here, we for the first time reported that fullerene-like MoS 2 (F-MoS 2 ) nanoparticles are efficient lubricants and antioxidants for artificial synovial fluid. A model of arthrosis was built, to evaluate the tribological behavior of F-MoS 2 nanoparticles. The tests showed that they significantly improve the antiwear and friction-reducing abilities of the artificial synovial fluid. More importantly, the F-MoS 2 nanoparticles possess intrinsic dual-enzyme-like activity, mimicking superoxide dismutases (SOD) and catalases (CAT) under physiological conditions (pH 7.4, 25 °C). By coupling of these unique properties, a self-organized cascade catalytic system was constructed, which includes the disproportionation of superoxide radicals (O 2 •- ) to hydrogen peroxide (H 2 O 2 ) and subsequently the disproportionation of H 2 O 2 into oxygen (O 2 ). The effectiveness of the detox system was evaluated by human umbilical vein endothelial cells (HUVEC) models exposed to oxidative stress. After that, F-MoS 2 nanoparticles were used to regulate the ROS level in artificial synovial fluid containing HA. Relative viscosity measurements showed the excellent protective effect of F-MoS 2 nanoparticles against HA oxidative damage offered by O 2 •- . These results indicate that F-MoS 2 nanoparticles are promising candidates for treatment of OA and other diseases caused by lubrication deficiency or oxidative stress.

Exosomes shed by tumor cells have been recognized as promising biomarkers for cancer diagnostics due to their unique composition and functions. Quantification of low concentrations of specific exosomes present in very small volumes of clinical samples may be used for noninvasive cancer diagnosis and prognosis. We developed an immunosorbent assay for digital qualification of target exosomes using droplet microfluidics. The exosomes were immobilized on magnetic microbeads through sandwich ELISA complexes tagged with an enzymatic reporter that produces a fluorescent signal. The constructed beads were further isolated and encapsulated into a sufficient number of droplets to ensure only a single bead was encapsulated in a droplet. Our droplet-based single-exosome-counting enzyme-linked immunoassay (droplet digital ExoELISA) approach enables absolute counting of cancer-specific exosomes to achieve unprecedented accuracy. We were able to achieve a limit of detection (LOD) down to 10 enzyme-labeled exosome complexes per microliter (∼10 -17 M). We demonstrated the application of the droplet digital ExoELISA platform in quantitative detection of exosomes in plasma samples directly from breast cancer patients. We believe our approach may have the potential for early diagnosis of cancer and accelerate the discovery of cancer exosomal biomarkers for clinical diagnosis.

The enzymatic antioxidant system (EAS) protects aerobic cells from oxidative stress. However, it is brittle and susceptible of inactivation of reactive oxygen species (ROS) immoderate production. Here, we demonstrated that MoS 2 nanosheets (few-layer MoS 2 ), as a multifunctional nanozyme, possess intrinsic activity of mimicking enzymes of superoxide dismutases (SODs), catalases (CATs), and peroxidases (PODs) under physiological conditions (pH 7.4, 25 °C). Further, MoS 2 nanosheets showed POD-like activity by transferring electrons instead of generating ROS. Similar to EAS, a defense termed nanozymatic antioxidant system (NAS) was developed by MoS 2 nanosheets, for regulation of oxidative stress. Surprisingly, this NAS can effectively scavenge other free radicals including hydroxyl radicals ( • OH), nitrogen-centered free radicals ( • DPPH), and nitric oxide ( • NO). To evaluate these unique properties of MoS 2 -based NAS in vivo, Escherichia coli ( E. coli), Staphylococcus aureus ( S. aureus), and A549 cell models were established, respectively. These results showed MoS 2 nanosheets superiorly protect bacteria and cells against oxidative injury caused by H 2 O 2 . This work makes MoS 2 nanosheets promising antioxidants in the pathological processes and expands their application in biocatalysis and nano-biomedicine.

Accurate analysis of microRNAs (miRNAs) at the single-cell level seriously requires analytical methods possessing extremely high sensitivity, specificity and precision. By rational engineering of a structure-switchable symmetric toehold dumbbell-template (STD-template), we propose a novel isothermal symmetric exponential amplification reaction (SEXPAR) method. The sealed and symmetric structure of the STD-template allows exponential amplification reaction (EXPAR) to occur upon every annealing of target miRNA without loss of amplification efficiency. In addition, the rigid and compact structure of the STD-template with an appropriate standard free energy ensures SEXPAR only be activated by target miRNA. As a result, the SEXPAR method isothermally quantified let-7a down to 0.01 zmol (6.02 copies per 10 μL) with an ultrahigh specificity which is efficient enough to discriminate one-base-mismatched miRNAs, and a remarkably high precision even for the determination of 6.02 copies let-7a (the standard deviation was reduced from >60% down to 23%). The dynamic range was also extended to 10 orders of magnitude. The method was successfully applied for the determination of let-7a in human tissues, sera and even single-cell lysate, with obviously better precision than quantitative reverse transcription polymerase chain reaction (RT-qPCR) and other EXPAR-based methods. The SEXPAR method may serve as a powerful technique for the biological research and biomedical studies of miRNAs and other short nucleic acids.