Apoptotic Vesicular Metabolism Contributes to Organelle Assembly and Safeguards Liver Homeostasis and Regeneration.

BACKGROUND & AIMS: Apoptosis generates plenty of membrane-bound nanovesicles, the apoptotic vesicles (apoVs), which show promise for biomedical applications. The liver serves as a significant organ for apoptotic material removal. Whether and how the liver metabolizes apoptotic vesicular products and contributes to liver health and disease is unrecognized. METHODS: apoVs were labeled and traced after intravenous infusion. Apoptosis-deficient mice by Fas mutant (Fasmut) and Caspase-3 knockout (Casp3-/-) were used with apoV replenishment to evaluate the physiological apoV function. Combinations of morphologic, biochemical, cellular, and molecular assays were applied to assess the liver while hepatocyte analysis was performed. Partial hepatectomy and acetaminophen liver failure models were established to investigate liver regeneration and disease recovery. RESULTS: We discovered that the liver is a major metabolic organ of circulatory apoVs, in which apoVs undergo endocytosis by hepatocytes via a sugar recognition system. Moreover, apoVs play an indispensable role to counteract hepatocellular injury and liver impairment in apoptosis-deficient mice upon replenishment. Surprisingly, apoVs form a chimeric organelle complex with the hepatocyte Golgi apparatus through the soluble N-ethylmaleimide-sensitive factor attachment protein receptor machinery, which preserves Golgi integrity, promotes microtubule acetylation by regulating α-tubulin N-acetyltransferase 1, and consequently facilitates hepatocyte cytokinesis for liver recovery. The assembly of the apoV-Golgi complex is further revealed to contribute to liver homeostasis, regeneration, and protection against acute liver failure. CONCLUSIONS: These findings establish a previously unrecognized functional and mechanistic framework that apoptosis through vesicular metabolism safeguards liver homeostasis and regeneration, which holds promise for hepatic disease therapeutics.

A Holistic Perspective on Living Aggregate.

Aggregate is one of the most extensive existing modes of matters in the world. Besides the research objectives of inanimate systems in physical science, the entities in life science can be regarded as living aggregates, which are far from being thoroughly understood despite the great advances in molecular biology. Molecular biology follows the research philosophy of reductionism, which generally reduces the whole into parts to study. Although reductionism benefits the understanding of molecular behaviors, it encounters limitations when extending to the aggregate level. Holism is another epistemology comparable to reductionism, which studies objectives at the aggregate level, emphasizing the interactions and synergetic/antagonistic effects of a group of composed single entities in determining the characteristics of a whole. As a representative of holism, aggregation-induced emission (AIE) materials have made great achievements in the past two decades in both physical and life science. In particular, the unique properties of AIE materials endow them with in situ and real-time visual methods to investigate the inconsistency between microscopic molecules and macroscopic substances, offering researchers excellent toolkits to study living aggregates. The applications of AIE materials in life science are still in their infancy and worth expanding. In this Perspective, we summarize the research progress of AIE materials in unveiling some phenomena and processes of living systems, aiming to provide a general research approach from the viewpoint of holism. At last, insights into what we can do in the near future are also raised and discussed.

Red/NIR emissive aggregation-induced emission-active photosensitizers with strong donor-acceptor strength for image-guided photodynamic therapy of cancer.

Light-mediated therapies such as photodynamic therapy (PDT) are considered emerging cancer treatment strategies. However, there are still lots of defect with common photosensitizers (PSs), such as short emission wavelength, weak photostability, poor cell permeability, and low PDT efficiency. Therefore, it is very important to develop high-performance PSs. Recently, luminogens with aggregation-induced emission (AIE) characteristics and red/near-infrared (NIR) emissive have been reported as promising PSs for image-guided cancer therapy, due to them being able to prevent autofluorescence in physiological environments, their enhanced fluorescence in the aggregated state, and generation of reactive oxygen species (ROS). Herein, we developed PSs named TBTCPM and MTBTCPM with donor-acceptor (D-A) structures, strong red/NIR, excellent targeting specificities to good cell permeability, and high photostability. Interestingly, both of them can efficiently generate ROS under white light irradiation and possess excellent killing effect on cancer cells. This study, thus, not only demonstrates applications in cell image-guided PDT cancer therapy performances but also provides strategy for construction of AIEgens with long emission wavelengths.

Precise Molecular Engineering of Type I Photosensitizer with Aggregation-Induced Emission for Image-Guided Photodynamic Eradication of Biofilm.

Biofilm-associated infections exert more severe and harmful attacks on human health since they can accelerate the generation and development of the antibiotic resistance of the embedded bacteria. Anti-biofilm materials and techniques that can eliminate biofilms effectively are in urgent demand. Therefore, we designed a type I photosensitizer (TTTDM) with an aggregation-induced emission (AIE) property and used F-127 to encapsulate the TTTDM into nanoparticles (F-127 AIE NPs). The NPs exhibit highly efficient ROS generation by enhancing intramolecular D-A interaction and confining molecular non-radiative transitions. Furthermore, the NPs can sufficiently penetrate the biofilm matrix and then detect and eliminate mature bacterial biofilms upon white light irradiation. This strategy holds great promise for the rapid detection and eradication of bacterial biofilms.

Pursuing Phase Transitions of a Concentrated Polymer Solution by In Situ Fluorescence Measurements Based On Aggregation-Induced Emission.

Concentration-dependent phase transitions in concentrated solutions have remained speculation due to the serious impediment of macromolecule dynamics by intensive topological entanglement or intermolecular interaction as well as the absence of powerful tool for detecting changes in chain or segment movement. Herein, taking a general polymer, namely, poly(vinyl alcohol) (PVA), as an example, a water-soluble fluorescent molecule with aggregation-induced emission (AIE) is introduced into the PVA solutions as a chain dynamics indicator to investigate phase transitions at high concentrations through in situ monitoring of the solvent evaporation process. Two turning points of fluorescent intensity are observed for the first time at mean concentrations of ∼25% and ∼45%, corresponding to the gelation and amorphous-to-crystalline transitions, respectively. Our work offers a fundamental insight into the physical nature of concentrate-dependent nonequilibrium transitions and develops a reliable and sensitive approach based on the AIE phenomenon for following high-concentration-triggered property changes of a polymer solution.

Recent advances of aggregation-induced emission materials for fluorescence image-guided surgery.

Real-time intraoperative guidance is essential during various surgical treatment of many diseases. Aggregation-induced emission (AIE) materials have shown great potential for guiding surgeons during complex interventions, with the merits of deep tissue penetration, high quantum yield, high molar absorptivity, low background, good targeting ability and excellent photostability. Herein, we provided insights to design efficient AIE materials regarding three key parameters, i.e., deep-tissue penetration ability, high brightness of AIE luminogens (AIEgens), and precise tumor/other pathology nidus targeting strategies, for realizing better application of fluorescence image-guided surgery. Representative interdisciplinary achievements were outlined for the demonstration of this emerging field. Challenges and future opportunities of AIE materials were briefly discussed. The aim of this review is to provide a comprehensive view of AIE materials for intraoperative guidance for researchers and surgeons, and to inspire more further correlational studies in the new frontiers of image-guided surgery.

Recent advances in aggregation-induced emission luminogens in photoacoustic imaging.

Photoacoustic imaging (PAI) is a rapidly emerging modality in biomedical research with the advantages of noncontact operation, high optical resolution, and deep penetration. Great efforts and progress in the development of PAI agents with improved imaging resolution and sensitivity have been made over the past 2 decades. Among them, organic agents are the most promising candidates for preclinical/clinical applications due to their outstanding in vivo properties and facile biofunctionalities. Motivated by the unique properties of aggregation-induced emission (AIE) luminogens (AIEgens), various optical probes have been developed for bioanalyte detection, multimodal bioimaging, photodynamic/photothermal therapy, and imaging-guided therapeutics. In particular, AIE-active contrast agents have been demonstrated in PAI applications with excellent performance in imaging resolution and tissue permeability in vivo. This paper presents a brief overview of recent progress in AIE-based agents in the field of photoacoustic imaging. In particular, we focus on the basic concepts, data sorting and comparison, developing trends, and perspectives of photoacoustic imaging. Through numerous typical examples, the way each system realizes the desired photoacoustic performance in various biomedical applications is clearly illustrated. We believe that AIE-based PAI agents would be promising multifunctional theranostic platforms in clinical fields and will facilitate significant advancements in this research topic.

Tunable Linear and Nonlinear Optical Properties from Room Temperature Phosphorescent Cyclic Triimidazole-Pyrene Bio-Probe.

Organic materials with multiple emissions tunable by external stimuli represent a great challenge. TTPyr, crystallizing in different polymorphs, shows a very rich photophyisics comprising excitation-dependent fluorescence and phosphorescence at ambient conditions, and mechanochromic and thermochromic behavior. Transformation among the different species has been followed by thermal and X-ray diffraction analyses and the emissive features interpreted through structural results and DFT/TDDFT calculations. Particularly intriguing is the polymorph TTPyr(HT), serendipitously obtained at high temperature but stable also at room temperature, whose non-centrosymmetric structure guarantees an SHG efficiency 10 times higher than that of standard urea. Its crystal packing, where only the TT units are strongly rigidified by π-π stacking interactions while the Pyr moieties possess partial conformational freedom, is responsible for the observed dual fluorescence. The potentialities of TTPyr for bioimaging have been successfully established.

AIE-based theranostic systems for detection and killing of pathogens.

Pathogenic bacteria, fungi and viruses pose serious threats to the human health under appropriate conditions. There are many rapid and sensitive approaches have been developed for identification and quantification of specific pathogens, but many challenges still exist. Culture/colony counting and polymerase chain reaction are the classical methods used for pathogen detection, but their operations are time-consuming and laborious. On the other hand, the emergence and rapid spread of multidrug-resistant pathogens is another global threat. It is thus of utmost urgency to develop new therapeutic agents or strategies. Luminogens with aggregation-induced emission (AIEgens) and their derived supramolecular systems with unique optical properties have been developed as fluorescent probes for turn-on sensing of pathogens with high sensitivity and specificity. In addition, AIE-based supramolecular nanostructures exhibit excellent photodynamic inactivation (PDI) activity in aggregate, offering great potential for not only light-up diagnosis of pathogen, but also image-guided PDI therapy for pathogenic infection.

Theranostics based on AIEgens.

The utilization of luminogens with aggregation-induced emission (AIE) characteristics has recently been developed at a tremendous pace in the area of theranostics, mainly because AIE luminogens (AIEgens) hold various distinct advantages, such as good biocompatibility, excellent fluorescence properties, simple preparation and modification, perfect size of nano-aggregation for enhanced permeability and retention effect, promoted efficiencies of photodynamic and photothermal therapies, efficient photoacoustic imaging, and ready constructions of multimodal imaging and therapy. Significant breakthroughs and developments of theranostics based on AIEgens have been achieved in the past few years, and great progress has been witnessed in many theranostic modalities, indicating that AIEgens remarkably complement conventional theranostic materials and promote the development of theranostics. This review provides theoretical insights into the advantages of AIEgens in theranostics, and systematically summarizes the basic concepts, seminal studies, recent trends and perspectives in theranostics based on AIEgens. We believe that AIEgens would be promising multifunctional theranostic platforms in clinical fields and facilitate significant advancements in this research-active area.

Long-Term Real-Time In Vivo Drug Release Monitoring with AIE Thermogelling Polymer.

A new drug concentration meter is developed. In vivo drug release can be monitored precisely via a self-indicating drug delivery system consisting of a new aggregation-induced emission thermoresponsive hydrogel. By taking the advantage of a self-indicating system, one can easily detect the depletion of drugs, and reinject to maintain a dosage in the optimal therapeutic window.

A Lysosome-Targeting AIEgen for Autophagy Visualization.

In this work, a morpholine-functionalized aggregation-induced emission luminogen (AIEgen), AIE-LysoY, is reported for lysosomal imaging and autophagy visualization. To attain outstanding imaging contrast, AIE-LysoY is equipped with excited state intramolecular proton transfer (ESIPT) characteristic. AIE-LysoY provides a new platform for lysosome visualization with good biocompatibility, large Stokes shift, superior signal-to-noise ratio, and high photostability.

Detection of oligomers and fibrils of α-synuclein by AIEgen with strong fluorescence.

We report a fluorophore, TPE-TPP, with AIE characteristics which is utilized as a fluorescence probe to monitor the α-synuclein (α-Syn) fibrillation process. Compared with ThT, TPE-TPP shows a higher sensitivity in the detection of α-Syn oligomers as well as fibrils with a stronger fluorescence. The performance of TPE-TPP was evaluated using fluorescence, AFM, dot blot, and SEC.

Fluorescent light-up probe with aggregation-induced emission characteristics for alkaline phosphatase sensing and activity study.

Fluorogens with aggregation-induced emission (AIE) characteristics have attracted intensified research interest in biosensing applications, and those with specific targeting ability are especially desirable. In this work, we designed and synthesized an AIE fluorescent probe by functionalizing a tetraphenylethylene (TPE) fluorogen with two phosphate groups (TPE-phos) for the detection of alkaline phosphatase (ALP) and its enzymatic activity based on the specific interaction between the probe and ALP. The probe is virtually nonfluorescent in aqueous media due to good water solubility. In the presence of ALP, the phosphate groups are cleaved through enzymatic hydrolysis, yielding a highly fluorescent product as a result of activated AIE process. This light-up probe shows excellent selectivity toward ALP among a group of proteins. The detection limit is found to be 11.4 pM or 0.2 U L(-1) in Tris buffer solution with a linear quantification range of 3-526 U L(-1). The assay is also successfully performed in diluted serum with a linear range up to 175 U L(-1), demonstrating its potential application in clinical analysis of ALP levels in real samples. Furthermore, by conducting kinetic analysis of the enzyme using TPE-phos as the substrate, the kinetic parameter kcat/KM is determined to be 5.1×10(5) M(-1) s(-1), indicating a high efficiency of the substrate.

Fluorogenic Zn(II) and chromogenic Fe(II) sensors based on terpyridine-substituted tetraphenylethenes with aggregation-induced emission characteristics.

Terpyridine-containing tetraphenylethenes (TPEs) are synthesized and their optical and metal sensing properties are investigated. They are practically nonluminescent in the solution state but become highly emissive as nanoparticle suspensions in poor solvents or thin films in the solid state, demonstrating a novel phenomenon of aggregation-induced emission (AIE). The emission of the nanoaggregates of TPEs is pH-sensitive: it is decreased and eventually quenched upon protonation of their terpyridine units because of their AIE nature. The TPEs can work as "turn-off" fluorescent chemosensors for metal ions and display different fluorescence responses to various metal ions. A characteristic red shift in the emission spectra is observed in the presence of Zn(2+), which facilitates the discrimination of Zn(2+) from other metal ions. Because of the metal-to-ligand-charge-transfer process, terpyridine-substituted TPEs display an obvious magenta color upon selectively binding with Fe(2+), allowing a rapid identification of Fe(2+) in the aqueous media by naked eyes.