Unrestricted molecular motions enable mild photothermy for recurrence-resistant FLASH antitumor radiotherapy.

Ultrahigh dose-rate (FLASH) radiotherapy is an emerging technology with excellent therapeutic effects and low biological toxicity. However, tumor recurrence largely impede the effectiveness of FLASH therapy. Overcoming tumor recurrence is crucial for practical FLASH applications. Here, we prepared an agarose-based thermosensitive hydrogel containing a mild photothermal agent (TPE-BBT) and a glutaminase inhibitor (CB-839). Within nanoparticles, TPE-BBT exhibits aggregation-induced emission peaked at 900 nm, while the unrestricted molecular motions endow TPE-BBT with a mild photothermy generation ability. The balanced photothermal effect and photoluminescence are ideal for phototheranostics. Upon 660-nm laser irradiation, the temperature-rising effect softens and hydrolyzes the hydrogel to release TPE-BBT and CB-839 into the tumor site for concurrent mild photothermal therapy and chemotherapy, jointly inhibiting homologous recombination repair of DNA. The enhanced FLASH radiotherapy efficiently kills the tumor tissue without recurrence and obvious systematic toxicity. This work deciphers the unrestricted molecular motions in bright organic fluorophores as a source of photothermy, and provides novel recurrence-resistant radiotherapy without adverse side effects.

Glutathione-responsive Aggregation-induced Emission Photosensitizers for Enhanced Photodynamic Therapy of Lung Cancer.

Lung cancer, a highly prevalent and lethal form of cancer, is often associated with oxidative stress. Photodynamic therapy (PDT) has emerged as a promising alternative therapeutic tool in cancer treatments, but its efficacy is closely correlated to the photosensitizers generating reactive oxygen species (ROS) and the antioxidant capacity of tumor cells. In particular, glutathione (GSH) can reduce the ROS and thus compromise PDT efficacy. In this study, a GSH-responsive near-infrared photosensitizer (TBPPN) based on aggregation-induced emission for real-time monitoring of GSH levels and enhanced PDT for lung cancer treatment is developed. The strategic design of TBPPN, consisting of a donor-acceptor structure and incorporation of dinitrobenzene, enables dual functionality by not only the fluorescence being activated by GSH but also depleting GSH to enhance the cytotoxic effect of PDT. TBPPN demonstrates synergistic PDT efficacy in vitro against A549 lung cancer cells by specifically targeting different cellular compartments and depleting intracellular GSH. In vivo studies further confirm that TBPPN can effectively inhibit tumor growth in a mouse model with lung cancer, highlighting its potential as an integrated agent for the diagnosis and treatment of lung cancer. This approach enhances the effectiveness of PDT for lung cancer and deserves further exploration of its potential for clinical application.

Platinum complexes with aggregation-induced emission.

Transition metal-containing materials with aggregation-induced emission (AIE) have brought new opportunities for the development of biological probes, optoelectronic materials, stimuli-responsive materials, sensors, and detectors. Coordination compounds containing the platinum metal have emerged as a promising option for constructing effective AIE platinum complexes. In this review, we classified AIE platinum complexes based on the number of ligands. We focused on the development and performance of AIE platinum complexes with different numbers of ligands and discussed the impact of platinum ion coordination and ligand structure variation on the optoelectronic properties. Furthermore, this review analyzes and summarizes the influence of molecular geometries, stacking models, and aggregation environments on the optoelectronic performance of these complexes. We provided a comprehensive overview of the AIE mechanisms exhibited by various AIE platinum complexes. Based on the unique properties of AIE platinum complexes with different numbers of ligands, we systematically summarized their applications in electronics, biological fields, etc. Finally, we illustrated the challenges and opportunities for future research on AIE platinum complexes, aiming at giving a comprehensive summary and outlook on the latest developments of functional AIE platinum complexes and also encouraging more researchers to contribute to this promising field.

Exciting Bacteria to a Hypersensitive State for Enhanced Aminoglycoside Therapy by a Rationally Constructed AIE Luminogen.

The diminishing effectiveness of existing aminoglycoside antibiotics (AGs) compels scientists to seek new approaches to enhance the sensitivity of current AGs. Despite ongoing efforts, currently available approaches remain restricted. Herein, a novel strategy involving the rational construction of an aggregation-induced-emission luminogen (AIEgen) is introduced to significantly enhance Gram-positive bacteria's susceptibility to AGs. The application of this approach involves the simple addition of AIEgens to bacteria followed by a 5 min light irradiation. Under light exposure, AIEgens efficiently generate reactive oxygen species (ROS), elevating intrabacterial ROS levels to a nonlethal threshold. Post treatment, the bacteria swiftly enter a hypersensitive state, resulting in a 21.9-fold, 15.5-fold, or 7.2-fold increase in susceptibility to three AGs: kanamycin, gentamycin, and neomycin, respectively. Remarkably, this approach is specific to AGs, and the induced hypersensitivity displays unparalleled longevity and heritability. Further in vivo studies confirm a 7.0-fold enhanced bactericidal ability of AGs against Gram-positive bacteria through this novel approach. This research not only broadens the potential applications of AIEgens but also introduces a novel avenue to bolster the effectiveness of AGs in combating bacterial infections.

Regulation of urea cycle by reversible high-stoichiometry lysine succinylation.

The post-translational modification lysine succinylation is implicated in the regulation of various metabolic pathways. However, its biological relevance remains uncertain due to methodological difficulties in determining high-impact succinylation sites. Here, using stable isotope labelling and data-independent acquisition mass spectrometry, we quantified lysine succinylation stoichiometries in mouse livers. Despite the low overall stoichiometry of lysine succinylation, several high-stoichiometry sites were identified, especially upon deletion of the desuccinylase SIRT5. In particular, multiple high-stoichiometry lysine sites identified in argininosuccinate synthase (ASS1), a key enzyme in the urea cycle, are regulated by SIRT5. Mutation of the high-stoichiometry lysine in ASS1 to succinyl-mimetic glutamic acid significantly decreased its enzymatic activity. Metabolomics profiling confirms that SIRT5 deficiency decreases urea cycle activity in liver. Importantly, SIRT5 deficiency compromises ammonia tolerance, which can be reversed by the overexpression of wild-type, but not succinyl-mimetic, ASS1. Therefore, lysine succinylation is functionally important in ammonia metabolism.

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.

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.

Recyclable and Environmentally Friendly Magnetic Nanoparticles with Aggregation-Induced Emission Photosensitizer for Sustainable Bacterial Inactivation in Water.

Bacterial photodynamic inactivation based on the combined actions of photosensitizers, light, and oxygen presents a promising alternative for eliminating bacteria compared to conventional water disinfection methods. However, a significant challenge in this approach is the inability to retrieve photosensitizers after phototreatment, posing potential adverse environmental impacts. Additionally, conventional photosensitizers often exhibit limited photostability and photodynamic efficiency. This study addresses these challenges by employing an aggregation-induced emission (AIE) photosensitizer, iron oxide magnetic nanoparticles (Fe3O4 MNPs), and Pluronic F127 to fabricate AIE magnetic nanoparticles (AIE MNPs). AIE MNPs not only exhibit fluorescence imaging capabilities and superior photosensitizing ability but also demonstrate broad-spectrum bactericidal activities against both Gram-positive and Gram-negative bacteria. The controlled release of TPA-Py-PhMe and magnetic characteristics of the AIE MNPs facilitate reuse and recycling for multiple cycles of bacterial inactivation in water. Our findings contribute valuable insights into developing environmentally friendly disinfectants, emphasizing the full potential of AIE photosensitizers in photodynamic inactivation beyond biomedical applications.

Co-aggregation as A Simple Strategy for Preparing Fluorogenic Tetrazine Probes with On-Demand Fluorogen Selection.

Life science has progressed with applications of fluorescent probes-fluorophores linked to functional units responding to biological events. To meet the varied demands across experiments, simple organic reactions to connect fluorophores and functional units have been developed, enabling the on-demand selection of fluorophore-functional unit combinations. However, organic synthesis requires professional equipment and skills, standing as a daunting task for life scientists. In this study, we present a simple, fast, and convenient strategy for probe preparation: co-aggregation of hydrophobic molecules. We focused on tetrazine-a difficult-to-prepare yet useful functional unit that provides effective bioorthogonal reactivity and strong fluorogenicity. Simply mixing the tetrazine molecules and aggregation-induced emission (AIE) luminogens in water, co-aggregation is induced, and the emission of AIE luminogens is quenched. Subsequent click reaction bioorthogonally turns on the emission, identifying these coaggregates as fluorogenic probes. Thanks to this bioorthogonal fluorogenicity, we established a new time-gated fluorescence bioimaging technique to distinguish overlapping emission signals, enabling multi-organelle imaging with two same-color fluorophores. Our study showcases the potential of this co-aggregation method for the on-demand preparation of fluorescent probes as well as protocols and molecular design principles in this approach, offering an effective solution to evolving needs in life science research.

Origins of Selectivity in Glycosylation Reactions with Saccharosamine Donors.

A combination of DFT calculations and experiments is used to describe how the selection of a promoter can control the stereochemical outcome of glycosylation reactions with the deoxy sugar saccharosamine. Depending on the promoter, either α- or ß-linked reactive intermediates are formed. These studies show that differential modes of activation lead to the formation of distinct intermediates that undergo highly selective reactions through an SN2-like mechanism.

Hodgkin lymphoma associated vanishing bile duct syndrome treated successfully with a brentuximab based regimen.

We report a combination therapy to successfully treat a patient with Hodgkin's lymphoma complicated by vanishing bile duct syndrome. Our patient was in his 20s and presented with jaundice, emesis, B symptoms and diffuse lymphadenopathy along with cholestatic liver injury prompting a liver biopsy, which revealed this diagnosis, after the exclusion of other aetiologies. Our treatment regimen incorporated brentuximab along with other more conventional agents which attempted to maximise therapeutic efficacy while minimising the consequences of hepatotoxicity on the treatment protocol. Although this patient's treatment course was complicated because of neutropenic infections, the patient achieved a complete metabolic response and is now more than 1 year off therapy.

Conformational Properties of Aryl S-Glucosides in Solution.

The conformational study of saccharides and glycomimetics in solution is critical for a comprehensive understanding of their interactions with biological receptors and enabling the design of optimized glycomimetics. Here, we report a nuclear magnetic resonance (NMR) study centered on the conformational properties of the hydroxymethyl group and glycosidic bond of four series of aryl S-glucosides. We found that in acetyl-protected and free aryl S-ß-glucosides, the rotational equilibrium around the C5-C6 bond (hydroxymethyl group) exhibits a linear dependence on the electronic properties of the aglycone, namely, as the aryl's substituent electron-withdrawing character increases, the dominance of the gg rotamer declines and the gt contribution rises. Likewise, the conformational equilibrium around the glycosidic C1-S bond also depends on the aglycone's electronic properties, where glucosides carrying electron-poor aglycones exhibit stiffer glycosidic bonds in comparison to their electron-rich counterparts. In the case of the α anomers, the aglycone's effect over the glycosidic bond conformation is like that observed on their ß isomers; however, we observe no aglycone's influence over the hydroxymethyl group conformation in the α-glucosides.

Integrating Anion-π+ Interaction and Crowded Conformation to Develop Multifunctional NIR AIEgen for Effective Tumor Theranostics via Hippo-YAP Pathway.

The technology of aggregation-induced emission (AIE) presents a promising avenue for fluorescence imaging-guided photodynamic cancer therapy. However, existing near-infrared AIE photosensitizers (PSs) frequently encounter limitations, including tedious synthesis, poor tumor retention, and a limited understanding of the underlying molecular biology mechanism. Herein, an effective molecular design paradigm of anion-π+ interaction combined with the inherently crowded conformation that could enhance fluorescence efficacy and reactive oxygen species generation was proposed through a concise synthetic method. Mechanistically, upon photosensitization, the Hippo signaling pathway contributes to the death of melanoma cells and promotes the nuclear location of its downstream factor, yes-associated protein, which regulates the transcription and expression of apoptosis-related genes. The finding in this study would trigger the development of high-performance and versatile AIE PSs for precision cancer therapy based on a definite regulatory mechanism.

More Is Better: Dual-Acceptor Engineering for Constructing Second Near-Infrared Aggregation-Induced Emission Luminogens to Boost Multimodal Phototheranostics.

The manipulation of electron donor/acceptor (D/A) shows an endless impetus for innovating optical materials. Currently, there is booming development in electron donor design, while research on electron acceptor engineering has received limited attention. Inspired by the philosophical idea of "more is different", two systems with D'-D-A-D-D' (1A system) and D'-D-A-A-D-D' (2A system) structures based on acceptor engineering were designed and studied. It was demonstrated that the 1A system presented a weak aggregation-induced emission (AIE) to aggregation-caused quenching (ACQ) phenomenon, along with the increased acceptor electrophilicity and planarity. In sharp contrast, the 2A system with one more acceptor exhibited an opposite ACQ-to-AIE transformation. Interestingly, the fluorophore with a more electron-deficient A-A moiety in the 2A system displayed superior AIE activity. More importantly, all compounds in the 2A system showed significantly higher molar absorptivity (ε) in comparison to their counterparts in the 1A system. Thanks to the highest ε, near-infrared-II (NIR-II, 1000-1700 nm) emission, desirable AIE property, favorable reactive oxygen species (ROS) generation, and high photothermal conversion efficiency, a representative member of the 2A system handily performed in fluorescence-photoacoustic-photothermal multimodal imaging-guided photodynamic-photothermal collaborative therapy for efficient tumor elimination. Meanwhile, the NIR-II fluorescence imaging of blood vessels and lymph nodes in living mice was also accomplished. This study provides the first evidence that the dual-connected acceptor tactic could be a new molecular design direction for the AIE effect, resulting in high ε, aggregation-intensified NIR-II fluorescence emission, and improved ROS and heat generation capacities of phototheranostic agents.

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.

Powerful Synergy of Traditional Chinese Medicine and Aggregation-Induced Emission-Active Photosensitizer in Photodynamic Therapy.

Breast cancer (BC) remains a significant global health challenge for women despite advancements in early detection and treatment. Isoliquiritigenin (ISL), a compound derived from traditional Chinese medicine, has shown potential as an anti-BC therapy, but its low bioavailability and poor water solubility restrict its effectiveness. In this study, we created theranostic nanoparticles consisting of ISL and a near-infrared (NIR) photosensitizer, TBPI, which displays aggregation-induced emission (AIE), with the goal of providing combined chemo- and photodynamic therapies (PDT) for BC. Initially, we designed an asymmetric organic molecule, TBPI, featuring a rotorlike triphenylamine as the donor and 1-methylpyridinium iodide as the acceptor, which led to the production of reactive oxygen species in mitochondria. We then combined TBPI with ISL and encapsulated them in DSPE-PEG-RGD nanoparticles to produce IT-PEG-RGD nanoparticles, which showed high affinity for BC, better intersystem crossing (ISC) efficiency, and Förster resonance energy transfer (FRET) between TBPI and ISL. In both 4T1 BC cell line and a 4T1 tumor-bearing BC mouse model, the IT-PEG-RGD nanoparticles demonstrated excellent drug delivery, synergistic antitumor effects, enhanced tumor-killing efficacy, and reduced drug dosage and side effects. Furthermore, we exploited the optical properties of TBPI with ISL to reveal the release process and distribution of nanoparticles in cells. This study provides a valuable basis for further exploration of IT-PEG-RGD nanoparticles and their anticancer mechanisms, highlighting the potential of theranostic nanoparticles in BC treatment.

Integration of AIEgens into covalent organic frameworks for pyroptosis and ferroptosis primed cancer immunotherapy.

Immunogenic programmed cell death, such as pyroptosis and ferroptosis, efficiently induces an acute inflammatory response and boosts antitumor immunity. However, the exploration of dual-inducers, particularly nonmetallic inducers, capable of triggering both pyroptosis and ferroptosis remains limited. Here we show the construction of a covalent organic framework (COF-919) from planar and twisted AIEgen-based motifs as a dual-inducer of pyroptosis and ferroptosis for efficient antitumor immunity. Mechanistic studies reveal that COF-919 displays stronger near-infrared light absorption, lower band energy, and longer lifetime to favor the generation of reactive oxygen species (ROS) and photothermal conversion, triggering pyroptosis. Because of its good ROS production capability, it upregulates intracellular lipid peroxidation, leading to glutathione depletion, low expression of glutathione peroxidase 4, and induction of ferroptosis. Additionally, the induction of pyroptosis and ferroptosis by COF-919 effectively inhibits tumor metastasis and recurrence, resulting in over 90% tumor growth inhibition and cure rates exceeding 80%.

AIEgen-Based Covalent Organic Frameworks for Preventing Malignant Ventricular Arrhythmias Via Local Hyperthermia Therapy.

The engineering of aggregation-induced emission luminogens (AIEgen) based covalent organic frameworks (COFs), TDTA-COF, BTDTA-COF, and BTDBETA-COF are reported, as hyperthermia agents for inhibiting the occurrence of malignant ventricular arrhythmias (VAs). These AIE COFs exhibit dual functionality, as they not only directly modulate the function and neural activity of stellate ganglion (SG) through local hyperthermia therapy (LHT) but also induce the browning of white fat and improve the neuroinflammation peri-SG microenvironment, which is favorable for inhibiting ischemia-induced VAs. In vivo studies have confirmed that BTDBETA-COF-mediated LHT enhances thermogenesis and browning-related gene expression, thereby serving a synergistic role in combating VAs. Transcriptome analysis of peri-SG adipose tissue reveals a substantial downregulation of inflammatory cytokines, highlighting the potency of BTDBETA-COF-mediated LHT in ameliorating the neuroinflammation peri-SG microenvironment and offering myocardial and arrhythmia protection. The work on AIE COF-based hyperthermia agent for VAs inhibition provides a new avenue for mitigating cardiac sympathetic nerve hyperactivity.

The Role of Structural Hydrophobicity on Cationic Amphiphilic Aggregation-Induced Emission Photosensitizer-Bacterial Interaction and Photodynamic Efficiency.

The aggregation-induced emission photosensitizer (AIE PS) has stood out as an alternative and competent candidate in bacterial theranostics, particularly with the use of cationic AIE PS in bacterial discrimination and elimination. Most reported work emphasizes the role of electrostatic interaction between cationic AIE PS and negatively charged bacterial surfaces, enabling broad applications from bacterial discrimination to bacterial killing. However, the underlying targeting mechanism and the design rationale of the cationic AIE PS for effective bacterial labeling remain poorly investigated. In this Article, we designed and synthesized a series of cationic amphiphilic AIE PSs with different calculated log P values. Then, we systemically studied the relationship between the hydrophobicity variation of AIE PS and bacterial targeting outcomes, the dose of AIE PS needed to label various species of bacteria, and their photodynamic antibacterial efficiency. The findings in this work provide a better understanding of the unclear AIE PS-bacterial interaction mechanism and some insights into the structural design strategies of cationic amphiphilic AIE PS for better development in bacterial theranostics.

In Vivo Aggregation of Clearable Bimetallic Nanoparticles with Interlocked Surface Motifs for Cancer Therapeutics Amplification.

Although renal-clearable luminescent metal nanoparticles (NPs) have been widely developed, their application to efficient cancer therapy is still limited due to low reactive oxygen species (ROS) production. Here, a novel system of clearable mercaptosuccinic acid (MSA) coated Au-Ag bimetallic NPs is designed to enhance ROS production. The results show that the strong COO-Ag coordination bonds between the carboxylic acid groups of MSA and Ag atoms on the Au-Ag bimetallic NPs could construct high-rigidity interlocked surface motifs to restrict the intrananoparticle motions for enhanced ROS generation. Moreover, bimetallic NPs exhibit pH-responsive self-assembly capability under the acidic environment inside lysosomes of cancer cells at both in vitro and in vivo, restricting the internanoparticle motions to further boost ROS production. The well-designed bimetallic NPs show high tumor targeting efficiency, fast elimination from the body through rapid liver biotransformation, and extensive destruction to cancer cells, resulting in good security and prominent therapeutic performance.