An All-Rounder for NIR-II Phototheranostics: Well-Tailored 1064 nm-Excitable Molecule for Photothermal Combating of Orthotopic Breast Cancer.

The second near-infrared (NIR-II, 1000-1700 nm) light-activated organic photothermal agent that synchronously enables satisfying NIR-II fluorescence imaging is highly warranted yet rather challenging on the basis of the overwhelming nonradiative decay. Herein, such an agent, namely TPABT-TD, was tactfully designed and constructed via employing benzo[c]thiophene moiety as bulky electron donor/π-bridge and tailoring the peripheral molecular rotors. Benefitting from its high electron donor-acceptor strength and finely modulated intramolecular motion, TPABT-TD simultaneously exhibits ultralong absorption in NIR-II region, intense fluorescence emission in the NIR-IIa (1300-1500 nm) region as nanoaggregates, and high photothermal conversion upon 1064 nm laser irradiation. Those intrinsic advantages endow TPABT-TD nanoparticles with prominent fluorescence/photoacoustic/photothermal trimodal imaging-guided NIR-II photothermal therapy against orthotopic 4T1 breast tumor with negligible adverse effect.

Photothermal therapy of tuberculosis using targeting pre-activated macrophage membrane-coated nanoparticles.

Conventional antibiotics used for treating tuberculosis (TB) suffer from drug resistance and multiple complications. Here we propose a lesion-pathogen dual-targeting strategy for the management of TB by coating Mycobacterium-stimulated macrophage membranes onto polymeric cores encapsulated with an aggregation-induced emission photothermal agent that is excitable with a 1,064 nm laser. The coated nanoparticles carry specific receptors for Mycobacterium tuberculosis, which enables them to target tuberculous granulomas and internal M. tuberculosis simultaneously. In a mouse model of TB, intravenously injected nanoparticles image individual granulomas in situ in the lungs via signal emission in the near-infrared region IIb, with an imaging resolution much higher than that of clinical computed tomography. With 1,064 nm laser irradiation from outside the thoracic cavity, the photothermal effect generated by these nanoparticles eradicates the targeted M. tuberculosis and alleviates pathological damage and excessive inflammation in the lungs, resulting in a better therapeutic efficacy compared with a combination of first-line antibiotics. This precise photothermal modality that uses dual-targeted imaging in the near-infrared region IIb demonstrates a theranostic strategy for TB management.

Thiophene π-Bridge Manipulation of NIR-II AIEgens for Multimodal Tumor Phototheranostics.

The fabrication of a multimodal phototheranostic platform on the basis of single-component theranostic agent to afford both imaging and therapy simultaneously, is attractive yet full of challenges. The emergence of aggregation-induced emission luminogens (AIEgens), particularly those emit fluorescence in the second near-infrared window (NIR-II), provides a powerful tool for cancer treatment by virtue of adjustable pathway for radiative/non-radiative energy consumption, deeper penetration depth and aggregation-enhanced theranostic performance. Although bulky thiophene π-bridges such as ortho-alkylated thiophene, 3,4-ethoxylene dioxythiophene and benzo[c]thiophene are commonly adopted to construct NIR-II AIEgens, the subtle differentiation on their theranostic behaviours has yet to be comprehensively investigated. In this work, systematical investigations discovered that AIEgen BT-NS bearing benzo[c]thiophene possesses acceptable NIR-II fluorescence emission intensity, efficient reactive oxygen species generation, and high photothermal conversion efficiency. Eventually, by using of BT-NS nanoparticles, unprecedented performance on NIR-II fluorescence/photoacoustic/photothermal imaging-guided synergistic photodynamic/photothermal elimination of tumors was demonstrated. This study thus offers useful insights into developing versatile phototheranostic systems for clinical trials.

Thiophene π-bridge-based second near-infrared luminogens with aggregation-induced emission for biomedical applications.

In the past 5 years, aggregation-induced emission luminogens (AIEgens) with emission in the second near-infrared (NIR-II) optical window have aroused great interest in bioimaging and disease phototheranostics, benefiting from the merits of deep penetration depth, reduced light scatting, high spatial resolution, and minimal photodamage. To construct NIR-II AIEgens, thiophene derivatives are frequently adopted as π-bridge by virtue of their electron-rich feature and good modifiability. Herein, we summarize the recent progress of NIR-II AIEgens by employing thiophene derivatives as π-bridge mainly compassing unsubstituted thiophene, alkyl thiophene, 3,4-ethylenedioxythiophene, and benzo[c]thiophene, with a discussion on their structure-property relationships and biomedical applications. Finally, a brief conclusion and perspective on this fascinating area are offered.

Aggregation-Induced Emission-Based Macrophage-Like Nanoparticles for Targeted Photothermal Therapy and Virus Transmission Blockage in Monkeypox.

The recent prevalence of monkeypox has led to the declaration of a Public Health Emergency of International Concern. Monkeypox lesions are typically ulcers or pustules (containing high titers of replication-competent virus) in the skin and mucous membranes, which allow monkeypox virus to transmit predominantly through intimate contact. Currently, effective clinical treatments for monkeypox are lacking, and strategies for blocking virus transmission are fraught with drawbacks. Herein, this work constructs a biomimetic nanotemplate (termed TBD@M NPs) with macrophage membranes as the coat and polymeric nanoparticles loading a versatile aggregation-induced emission featured photothermal molecule TPE-BT-DPTQ as the core. In a surrogate mouse model of monkeypox (vaccinia-virus-infected tail scarification model), intravenously injected TBD@M NPs show precise tracking and near-infrared region II fluorescence imaging of the lesions. Upon 808 nm laser irradiation, the virus is eliminated by the photothermal effect and the infected wound heals rapidly. More importantly, the inoculation of treated lesion tissue suspensions does not trigger tail infection or inflammatory activation in healthy mice, indicating successful blockage of virus transmission. This study demonstrates for the first time monkeypox theranostics using nanomedicine, and may bring a new insight into the development of a viable strategy for monkeypox management in clinical trials.

Adding Flying Wings: Butterfly-Shaped NIR-II AIEgens with Multiple Molecular Rotors for Photothermal Combating of Bacterial Biofilms.

The ever-increasing threats of multidrug-resistant bacteria and their biofilm-associated infections have bred a desperate demand for alternative remedies to combat them. Near-infrared (NIR)-absorbing photothermal agent (PTAs)-mediated photothermal therapy (PTT) is particularly attractive for biofilm ablation thanks to its superiorities of noninvasive intervention, satisfactory antibacterial efficiency, and less likelihood to develop resistance. Herein, three butterfly-shaped aggregation-induced emission luminogens (AIEgens) with balanced nonradiative decay (for conducting PTT) and radiative decay (for supplying fluorescence in the NIR-II optical window) are rationally designed for imaging-assisted photothermal obliteration of bacterial biofilms. After being encapsulated into cationic liposomes, AIEgens-fabricated nanoparticles can eradicate a wide spectrum of biofilms formed by Gram-positive bacteria (methicillin-resistant Staphylococcus aureus and Enterococcus faecalis) and Gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) upon an 808 nm laser irradiation. In vivo experiments firmly demonstrate that the NIR-II AIE liposomes with excellent biocompatibility perform well in both the P. aeruginosa biofilm-induced keratitis mouse model and the MSRA biofilm-induced skin infection mouse model.

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.

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.

Recent advances of AIE-active materials for orthotopic tumor phototheranostics.

Cancer ranks as a leading threat to human life and health. Compared to conventional cancer treatments, phototheranostics shares the advantages of integrated diagnosis and therapy, outstanding therapeutic performance and good controllability. Amid diverse phototheranostic agents, small organic luminogens with aggregation-induced emission (AIEgen) tendency show predominant advantages in terms of superior photostability, large Stokes shifts, and boosted theranostic capacity as aggregates. In the past two decades, AIE-active materials have demonstrated formidable applications in disease theranostics, especially for tumors. This review mainly highlights the recent advances of orthotopic tumor phototheranostics mediated by AIEgens with a classification of different organs. Additionally, a brief discussion of current bottlenecks and future directions is outlined. We believe this review can deepen the understanding and spur more innovations on tumor theranostics by employing AIEgens. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging.

"Trojan Horse" Phototheranostics: Fine-Engineering NIR-II AIEgen Camouflaged by Cancer Cell Membrane for Homologous-Targeting Multimodal Imaging-Guided Phototherapy.

Multimodal phototheranostics on the basis of a single molecule with one-for-all characteristics represents a convenient approach for effective cancer treatment. In this report, a versatile molecule featured by aggregation-induced emission, namely DHTDP, synchronously enabling second near-infrared (NIR-II) fluorescence emission and efficient photothermal conversion is developed by elaborate structural modulation. By camouflaging DHTDP nanoparticles with cancer cell membrane, the resultant biomimetic nanoparticles exhibit significantly both facilitated delivery efficiency and homologous targeting capability, and afford precise imaging guidance and maximize therapeutic outcomes in form of NIR-II fluorescence imaging (FLI)-photoacoustic imaging (PAI)-photothermal imaging (PTI) trimodal imaging-guided photothermal therapy (PTT). This study presents the first example of biomimetic multimodal phototheranostics loaded by homogeneity-targeting cell membrane, thus brings a new insight into the exploration of superior phototheranostics for practical cancer theranostics.

AIEgen-Based Nanomaterials for Bacterial Imaging and Antimicrobial Applications: Recent Advances and Perspectives.

Microbial infections have always been a thorny problem. Multi-drug resistant (MDR) bacterial infections rendered the antibiotics commonly used in clinical treatment helpless. Nanomaterials based on aggregation-induced emission luminogens (AIEgens) recently made great progress in the fight against microbial infections. As a family of photosensitive antimicrobial materials, AIEgens enable the fluorescent tracing of microorganisms and the production of reactive oxygen (ROS) and/or heat upon light irradiation for photodynamic and photothermal treatments targeting microorganisms. The novel nanomaterials constructed by combining polymers, antibiotics, metal complexes, peptides, and other materials retain the excellent antimicrobial properties of AIEgens while giving other materials excellent properties, further enhancing the antimicrobial effect of the material. This paper reviews the research progress of AIEgen-based nanomaterials in the field of antimicrobial activity, focusing on the materials' preparation and their related antimicrobial strategies. Finally, it concludes with an outlook on some of the problems and challenges still facing the field.

Multifunctional AIE Nanosphere-Based "Nanobomb" for Trimodal Imaging-Guided Photothermal/Photodynamic/Pharmacological Therapy of Drug-Resistant Bacterial Infections.

Injudicious or inappropriate use of antibiotics has led to the prevalence of drug-resistant bacteria, posing a huge menace to global health. Here, a self-assembled aggregation-induced emission (AIE) nanosphere (AIE-PEG1000 NPs) that simultaneously possesses near-infrared region II (NIR-II) fluorescence emissive, photothermal, and photodynamic properties is prepared using a multifunctional AIE luminogen (AIE-4COOH). The AIE-PEG1000 NPs were encapsulated with teicoplanin (Tei) and ammonium bicarbonate (AB) into lipid nanovesicles to form a laser-activated "nanobomb" (AIE-Tei@AB NVs) for the multimodal theranostics of drug-resistant bacterial infections. In vivo experiments validate that the "nanobomb" enables high-performance NIR-II fluorescence, infrared thermal, and ultrasound (AB decomposition during the photothermal process to produce numerous CO2/NH3 bubbles, which is an efficient ultrasound contrast agent) imaging of multidrug-resistant bacteria-infected foci after intravenous administration of AIE-Tei@AB NVs followed by 660 nm laser stimulation. The highly efficient photothermal and photodynamic features of AIE-Tei@AB NVs, combined with the excellent pharmacological property of rapidly released Tei during bubble generation and NV disintegration, collectively promote broad-spectrum eradication of three clinically isolated multidrug-resistant bacteria strains and rapid healing of infected wounds. This multimodal imaging-guided synergistic therapeutic strategy can be extended for the theranostics of superbugs.

Ir(III) Complexes with AIE Characteristics for Biological Applications.

Both biological process detection and disease diagnosis on the basis of luminescence technology can provide comprehensive insights into the mechanisms of life and disease pathogenesis and also accurately guide therapeutics. As a family of prominent luminescent materials, Ir(III) complexes with aggregation-induced emission (AIE) tendency have been recently explored at a tremendous pace for biological applications, by virtue of their various distinct advantages, such as great stability in biological media, excellent fluorescence properties and distinctive photosensitizing features. Significant breakthroughs of AIE-active Ir(III) complexes have been achieved in the past few years and great progress has been witnessed in the construction of novel AIE-active Ir(III) complexes and their applications in organelle-specific targeting imaging, multiphoton imaging, biomarker-responsive bioimaging, as well as theranostics. This review systematically summarizes the basic concepts, seminal studies, recent trends and perspectives in this area.

A Water-Soluble AIEgen for Noninvasive Diagnosis of Kidney Fibrosis via SWIR Fluorescence and Photoacoustic Imaging.

Early diagnosis of renal fibrosis is crucially significant on account of its worldwide prevalent tendency. Optical imaging in the near-infrared window has been recognized as an appealing technique for the timely detection of renal dysfunction. However, formulating a contrast agent that allows early monitoring of renal fibrosis and concurrently renally clearable in a normal group is still challenging. Herein, a nanosized fluorophore with aggregation-induced emission (AIE) features, namely AIE-4PEG550 NPs, is well-tailored and amenable to longitudinal visualization of the fibrosis progression specifically in the early-stage via short-wave infrared (SWIR, 900-1700 nm) fluorescence and photoacoustic bimodal imaging. The small size (≈26 nm), renally filtrable molecular weight (3.3 kDa), high renal clearance efficiency (93.1 ± 1.7% excretion through the kidneys within 24 h), outstanding imaging performance, and good biocompatibility, together make AIE-4PEG550 NPs remarkably impressive and far superior to clinical diagnostic assays. The finding in this study would provide a blueprint for the next generation of diagnostic agents for the extent of renal fibrosis.

Near-Infrared-Emissive AIE Bioconjugates: Recent Advances and Perspectives.

Near-infrared (NIR) fluorescence materials have exhibited formidable power in the field of biomedicine, benefiting from their merits of low autofluorescence background, reduced photon scattering, and deeper penetration depth. Fluorophores possessing planar conformation may confront the shortcomings of aggregation-caused quenching effects at the aggregate level. Fortunately, the concept of aggregation-induced emission (AIE) thoroughly reverses this dilemma. AIE bioconjugates referring to the combination of luminogens showing an AIE nature with biomolecules possessing specific functionalities are generated via the covalent conjugation between AIEgens and functional biological species, covering carbohydrates, peptides, proteins, DNA, and so on. This perfect integration breeds unique superiorities containing high brightness, good water solubility, versatile functionalities, and prominent biosafety. In this review, we summarize the recent progresses of NIR-emissive AIE bioconjugates focusing on their design principles and biomedical applications. Furthermore, a brief prospect of the challenges and opportunities of AIE bioconjugates for a wide range of biomedical applications is presented.

Multimodal Imaging-Guided Photothermal Immunotherapy Based on a Versatile NIR-II Aggregation-Induced Emission Luminogen.

Synergistic photothermal immunotherapy has captured great attention owing to the mutually strengthening therapeutic outcomes towards both original tumors and abscopal tumors. Herein, a versatile theranostic agent displaying aggregation-induced emission, namely TPA-BT-DPTQ, was designed and prepared based on benzo[c]thiophene unit as a building block; it can be used for simultaneous fluorescence imaging (FLI) in the second near-infrared (NIR-II) window, photoacoustic imaging (PAI), photothermal imaging (PTI), and thermal eradication of tumors. Further experiments validate that photothermal therapy (PTT) mediated by TPA-BT-DPTQ nanoparticles not only destroys the primary tumor but also enhances immunogenicity for further suppressing the growth of tumors at distant sites. Furthermore, PTT combining a programmed death-ligand 1 (PD-L1) antibody prevents the metastasis and recurrence of cancer by potentiating the effect of immunotherapy.

The fast-growing field of photo-driven theranostics based on aggregation-induced emission.

Photo-driven theranostics, also known as phototheranostics, relying on the diverse excited-state energy conversions of theranostic agents upon photoexcitation represents a significant branch of theranostics, which ingeniously integrate diagnostic imaging and therapeutic interventions into a single formulation. The combined merits of photoexcitation and theranostics endow photo-driven theranostics with numerous superior features. The applications of aggregation-induced emission luminogens (AIEgens), a particular category of fluorophores, in the field of photo-driven theranostics have been intensively studied by virtue of their versatile advantageous merits of favorable biocompatibility, tuneable photophysical properties, unique aggregation-enhanced theranostic (AET) features, ideal AET-favored on-site activation ability and ready construction of one-for-all multimodal theranostics. This review summarised the significant achievements of photo-driven theranostics based on AIEgens, which were detailedly elaborated and classified by their diverse theranostic modalities into three groups: fluorescence imaging-guided photodynamic therapy, photoacoustic imaging-guided photothermal therapy, and multi-modality theranostics. Particularly, the tremendous advantages and individual design strategies of AIEgens in pursuit of high-performance photosensitizing output, high photothermal conversion and multimodal function capability by adjusting the excited-state energy dissipation pathways are emphasized in each section. In addition to highlighting AIEgens as promising templates for modulating energy dissipation in the application of photo-driven theranostics, current challenges and opportunities in this field are also discussed.

Donor/π-Bridge Manipulation for Constructing a Stable NIR-II Aggregation-Induced Emission Luminogen with Balanced Phototheranostic Performance*.

Owing to their versatile functionality and tunable energy dissipation, aggregation-induced emission luminogens (AIEgens) have emerged as a potential platform for multimodal theranostics. Nevertheless, the construction of AIE-active phototheranostic agents in the second near-infrared window (NIR-II, 1000-1700 nm), which allows superior resolution and minimized photodamage, is still a formidable challenge. Herein, benzo[c]thiophene serves as an electron-rich and bulky donor (D)/π-bridge, which can enlarge the conjugation length and distort the backbone of an AIEgen. By precise D/π-bridge engineering, highly stable NIR-II AIEgen DPBTA-DPTQ nanoparticles are obtained with acceptable NIR-II fluorescence quantum yield and excellent photothermal conversion efficiency. In addition, the spatial conformation of DPBTA-DPTQ is determined for the first time by X-ray single crystal diffraction and theoretical simulations. DPBTA-DPTQ NPs have good biocompatibility and show efficient photothermal therapeutic effects in in vitro tests. Furthermore, DPBTA-DPTQ NPs were used in fluorescence-photoacoustic-photothermal trimodal imaging-guided photothermal eradication of tumors in HepG2 and B16-F10 tumor-xenografted mice.

Molecular Engineering of High-Performance Aggregation-Induced Emission Photosensitizers to Boost Cancer Theranostics Mediated by Acid-Triggered Nucleus-Targeted Nanovectors.

Phototheranostics involving both fluorescence imaging and photodynamic therapy has been recognized to be potentially powerful for cancer treatment by virtue of various intrinsic advantages. However, the state-of-the-art materials in this area are still far from ideal toward practical applications, ascribed to their respective and collective drawbacks, such as inefficient imaging quality, inferior reactive oxygen species (ROS) production, the lack of subcellular-targeting capability, and dissatisfactory delivery. In this paper, these shortcomings are successfully addressed through the integration of finely engineered photosensitizers with aggregation-induced emission (AIE) features and well tailored nanocarrier systems. The yielded AIE NPs simultaneously exhibit broad absorption in the visible-light region, bright near-infrared fluorescence emission, high ROS generation, as well as tumor lysosomal acidity-activated and nucleus-targeted delivery functions, making them promising for precise and efficient phototheranostics. Both in vitro and in vivo evaluations show that the presented nanotheranostic systems bearing good photostability and appreciable biosecurity perform well in fluorescence imaging-guided photodynamic cancer therapy. This study thus not only extends the application scopes of AIE nanomaterials but also offers useful insights into constructing advanced cancer phototheranostics.

Aggregation-Induced Emission Luminogens Sensitized Quasi-2D Hybrid Perovskites with Unique Photoluminescence and High Stability for Fabricating White Light-Emitting Diodes.

In order to endow quasi-2D organic-inorganic hybrid metal halide perovskites (quasi-2D-PVK) with superior performance, an aromatic organic ligand with aggregation-induced emission (AIE) features is rationally designed and utilized for constructing distinctive quasi-2D-PVK materials. This AIE-active ligand, TTPy-NH2 , well fits into the lattices of quasi-2D-PVK and leaves hydrophobic tails surrounding PVK layers, making the presented TTPy-NH2 /PVK film extraordinary in terms of both luminescence and stability. Benefiting from the prominent sensitization function and AIE tendency of TTPy-NH2 , the presented TTPy-NH2 /PVK film exhibits a high quantum yield of 62.2%, unique blue-red dual-emission property of both blue and red, high stability with the remnant of more than 94% fluorescence intensity remnant after 21 days. As a result, TTPy-NH2 /PVK film is capable of constituting high-performance white light-emitting diodes, with its color gamut reaching 138% of the National Television System Committee （NTSC） standard and the maximum efficiency is 105 lm W-1 at 20 mA. Evidently, a win-win effect is achieved by the integration of AIE-active ligands and quasi-2D-PVK, which are two of the most reputable solid-state luminogens. This developed protocol thus opens up a new avenue for exploring the next generation of luminescent devices.