Aggregation-induced emission (AIE) describes a photophysical phenomenon in which molecular aggregates exhibit stronger emission than the single molecules. Over the course of the last 20 years, AIE research has made great strides in material development, mechanistic study and high-tech applications. The achievements of AIE research demonstrate that molecular aggregates show many properties and functions that are absent in molecular species. In this review, we summarize the advances in the field of AIE and its related areas. We specifically focus on the new properties of materials attained by molecular aggregates beyond the microscopic molecular level. We hope this review will inspire more research into molecular ensembles at and beyond the meso level and lead to the significant progress in material and biological science.

Aggregation-Induced Emission: New Vistas at the Aggregate Level

Fluorescence bioimaging affords a vital tool for both researchers and surgeons to molecularly target a variety of biological tissues and processes. This review focuses on summarizing organic dyes emitting at a biological transparency window termed the near-infrared-II (NIR-II) window, where minimal light interaction with the surrounding tissues allows photons to travel nearly unperturbed throughout the body. NIR-II fluorescence imaging overcomes the penetration/contrast bottleneck of imaging in the visible region, making it a remarkable modality for early diagnosis of cancer and highly sensitive tumor surgery. Due to their convenient bioconjugation with peptides/antibodies, NIR-II molecular dyes are desirable candidates for targeted cancer imaging, significantly overcoming the autofluorescence/scattering issues for deep tissue molecular imaging. To promote the clinical translation of NIR-II bioimaging, advancements in the high-performance small molecule-derived probes are critically important. Here, molecules with clinical potential for NIR-II imaging are discussed, summarizing the synthesis and chemical structures of NIR-II dyes, chemical and optical properties of NIR-II dyes, bioconjugation and biological behavior of NIR-II dyes, whole body imaging with NIR-II dyes for cancer detection and surgery, as well as NIR-II fluorescence microscopy imaging. A key perspective on the direction of NIR-II molecular dyes for cancer imaging and surgery is also discussed.

Near-Infrared-II Molecular Dyes for Cancer Imaging and Surgery.

Since the introduction of the concept of aggregation-induced emission (AIE) in 2001, many research groups have become involved in AIE research. Aggregation-induced emission luminogens (AIEgens) have emerged as a novel type of advanced material with excellent performance in various fields. Much effort has been devoted to determining the AIE mechanism(s) by theoreticians and experimentalists. Restriction of intramolecular motion has been recognized as the general working mechanism of AIE, but the mechanims of some AIE systems still remain unclear. In this focus article, the progress of the fundamental understanding of the AIE mechanism is reviewed and the future developments in AIE research are discussed. The goal is to provide a brief yet insightful introduction and interpretation of the subject to both new and experienced AIE researchers.

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Aggregation-induced emission: fundamental understanding and future developments

ConspectusTheranostic nanolights refer to luminescent nanoparticles possessing both imaging and therapeutic functions. Their shape, size, surface functions, and optical properties can be precisely manipulated through integrated efforts of chemistry, materials, and nanotechnology for customized applications. When localized photons are used to activate both imaging and therapeutic functions such as photodynamic or photothermal therapy, these theranostic nanolights increase treatment efficacy with minimized damage to surrounding healthy tissues, which represents a promising noninvasive nanomedicine as compared to conventional theranostic approaches.As one of the most promising theranostic nanolights, organic dots with aggregation-induced emission (AIE dots) are biocompatible nanoparticles with a dense core of AIE fluorogens (AIEgens) and protective shells, whose sizes are in the range of a few to tens of nanometers. Different from conventional fluorophores that suffer from aggregation-caused quenching (ACQ) ...

Aggregation-Induced Emission (AIE) Dots: Emerging Theranostic Nanolights.

The emergence of aggregation-induced emission luminogens (AIEgens) has significantly stimulated the development of luminescent supramolecular materials because their strong emissions in the aggregated state have resolved the notorious obstacle of the aggregation-caused quenching (ACQ) effect, thereby enabling AIEgen-based supramolecular materials to have a promising prospect in the fields of luminescent materials, sensors, bioimaging, drug delivery, and theranostics. Moreover, in contrast to conventional fluorescent molecules, the configuration of AIEgens is highly twisted in space. Investigating AIEgens and the corresponding supramolecular materials provides fundamental insights into the self-assembly of nonplanar molecules, drastically expands the building blocks of supramolecular materials, and pushes forward the frontiers of supramolecular chemistry. In this review, we will summarize the basic concepts, seminal studies, recent trends, and perspectives in the construction and applications of AIEgen-based supramolecular materials with the hope to inspire more interest and additional ideas from researchers and further advance the development of supramolecular chemistry.

Supramolecular materials based on AIE luminogens (AIEgens): construction and applications

The near-infrared window between 1000 and 1700 nm, commonly termed the "second near-infrared (NIR-II) window," has quickly emerged as a highly attractive optical region for biological imaging. In contrast to conventional imaging in the visible region between 400 and 700 nm, as well as in the first NIR (NIR-I) window between 700 and 900 nm, NIR-II biological imaging offers numerous merits, including higher spatial resolution, deeper penetration depth, and lower optical absorption and scattering from biological substrates with minimal tissue autofluorescence. Noninvasive imaging techniques, specifically NIR-II fluorescence and photoacoustic (PA) imaging, have embodied the attractiveness of NIR-II optical imaging, with several NIR-II contrast agents demonstrating superior performance to the clinically approved NIR-I agents. Consequently, NIR-II biological imaging has been increasingly explored due to its tremendous potential for preclinical studies and clinical utility. Herein, the progress of optical imaging in the NIR-II window is reported. Starting with highlighting the importance of biological imaging in the NIR-II spectral region, the emergence and latest development of various NIR-II fluorescence and PA imaging probes and their applications are then discussed. Perspectives on the promises and challenges facing this nascent yet exciting field are then given.

Recent Advances of Optical Imaging in the Second Near-Infrared Window

Precise design of fluorescent molecules with desired properties has enabled the rapid development of many research fields. Among the different types of optically active materials, luminogens with aggregation-induced emission (AIEgens) have attracted significant interest over the past two decades. The negligible luminescence of AIEgens as a molecular species and high brightness in aggregate states distinguish them from conventional fluorescent dyes, which has galvanized efforts to bring AIEgens to a wide array of multidisciplinary applications. Herein, the useful principles and emerging structure-property relationships for precise molecular design toward AIEgens with desirable properties using concrete examples are revealed. The cutting-edge applications of AIEgens and their excellent performance in enabling new research directions in biomedical theranostics, optoelectronic devices, stimuli-responsive smart materials, and visualization of physical processes are also highlighted.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/adma.201903530

Precise Molecular Design for High-Performance Luminogens with Aggregation-Induced Emission

Photodynamic therapy (PDT) has been a well-accepted clinical treatment for malignant tumors owing to its noninvasiveness and high spatiotemporal selectivity. However, the efficiency of PDT is still severely hindered by an inherent aggregation-caused quenching (ACQ) effect of traditional photosensitizers (PSs), the presence of B-cell lymphoma 2 (Bcl-2), an antiapoptosis protein in cells, and hypoxia in the tumor microenvironment. To address these issues, hybrid nanospheres containing Fe3+, aggregation-induced emission (AIE) PS, and Bcl-2 inhibitor of sabutoclax were constructed via coordination-driven self-assembly in aqueous media. Once the hybrid nanospheres are taken up by tumor cells, intracellular O2 concentration is observed to increase via Fenton reaction driven by Fe3+, whereas intracellular PDT resistance of the AIE PS was mitigated by sabutoclax. The design of the multifunctional hybrid nanospheres demonstrates a prospective nanoplatform for image-guided enhanced PDT of tumors.

Hybrid Nanospheres to Overcome Hypoxia and Intrinsic Oxidative Resistance for Enhanced Photodynamic Therapy.

Pyroptosis as a lytic and inflammatory form of cell death is a powerful tool to fight against cancer. However, pyroptosis is usually activated by chemotherapeutic drugs, which limits its anti-tumor applications due to drug resistance and severe side effects. Herein, we demonstrate that membrane targeting photosensitizers can induce pyroptosis for cancer cell ablation with noninvasiveness and low side effects. A series of membrane anchoring photosensitizers (TBD-R PSs) with aggregation-induced emission (AIE) characteristics were prepared through conjugation of TBD and phenyl ring with cationic chains. Upon light irradiation, cytotoxic ROS were produced in situ, resulting in direct membrane damage and superior cancer cell ablation. Detailed study revealed that pyroptosis gradually became the dominant cell death pathway along with the increase of TBD-R PSs membrane anchoring capability. This study offers a photo-activated pyroptosis-based intervention strategy for cancer cell ablation.

Activation of Pyroptosis by Membrane‐Anchoring AIE Photosensitizer Design: New Prospect for Photodynamic Cancer Cell Ablation

Nanomaterials are indispensable tools for imaging and therapy. Organic dots with aggregation-induced emission characteristics (AIE dots) have emerged as a new nanolight for their ultra-brightness, excellent photostability and biocompatibility. Due to the rotor structures, most of the reported AIE luminogens show short wavelength absorption and emission, an intrinsic disadvantage for their biomedical applications. Recently, more exciting examples reveal that properly designed AIE dots can easily reach NIR emission, excitable by near-infrared (NIR) light via multiphoton processes, which also have great potentials in photoacoustic imaging (PAI) and phototherapy. In this review, we summarize the recent advances of AIE nanomaterials for NIR fluorescence imaging, PAI, image-guided photodynamic and photothermal therapy (PDT and PTT). We highlight various strategies to improve the energy conversion efficiency of AIE dots through controlling different energy decay pathways. With this review, we hope to encourage more precise design of organic nanomaterials for biomedical applications.

Yukun Duan

Papers

Recent Advances of Optical Imaging in the Second Near-Infrared Window

Precise Molecular Design for High-Performance Luminogens with Aggregation-Induced Emission

Hybrid Nanospheres to Overcome Hypoxia and Intrinsic Oxidative Resistance for Enhanced Photodynamic Therapy.

Activation of Pyroptosis by Membrane‐Anchoring AIE Photosensitizer Design: New Prospect for Photodynamic Cancer Cell Ablation

Recent advances of AIE dots in NIR imaging and phototherapy