Advances in Improving Healthcare with Aggregation-Induced Emission.

Abstract

Light is not only indispensable to life on Earth, but also a strong driving force to promote the development of human healthcare. The prosperous progress in optical bioimaging/sensing techniques and materials has been advancing the field of disease diagnosis and therapeutics by virtue of advantages such as excellent sensitivity, large signal-to-noise ratio, high safety, low cost, and so on. Nevertheless, the optical agents, in particular the organic fluorophores, are often prone to aggregation in biological systems, leading to impaired light emission, partially or completely, due to the notorious effect of aggregation-cased quenching (ACQ). To address this long-standing challenge, organic molecules with aggregation-induced emission (AIE) characteristics emerged as the times required in 2001. Exactly opposite to the ACQ luminophores, the AIE luminogens (AIEgens) usually equipped with freely moving units (e.g., phenyl rings as rotors) are non-emissive when molecularly dissolved because of the active intramolecular motions consuming the absorbed photoexcitation energy. In the aggregated state, however, the intermolecular steric hindrance that results in the substantial restriction of intramolecular motions (RIM) makes the absorbed light excitation energy flow to fluorescent emission and/or intersystem crossing pathways significantly, which therefore realize the fluorescence “turn-on” and/or amplification of ability to generate reactive oxygen species (ROS). Overcoming the limitation of ACQ effect thus enables AIEgens more suitable for biomedical applications with larger working concentration and higher sensitivity. Since the notion of AIE was introduced in 2001, the past two decades have witnessed the rapid progress of AIE research. AIEgens have been highlighted by Nature as one of the four nanomaterials that will support the coming nanolight revolution, which have also been identified by the International Union of Pure and Applied Chemistry (IUPAC) as one of the 2020 Top Ten Emerging Technologies in Chemistry. Among various applications of AIEgens, biomedicine and healthcare have received the highest attention. To date, a library of AIEgen-based healthcare materials have been developed and used for versatile biomedical applications including disease diagnosis, functional cell tracking, pathogen imaging, biomarker-responsive sensing, photodynamic and photothermal therapies, cancer immunotherapy, drug delivery, and in vitro detection. They have provided a rather powerful platform to visualize the biological processes and trace the biological molecules never investigated before, which have shown great strengths in biomedical applications in terms of excellent fluorescent signal output, strong photobleaching resistance, large Stokes shift, wash-free mode for biomarker detection, specific organelle localization, high ROS generation efficiency, and good biocompatibility. To shine light on ongoing and future biomedical applications of AIEgens, we organized this special issue of Advanced Healthcare Materials entitled “Advances in Improving Healthcare with AIE”, which focuses on underlining recent avenues of AIE-related biomaterial developments and their potential clinical applications in diagnostics and therapeutics. A number of leading experts in this research field have made original contributions and this special issue contains 11 reviews and 13 research articles that cover the design and preparation of AIEgen-based healthcare materials as well as their advances in disease diagnosis (fluorescence imaging and multimodal imaging) and image-guided therapy (treatments of tumors and pathogen-induced infections). Fluorescence imaging has been extensively investigated in disease diagnosis, as it permits sensitive visualization at both microscopic and macroscopic levels. So far, fluorescence imaging has been successfully utilized for image-guided cancer surgery and in vitro biomarker detection in the clinic. The superiority of AIE over ACQ makes the AIEgen-based healthcare materials much more promising for utilization in biological systems. Jun Qian and co-workers (article number 2101043) designed and prepared a biocompatible AIE nanoprobe with bright emission in the second near-infrared window (NIR-II, 1000–1700 nm). With an inflammatory bowel disease mouse model, such AIE nanoprobes were efficacious to guide the resection of severe inflammatory bowels during surgery. Through molecular design approach, Yang-Hsiang Chan and co-workers (article number 2100993) synthesized an NIR-II fluorescent nanoprobe as well, which showed ultrahigh NIR-II emission, permitting 3D tumor mapping in vivo. Yuning Hong and co-workers (article number 2101300) reported a peptide-conjugated thiol-reactive AIEgen capable of labeling and tracking unfold proteins in cells. The non-fluorescent AIEgen became highly emissive in the presence of unfold proteins rather than folded protein. As reactive oxygen species are important signaling molecules for many physiological and pathological processes, Youhong Tang et al. (article number 2101223) discussed the recent progress of AIEgens to understand the ROS-mediated physiological processes in microalgae for better healthcare benefits. Anjun Qin et al. (article number 2101067) reviewed the recent advances of AIEgen-based healthcare materials in pharmaceutical research for example to serve as fluorescent carriers for simultaneous drug delivery and tracking. Hao Wang et al. (article number 2100333) developed a system using fluorescence alteration to trace the peptide drug in cancer cells and in vivo. Xinggui Gu et al. (article number 2101177) reviewed the photoactivation mechanisms and molecular design strategies of AIEgen-based photoactivatable fluorescent materials and highlighted their smartness in biomedical applications. Zhen Li et al. (article number 2101169) summarized recent progress of photoresponsive AIEgens in comprehensive healthcare utilizations including super-resolution imaging, light-induced drug delivery, as well as recognition and photo-induced eradication of bacteria. In recent years, multimodal imaging probes are attracting increasing interest as each individual imaging modality has its own limitation and multimodal imaging can offer complementary/synergistic information. AIE has been demonstrated as an ideal platform for constructing advanced multimodal imaging probes for disease diagnosis. Yumiao Zhang and co-workers (article number 2100356) prepared a series of surfactant-stripped AIEgen micelles with simultaneous fluorescence and photoacoustic imaging capabilities. By integrating high sensitivity of fluorescence imaging and deep tissue penetration depth of photoacoustic imaging, such AIEgen micelles were able to visualize intestine and gut microbiota in the gastrointestinal tract in vivo. Shuizhu Wu and co-workers (article number 2100867) reported the design and synthesis of an activatable AIE probe, which turned out to show concurrently intense NIR-II fluorescence and photoacoustic signals after reaction with nitric oxide (NO). Since NO is an important biomarker for detecting herbal-medicine-induced liver injury, this intelligent AIE probe can well delineate the site and size of liver injury by offering both temporal and spatial information. Dong Wang and co-workers (article number 2101167) converted the ACQ properties of a series of poly(phenyleneethynylene)s (PPEs) to AIE by introducing typical AIE moieties into these conjugated polymers. In addition to the highly amplified aggregate-state fluorescence, the resultant AIE-active PPEs also possessed inherently enhanced alkyne vibrations in the Raman-silent region of cells, therefore allowing for boosted image-guided cancer surgery and bacterial detection through simultaneous fluorescence and Raman imaging. Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) has opened a new avenue for cancer treatment due to the merits of in situ and on demand therapeutic mode, minimal damage to normal tissues, and high potency. Dan Ding and co-workers (article number 2101063) reported an interesting approach to synthesize advanced organic photothermal molecules by taking advantage of excited-state intramolecular motions to improve photothermal conversion efficiency. Similar to AIEgens, such kind of photothermal molecules are rich of intramolecular motion units. The active excited-state intramolecular motions within the nanoparticles led to highly effective PTT against muscle-invasive bladder cancer. Deqing Zhang and co-workers (article number 2100896) designed and prepared a photosensitizer, i.e., 4,6-dibromothieno[3,4-b]thiophene, with light-triggered oligomerization feature. The formed oligomers exhibited high ROS generation efficiency, benefiting for effective cancer PDT. Hypoxia refers to a general solid tumor microenvironment owing to the dislocation between fast cancer cell proliferation and insufficient oxygen supply from tumor vasculature, which significantly limits the efficacy of PDT. Chun-Sing Lee and co-workers (article number 2101607) reviewed representative strategies for AIE photosensitizers to overcome the hypoxic tumor microenvironment. Kai Li et al. (article number 2101066) summarized the recent progress in AIE photosensitizer-based enhanced PDT with a special focus on the PDT-evoked immunotherapy. As two-photon excitation has unique advantage of deep tissue penetration, Liang Luo and co-workers (article number 2101056) introduced an AIE photosensitizer capable of achieving two-photon PDT of deep tumor tissues via two-photon laser irradiation in NIR-II window. Furthermore, Xiaowei Zhao et al. (article number 2100360) balanced the intraparticle molecular packing of AIEgens between the twisted molecular structure and effective π-conjugation, thus obtaining optimized fluorescence/photoacoustic/photothermal trimodel imaging-guided synergistic PDT and PTT. More synergistic anticancer activities resulted from concurrent PDT and PTT of AIEgens are discussed by Fan Xia and co-workers (article number 2101036). In addition to cancer therapy, AIEgens have also been investigated for treatment of infections induced by bacteria, fungi or viruses. Jian Ji and co-workers (article number 2100736) reviewed the current approaches and ongoing development of AIEgens for treatment of aforementioned pathogen-induced infectious diseases. Ying-Wei Yang and co-workers (article number 2100877) also summarized the recent progress of AIEgens in imaging and ablation of various kinds of bacteria. Sijie Chen et al. (article number 2100706) introduced a series of cationic and heteroleptic cyclometalated Ir(III) complexes with AIE signatures and red emission. Through the comparison and optimization of molecular structure, the Ir(III) complexes with the highest ROS generation ability were selected, which gave efficient performance in fluorescent image-guided PDT of both Gram-positive and Gram-negative bacteria. Bin Liu et al. (article number 2100885) developed a positively charged AIEgen, whose fluorescence could be greatly enhanced after specifically binding to Gram-positive bacteria. More importantly, such AIEgens also displayed superb killing effects against both extracellular and intracellular Gram-positive bacteria via a membrane depolarization mechanism. Lastly, Ben Zhong Tang et al. (article number 2101055) and Xing-Jie Liang et al. (article number 2100945) presented comprehensive reviews summarizing the major developments on the biomedical applications of AIEgens and highlighting why AIEgens have advanced the field of biomedicine and healthcare. The challenges and future opportunities of AIEgen-based healthcare materials were discussed as well. We hope that this special issue will inspire more exciting works and new insights in this flourishing research field. We also hope that this special issue will lead to further interactions among AIE researchers, scientists in relevant disciplines, as well as clinicians. We would like to thank all the authors for their great contributions with extremely high quality and current state-of-the-art. We are also grateful to Dr. Emily Hu and other editors at Advanced Healthcare Materials for their kind support and dedication. The authors declare no conflict of interest. Dan Ding received Ph.D. degree from the Department of Polymer Science and Engineering in Nanjing University in 2010. After postdoctoral training in the National University of Singapore, he joined Nankai University, where he is currently a professor in the Frontiers Science Center for Cell Responses, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials, Ministry of Education, and College of Life Science. He also conducted his work in the Hong Kong University of Science & Technology as a visiting scholar. His current research focuses on the design and synthesis of smart/functional molecular imaging probes and exploration of their biomedical applications. Ben Zhong Tang received Ph.D. degree from Kyoto University in 1988 and conducted postdoctoral research at University of Toronto in 1989–1994. He joined the Hong Kong University of Science & Technology in 1994 and was promoted to Stephen K. C. Cheong Professor of Science in 2013. He was elected to the Chinese Academy of Sciences in 2009. He now works as a Distinguished Presidential Chair Professor at The Chinese University of Hong Kong, Shenzhen. His research interests include exploration of new advanced materials, new luminescent processes and new polymerization reactions.