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Photodynamic therapy (PDT), as an emerging cancer treatment, requires the development of highly desirable photosensitizers (PSs) with integrated functional groups to achieve enhanced therapeutic efficacy. Coordination‐driven self‐assembly (CDSA) would provide an alternative approach for combining multiple PSs synergistically. Here, we demonstrate a simple yet powerful strategy of combining conventional chromophores (tetraphenylethylene, porphyrin, or Zn‐porphyrin) with pyridinium salt PSs together through condensation reactions, followed by CDSA to construct a series of novel metallo‐supramolecular PSs (S1–S3). The generation of reactive oxygen species (ROS) is dramatically enhanced by the direct combination of two different PSs, and further reinforced in the subsequent ensembles. Among all the ensembles, S2 with two porphyrin cores shows the highest ROS generation efficiency, specific interactions with lysosome, and strong emission for probing cells. Moreover, the cellular and living experiments confirm that S2 has excellent PDT efficacy, biocompatibility, and biosafety. As such, this study will enable the development of more efficient PSs with potential clinical applications. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT), emerging as a minimally invasive therapeutic modality with precise controllability and high spatiotemporal accuracy, has earned significant advancements in the field of cancer and other non-cancerous diseases treatment. Thereinto, type I PDT represents an irreplaceable and meritorious part in contributing to these delightful achievements since its distinctive hypoxia tolerance can perfectly compensate for the high oxygen-dependent type II PDT, particularly in hypoxic tissues. Regarding the diverse type I photosensitizers (PSs) that light up type I PDT, aggregation-induced emission (AIE)-active type I PSs are currently arousing great research interest owing to their distinguished AIE and aggregation-induced generation of reactive oxygen species (AIE-ROS) features. In this review, we offer a comprehensive overview of the cutting-edge advances of novel AIE-active type I PSs by delineating the photophysical and photochemical mechanisms of the type I pathway, summarizing the current molecular design strategies for promoting the type I process, and showcasing current bioapplications, in succession. Notably, the strategies to construct highly efficient type I AIE PSs were elucidated in detail from the two aspects of introducing high electron affinity groups, and enhancing intramolecular charge transfer (ICT) intensity. Lastly, we present a brief conclusion, and a discussion on the current limitations and proposed opportunities. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Molecular motions are ubiquitous in nature and they immutably play intrinsic roles in all actions. However, exploring appropriate models to decipher molecular motions is an extremely important but very challenging task for researchers. Considering aggregation‐induced emission (AIE) luminogens possess their unique merits to visualize molecular motions, it is particularly fascinating to construct new AIE systems as models to study molecular motion. Herein, a novel quinolizine (QLZ) AIE system was constructed based on the restriction intramolecular vibration (RIV) mechanism. It was demonstrated that QLZ could act as an ideal model to visualize single‐molecule motion and macroscopic molecular motion via fluorescence change. Additionally, further elaborate tailoring of this impressive core achieved highly efficient reactive oxygen species production and realized fluorescence imaging‐guided photodynamic therapy applications, which confirms the great application potential of this new AIE‐active QLZ core. Therefore, this work not only provides an ideal model to visualize molecular motion but also opens a new way for the application of AIEgens. [ABSTRACT FROM AUTHOR]

The ingenious construction of versatile cancer phototheranostics involving fluorescence imaging (FLI) and photodynamic and photothermal therapies (PDT, PTT) concurrently has attracted great interest. By virtue of their inherent twisted structures and plentiful motion moieties, aggregation‐induced emission luminogens (AIEgens) have been proven to be perfect templates for the development of multimodal phototheranostic systems as their diverse energy consumption pathways can be flexibly regulated through tuning the intramolecular motions. Side‐chain engineering is generally accepted as a useful regulation strategy for intramolecular motions through altering the side‐chain structure of the molecule, but has rarely been reported for the construction of AIE‐active multimodal phototheranostics. Herein, by taking full advantage of the side‐chain engineering strategy, an AIE‐active multifunctional phototheranostic system (TBFT2 nanoparticles) is successfully constructed by intentionally manipulating the length of side chains. Bearing the longest alkyl chain, all of those three energy dissipation pathways including radiative decay, nonradiative thermal deactivation, and intersystem crossing process of TBFT2 are retained simultaneously and controllably in the aggregate state. In vitro and in vivo evaluations verify that TBFT2 nanoparticles perform well in terms of FLI‐guided PDT and PTT synergistic cancer therapy. This study thus provides new insight into the exploration of superior versatile phototheranostics through side‐chain engineering. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has long been recognized to be a promising approach for cancer treatment. However, the high oxygen dependency of conventional PDT dramatically impairs its overall therapeutic efficacy, especially in hypoxic solid tumors. Exploration of distinctive PDT strategy involving both high‐performance less‐oxygen‐dependent photosensitizers (PSs) and prominent drug delivery system is an appealing yet significantly challenging task. Herein, a precise nuclear targeting PDT protocol based on type‐I PSs with aggregation‐induced emission (AIE) characteristics is fabricated for the first time. Of the two synthesized AIE PSs, TTFMN is demonstrated to exhibit superior AIE property and stronger type‐I reactive oxygen species (ROS) generation efficiency owing to the introduction of tetraphenylethylene and smaller singlet–triplet energy gap, respectively. With the aid of a lysosomal acid‐activated TAT‐peptide‐modified amphiphilic polymer poly(lactic acid)12k–poly(ethylene glycol)5k–succinic anhydride‐modified TAT, the corresponding TTFMN‐loaded nanoparticles accompanied with acid‐triggered nuclear targeting peculiarity can quickly accumulate in the tumor site, effectively generate type‐I ROS in the nuclear region and significantly suppress the tumor growth under white light irradiation with minimized systematic toxicity. This delicate "Good Steel Used in the Blade" tactic significantly maximizes the PDT efficacy and offers a conceptual while practical paradigm for optimized cancer treatment in further translational medicine. [ABSTRACT FROM AUTHOR]

Supramolecular approaches have opened up vast possibilities to construct versatile materials, especially those with stimuli‐responsiveness and integrated functionalities of multi‐modal diagnosis and synergistic therapeutics. In this study, a hybrid theranostic nanosystem named TTPY‐Py⊂CP5@AuNR is constructed via facile host–guest interactions, where TTPY‐Py is a photosensitizer with aggregation‐induced emission and CP5@AuNR represents the carboxylatopillar[5]arene (CP5)‐modified Au nanorods. TTPY‐Py⊂CP5@AuNR integrates the respective advantages of TTPY‐Py and CP5@AuNR such as the high performance of reactive oxygen species generation and photothermal conversion, and meanwhile shows fluorescence responses to both temperature and pH stimuli. The successful modification of CP5 macrocycles on AuNRs surfaces can eliminate the cytotoxicity of AuNRs and enable them to serve as the nanocarrier of TTPY‐Py for further theranostic applications. Significantly, in vitro and in vivo evaluations demonstrate that this supramolecular nanotheranostic system possesses multiple modalities including intensive fluorescence imaging (FLI), photoacoustic imaging (PAI), efficient photodynamic therapy (PDT), and photothermal therapy (PTT), indicating its great potential for FLI‐PAI imaging‐guided synergistic PDT‐PTT therapy. Moreover, TTPY‐Py can be released upon activation by the acidic environment of lysosomes and then specifically light up mitochondria. This study demonstrates a new strategy for the design of versatile nanotheranostics for accurate tumor imaging and cancer therapies. [ABSTRACT FROM AUTHOR]

Fluorescence imaging in the second near‐infrared region (NIR‐II) can penetrate tissue at centimeter depths and obtain high image fidelity. However, facile synthesis of small‐molecule fluorescent photosensitizers for efficient NIR‐II fluorescence imaging as well as photodynamic and photothermal combinatorial therapies is still a challenging task. Herein, a rational design and facile synthesis protocol are reported for a series of novel NIR‐emissive zwitterionic luminogens with aggregation‐induced emission (AIE) features for cancer phototheranostics. Consistent with the intrinsic features including long emission wavelength, effective reactive oxygen species generation, and excellent photothermal conversion efficiency (35.76%), in vitro and in vivo evaluation show that one of these presented AIE luminogens provides excellent performance in NIR‐II fluorescence imaging‐guided synergistic phototherapy against cancer. [ABSTRACT FROM AUTHOR]

Graphical abstract AuNCs-HA exhibited PA imaging guided combined radiotherapy, PDT and PTT trimodalites, leading to effectively synergistic anticancer efficacy. Abstract In this work, we developed a novel multifunctional nanoplatform based on hyaluronic acid modified Au nanocages (AuNCs-HA). The rational design of AuNCs-HA renders the nanoplatform three functionalities: (1) AuNCs-HA with excellent LSPR peak in the NIR region act as contrast agent for enhanced photoacoustic (PA) imaging and photothermal therapy (PTT); (2) the nanoplatform with high-energy rays (X-ray) absorption and auger electrons generation acts as a radiosensitizer for radiotherapy; (3) good photocatalytic property and large surface area make AuNCs-HA a photosensitive agent for photodynamic therapy (PDT). In vivo results demonstrated that AuNCs-HA presented excellent PA imaging performance after intravenous injection, which provided contour, size, and location information of the tumor. Moreover, because AuNCs-HA could combine radiotherapy and phototherapy together, the tumors treated with AuNCs-HA showed complete growth inhibition, comparing to that with each therapy alone. Taken together, our present study demonstrates that AuNCs-HA is of great potential as a multifunctional nanoplatform for PA imaging-guided radio- and photo-therapy of tumor. Statement of Significance In this study, a commendable theranostic nanoplatform based on hyaluronic acid modified AuNCs (AuNCs-HA) was developed. In our approach, the dilute solution of Gold(III) chloride is slowly dripped into Ag nanocubes solution, then the Au nanocages were obtained by redox reaction, and followed by HA modification. We explored them, simultaneously, as radiosensitizers for RT, photosensitizers for PDT, and therapeutic agents for PTT. Compared to that of each therapies alone, the combination of radio-therapy and photo-therapy results in a considerably improved tumor eliminating effect and efficiently inhibited tumor growth. In addition, AuNCs-HA exhibited remarkably strong PA signals for precise identification of the location, size, and boundary of the tumor, thereby facilitating imaging-guided therapy. In brief, our design of AuNCs-HA represents a general and versatile strategy for building up cancer-targeted nanotheranostics with desired synergistic imaging and therapy functionalities. [ABSTRACT FROM AUTHOR]

Intersystem crossing (ISC) is of great significance in photochemistry, and has a decisive influence on the properties of photosensitizers (PSs) for use in photodynamic therapy (PDT). However, the rationally design PSs with efficient ISC processes to implement superb reactive oxygen species (ROS) production is still a very challenging work. In this contribution, we described how a series of high-performance PSs were constructed through electron acceptor and donor engineering by integrating the smaller singlet-triplet energy gap (Δ E ST) and larger spin-orbit coupling (SOC)-beneficial functional groups into the PS frameworks. Among the yielded various PSs, TaTIC was confirmed as the best candidate for application in PDT, which was due to its most outstanding ROS generation capability, bright near-infrared (NIR) fluorescence with peak over 840 nm, as well as desired aggregation-induced emission (AIE) features. Importantly, the ROS generation efficiency of TaTIC was even superior to that of some popularly used PSs, including the most reputable PS of Rose Bengal. In order to further extend therapeutic applications, TaTIC was encapsulated with biocompatible amphiphilic matrix and formulated into water-dispersed nanoparticles (NPs). More excitedly, the as-prepared TaTIC NPs gave wonderful PDT performance on tumor-bearing mouse model, actualizing complete tumor elimination outcomes. Coupled with excellent biosecurity, TaTIC NPs would be a promising theranostic agent for practical clinical application. [ABSTRACT FROM AUTHOR]

[Display omitted] • A two-photon photodynamic photosensitizer with mitochondrion-targeting and AIE characteristics was prepared. • The integration of Ir make 50 times enhancement of ROS production compared to its counterpart molecule. • TPABP-Ir@BSA NPs exhibits satisfactory biosafety. • A 90% tumor suppression was achieved by type-I&II synergetic photochemical reactions under hypoxic environment. In recent years, two-photon photodynamic therapy (TP-PDT) has received extensive attention in cancer treatment owing to its unique advantages of deep tissue penetration and high spatial–temporal controls. However, the high oxygen dependency of photosensitizers still remained as the major obstacle which undermined its overall therapeutic efficacy, especially in hypoxic-tolerant tumors. Exploration of new TP-PDT strategy with less-oxygen-dependency and subcellular organelle-targeting ability is an appealing yet seriously challenging task. In this work, a mitochondrion-targeting TP-PDT protocol based on type-I PSs with aggregation-induced emission (AIE) characteristics is proposed for the first time. Of the two synthesized AIE-active PSs, TPABP-Ir is demonstrated superior reactive oxygen species (ROS) production (both type I&II) owing to the doping of Ir(III). After encapsulation into bovine serum albumin (BSA) matrix, TPABP-Ir@BSA nanoparticles (Ir-NPs) are capable of realizing mitochondrion-targeting, high ROS production, and suppression of tumor growth under 880 nm femtosecond laser excitation. This study provides a novel treatment strategy which maximizes the PDT efficacy and offers a conceptual but practical paradigm for cancer treatment in translational nanomedicine. [ABSTRACT FROM AUTHOR]