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The phototoxicity of photosensitizers (PSs) pre and post photodynamic therapy (PDT), and the hypoxic tumor microenvironment are two major problems limiting the application of PDT. While activatable PSs can successfully address the PS phototoxicity pre PDT, and type I PS can generate reactive oxygen species (ROS) effectively in hypoxic environment, very limited approaches are available for addressing the phototoxicity post PDT. There is virtually no solution available to address all these issues using a single design. Herein, we propose a proof‐of‐concept on‐demand switchable photosensitizer with quenched photosensitization pre and post PDT, which could be activated only in tumor hypoxic environment. Particularly, a hypoxia‐normoxia cycling responsive type I PS TPFN‐AzoCF3 was designed to demonstrate the concept, which was further formulated into TPFN‐AzoCF3 nanoparticles (NPs) using DSPE‐PEG‐2000 as the encapsulation matrix. The NPs could be activated only in hypoxic tumors to generate type I ROS during PDT treatment, but remain non‐toxic in normal tissues, pre or after PDT, thus minimizing side effects and improving the therapeutic effect. With promising results in in vitro and in vivo tumor treatment, this presented strategy will pave the way for the design of more on‐demand switchable photosensitizers with minimized side effects in the future. [ABSTRACT FROM AUTHOR]

The nucleus is considered the ideal target for anti‐tumor therapy because DNA and some enzymes in the nucleus are the main causes of cell canceration and malignant proliferation. However, nuclear target drugs with good biosafety and high efficiency in cancer treatment are rare. Herein, a nuclear‐targeted material MeTPAE with aggregation‐induced emission (AIE) characteristics was developed based on a triphenylamine structure skeleton. MeTPAE can not only interact with histone deacetylases (HDACs) to inhibit cell proliferation but also damage telomere and nucleic acids precisely through photodynamic treatment (PDT). The cocktail strategy of MeTPAE caused obvious cell cycle arrest and showed excellent PDT anti‐tumor activity, which offered new opportunities for the effective treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

An ideal cancer treatment should not only destroy primary tumors but also improve the immunogenicity of the tumor microenvironment to achieve a satisfactory anti‐tumor immune effect. We designed a carbonic anhydrase IX (CAIX)‐anchored rhenium(I) photosensitizer, named CA‐Re, that not only performs type‐I and type‐II photodynamic therapy (PDT) with high efficiency under hypoxia (nanomolar‐level phototoxicity), but also evokes gasdermin D (GSDMD) mediated pyroptotic cell death to effectively stimulate tumor immunogenicity. CA‐Re could disrupt and self‐report the loss of membrane integrity simultaneously. This promoted the maturation and antigen‐presenting ability of dendritic cells (DCs), and fully activated T cells dependent adaptive immune response in vivo, eventually eliminating distant tumors at the same time as destroying primary tumors. To the best of our knowledge, CA‐Re is the first metal complex‐based pyroptosis inducer. [ABSTRACT FROM AUTHOR]

Maximization of phototoxic damage on tumor with minimized side effect on normal tissue is essential for effective anticancer photodynamic therapy (PDT). This requires highly cancer‐cell‐specific or even cancer‐cell‐organelle‐specific synthesis or delivery of efficient photosensitizers (PSs) in vitro and in vivo, which is difficult to achieve. Herein, we report a strategy of cancer‐cell‐activated PS synthesis, by which an efficient mitochondria‐targeting photosensitizer with aggregation‐induced‐emission (AIE) feature can be selectively synthesized as an efficient image‐guided PDT agent inside cancer cells. MOF‐199, a CuII‐based metal‐organic framework, was selected as an inert carrier to load the PS precursors for efficient delivery and served as a CuI catalyst source for in situ click reaction to form PSs exclusively in cancer cells. The in situ synthesized PS showed mitochondria‐targeting capability, allowing potent cancer‐cell‐specific ablation under light irradiation. The high specificity of PSs produced in cancer cells also makes it safer post‐treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

In order to promote the development of photodynamic therapy (PDT), undesired side effects like low tumor specificity and the "always‐on" phenomenon should be avoided. An effective solution is to construct an adaptive photosensitizer that can be activated to generate reactive oxygen species (ROS) in the tumor microenvironment. Herein, we design and synthesize a supramolecular switch based on a host–guest complex containing a water‐soluble pillar[5]arene (WP5) and an AIEgen photosensitizer (G). The formation of the host–guest complex WP5⊃G quenches the fluorescence and inhibits ROS generation of G. Benefitting from the pH‐responsiveness of WP5, the binding site between G and WP5 changes in an acidic environment through a shuttle movement. Consequently, fluorescence and ROS generation of the host–guest complex can be switched on at pH 5.0. This work offers a new paradigm for the construction of adaptive photosensitizers by using a supramolecular method. [ABSTRACT FROM AUTHOR]

Traditional photosensitizers (PSs) show reduced singlet oxygen (1O2) production and quenched fluorescence upon aggregation in aqueous media, which greatly affect their efficiency in photodynamic therapy (PDT). Meanwhile, non‐targeting PSs generally yield low efficiency in antibacterial performance due to their short lifetimes and small effective working radii. Herein, a water‐dispersible membrane anchor (TBD‐anchor) PS with aggregation‐induced emission is designed and synthesized to generate 1O2 on the bacterial membrane. TBD‐anchor showed efficient antibacterial performance towards both Gram‐negative (Escherichia coli) and Gram‐positive bacteria (Staphylococcus aureus). Over 99.8 % killing efficiency was obtained for methicillin‐resistant S. aureus (MRSA) when they were exposed to 0.8 μm of TBD‐anchor at a low white light dose (25 mW cm−2) for 10 minutes. TBD‐anchor thus shows great promise as an effective antimicrobial agent to combat the menace of multidrug‐resistant bacteria. [ABSTRACT FROM AUTHOR]

Activatable photosensitizers (PSs) have been widely used for the simultaneous fluorescence imaging and photodynamic ablation of cancer cells. However, the ready aggregation of traditional PSs in aqueous media can lead to fluorescence quenching as well as reduced phototoxicity even in the activated form. We have developed a series of PSs that show aggregation-enhanced emission and phototoxicity and thus the exact opposite behavior to that of previously reported PSs. We further developed a dual-targeted enzyme-activatable bioprobe based on the optimized photosensitizer and describe simultaneous light-up fluorescence imaging and activated photodynamic therapy for specific cancer cells. The design of smart probes should thus open new opportunities for targeted and image-guided photodynamic therapy. [ABSTRACT FROM AUTHOR]