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Increasing oxygen (O2) content and down‐regulating the concentration of glutathione (GSH) in tumor microenvironment (TME) by multiple approaches remain critical factors for the promotion of phototherapeutic effect, especially for photodynamic therapy (PDT). Herein, indocyanine green (ICG) laden dendritic mesoporous manganese‐silicon nanocomposite (NC) is designed and subsequently managed with calcification through in situ growth of calcium phosphate (IDMMS@CaP NC). As specific response behavior of the mildly acidic and GSH overexpressed TME, the IDMMS@CaP NC can rapidly collapse when accumulated at the tumor site, liberate Mn2+, Ca2+, and ICG, simultaneously reduce the concentration of GSH. Mn2+ can catalyze endogenous hydrogen peroxide to produce O2. Overloaded Ca2+ induces mitochondrial injury, and reduces cellular metabolism and O2 consumption. The photothermal effect from ICG with 808 nm laser irradiation can not only cause tumor cells necrosis but also accelerate blood flow to further improve the O2 content at the tumor site. Consequently, owing to effective GSH depletion and multiple O2 compensation, the PDT efficiency of ICG can be significantly increased. As proof of concept, the designed multifunctional nanocomposite will provide a general strategy for enhancing the role of phototherapy in cancer therapeutic area. [ABSTRACT FROM AUTHOR]

Single‐atom nanozyme (SAzyme) has sparked increasing interest for catalytic antitumor treatment due to their more tunable and diverse active sites than natural metalloenzymes in complex physiological conditions. However, it is usually a hard task to precisely conduct catalysis at tumor sites after intravenous injection of those SAzyme with high reactivity. Moreover, the explorations of SAzymes in the anticancer application are still in its infancy and need to be developed. Herein, an in situ synthesis strategy for Cu SAzyme was constructed to convert adsorbed copper ions into isolated atoms anchored by oxygen atoms (Cu−O2/Cu−O4) via GSH‐responsive deformability of supports. Our results suggest that the in situ activation process could further facilitate the dissociation of copper ions and the consumption of glutathione, thereby leading to copper deposition in cytoplasm and triggering cuproptosis. Moreover, the in situ synthesis of Cu SAzyme with peroxidase‐like activity enabled the intracellular reactive oxygen species production, resulting in specifically disturbance of copper metabolism pathway. Meanwhile, the in situ exposed glucose transporter (GLUT) inhibitor phloretin (Ph) can block the glycose uptake to boost cuproptosis efficacy. Overall, this in situ activation strategy effectively diminished the off‐target effects of SACs‐induced catalytic therapies and introduced a promising treatment paradigm for advancing cuproptosis‐associated therapies. [ABSTRACT FROM AUTHOR]

Single‐atom nanozyme (SAzyme) has sparked increasing interest for catalytic antitumor treatment due to their more tunable and diverse active sites than natural metalloenzymes in complex physiological conditions. However, it is usually a hard task to precisely conduct catalysis at tumor sites after intravenous injection of those SAzyme with high reactivity. Moreover, the explorations of SAzymes in the anticancer application are still in its infancy and need to be developed. Herein, an in situ synthesis strategy for Cu SAzyme was constructed to convert adsorbed copper ions into isolated atoms anchored by oxygen atoms (Cu−O2/Cu−O4) via GSH‐responsive deformability of supports. Our results suggest that the in situ activation process could further facilitate the dissociation of copper ions and the consumption of glutathione, thereby leading to copper deposition in cytoplasm and triggering cuproptosis. Moreover, the in situ synthesis of Cu SAzyme with peroxidase‐like activity enabled the intracellular reactive oxygen species production, resulting in specifically disturbance of copper metabolism pathway. Meanwhile, the in situ exposed glucose transporter (GLUT) inhibitor phloretin (Ph) can block the glycose uptake to boost cuproptosis efficacy. Overall, this in situ activation strategy effectively diminished the off‐target effects of SACs‐induced catalytic therapies and introduced a promising treatment paradigm for advancing cuproptosis‐associated therapies. [ABSTRACT FROM AUTHOR]

We herein present an approach of photo‐induced disproportionation for preparation of Type‐I photodynamic agents. As a proof of concept, BODIPY‐based photosensitizers were rationally designed and prepared. The photo‐induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2−⋅). One of our Type‐I photodynamic agents not only self‐assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2), with a half‐maximal inhibitory concentration (IC50) of 0.96 μM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors. [ABSTRACT FROM AUTHOR]

We herein present an approach of photo‐induced disproportionation for preparation of Type‐I photodynamic agents. As a proof of concept, BODIPY‐based photosensitizers were rationally designed and prepared. The photo‐induced intermolecular electron transfer between homotypic chromophores leads to the disproportionation reaction, resulting in the formation of charged intermediates, cationic and anionic radicals. The cationic radicals efficiently oxidize the cellularimportant coenzyme, tetrahydrobiopterin (BH4), and the anionic radicals transfer electrons to oxygen to produce superoxide radicals (O2−⋅). One of our Type‐I photodynamic agents not only self‐assembles in water but also effectively targets the endoplasmic reticulum. It displayed excellent photocytotoxicity even in highly hypoxic environments (2 % O2), with a half‐maximal inhibitory concentration (IC50) of 0.96 μM, and demonstrated outstanding antitumor efficacy in murine models bearing HeLa tumors. [ABSTRACT FROM AUTHOR]

With the rapid development of external minimally invasive or noninvasive therapeutic modalities, ultrasound‐based sonodynamic therapy (SDT) is a new alternative for treating deep tumors. However, inadequate sonosensitizer efficiency and poor biosecurity limit clinical applications. In this study, we prepared an oxygen‐vacancy‐engineered W18O49−x nanobrush with a band gap of 2.79 eV for highly efficient SDT using a simple solvothermal method. The suitable band structures of the W18O49−x nanobrush endows it with the potential to simultaneously produce singlet oxygen (1O2), superoxide anions (⋅O2−), and hydroxyl radicals (⋅OH) under ultrasound irradiation. Additionally, abundant oxygen vacancies that serve as further charge traps that inhibit electron‐hole recombination are incidentally introduced through one‐step thermal reduction. Collectively, the in vitro and in vivo results demonstrate that the oxygen‐vacancy‐engineered W18O49−x nanobrush delivers highly efficient reactive oxygen species (ROS) for SDT in a very biosafe manner. Overall, this study provides a new avenue for discovering and designing inorganic nanosonosensitizers with enhanced therapeutic efficiencies for use in SDT. [ABSTRACT FROM AUTHOR]

With the rapid development of external minimally invasive or noninvasive therapeutic modalities, ultrasound‐based sonodynamic therapy (SDT) is a new alternative for treating deep tumors. However, inadequate sonosensitizer efficiency and poor biosecurity limit clinical applications. In this study, we prepared an oxygen‐vacancy‐engineered W18O49−x nanobrush with a band gap of 2.79 eV for highly efficient SDT using a simple solvothermal method. The suitable band structures of the W18O49−x nanobrush endows it with the potential to simultaneously produce singlet oxygen (1O2), superoxide anions (⋅O2−), and hydroxyl radicals (⋅OH) under ultrasound irradiation. Additionally, abundant oxygen vacancies that serve as further charge traps that inhibit electron‐hole recombination are incidentally introduced through one‐step thermal reduction. Collectively, the in vitro and in vivo results demonstrate that the oxygen‐vacancy‐engineered W18O49−x nanobrush delivers highly efficient reactive oxygen species (ROS) for SDT in a very biosafe manner. Overall, this study provides a new avenue for discovering and designing inorganic nanosonosensitizers with enhanced therapeutic efficiencies for use in SDT. [ABSTRACT FROM AUTHOR]

Reactive oxygen species (ROS) play an important role in signal transduction and metabolism. Over-produced ROS in cells or tissues, however, often leads to oxidation stress that has implications in a series of diseases including cancer, aging, atherosclerosis and inflammation. Driven by the need for on-demand drug delivery and fuelled by recent development of ROS-responsive materials and nanomedicine, responsive drug delivery systems (DDSs) have gained increasing research interest. ROS-responsive DDS is designed to release therapeutic agents only in targets of interest that produce excessive ROS, which may lead to both enhanced therapeutic efficiency and reduced side effects. Multiple-stimuli responsive DDSs that are also sensitive to other stimuli can further enhance controlled drug release in sites where multiple stimuli coexist. Beyond drug delivery, multifunctional DDSs have great potential in achieving simultaneous imaging, combinatorial therapy and targeting ability by introducing multifunctional elements such as signal reporter, targeting elements and photosensitizer. This review will summarize the latest development of ROS-responsive DDSs and discuss their design principle and biomedical applications. [ABSTRACT FROM AUTHOR]

Owing to the high depth of tissue penetration, non‐invasiveness, and controllability, ultrasound (US)‐mediated sonodynamic therapy (SDT) has shown broad application prospects for tumor treatment. However, the electron‐hole separation inefficiency of sonosensitizers and the tumor hypoxia remain two major challenges limiting the effect of SDT. Here, ultrafine photoetched bismuth vanadate (BiVO4) nanorods modified with DSPE‐PEG2000 (PEBVO@PEG NRs) were fabricated to achieve in situ self‐supply of oxygen (O2) and reactive oxygen species (ROS) for hypoxic tumor therapy. The photoetching approach could enhance the charge separation by inducing enriched oxygen vacancies on the surface of BiVO4, thereby improving the generation efficiency of ROS and O2. The PEBVO@PEG overcome the main obstacles of traditional sonosensitizers in the SDT process and show promising sonodynamic therapeutic effects, thus providing new strategies for improving the performance of sonosensitizer and hypoxic tumor elimination. [ABSTRACT FROM AUTHOR]

Owing to the high depth of tissue penetration, non‐invasiveness, and controllability, ultrasound (US)‐mediated sonodynamic therapy (SDT) has shown broad application prospects for tumor treatment. However, the electron‐hole separation inefficiency of sonosensitizers and the tumor hypoxia remain two major challenges limiting the effect of SDT. Here, ultrafine photoetched bismuth vanadate (BiVO4) nanorods modified with DSPE‐PEG2000 (PEBVO@PEG NRs) were fabricated to achieve in situ self‐supply of oxygen (O2) and reactive oxygen species (ROS) for hypoxic tumor therapy. The photoetching approach could enhance the charge separation by inducing enriched oxygen vacancies on the surface of BiVO4, thereby improving the generation efficiency of ROS and O2. The PEBVO@PEG overcome the main obstacles of traditional sonosensitizers in the SDT process and show promising sonodynamic therapeutic effects, thus providing new strategies for improving the performance of sonosensitizer and hypoxic tumor elimination. [ABSTRACT FROM AUTHOR]

The sonodynamic activities of gold nanoparticles (GNPs) with different morphologies, gold nanospheres (GNSs), gold nanoflowers (GNFs) and gold nanorods (GNRs), were explored by multi‐spectroscopic methods, in which the lesion degree of human serum albumin (HSA) was used as assessment index. The results revealed that three GNPs all had certain sonosensitivity but varying from different morphologies. It was also found that GNPs concentration and ultrasonic parameters were all critical influencing factors of sonodynamic injury HSA. Investigating the physical damage mechanism, the results indicated that the secondary and tertiary structure of HSA were compromised by ultrasound (US) combined with GNPs, so that the conformation of HSA was altered and the function was variously disturbed due to GNPs different morphologies. Studying the chemical damage mechanism, the results discovered that the yield of singlet oxygen (1O2) produced by GNPs with various morphologies combined with US was significant difference. Therefore, comprehensively analyzing the research results under different factors, the order of sonodynamic activities of GNPs was GNSs≈GNFs>GNRs. These findings may provide reference for the application of GNPs as sonosensitizers in sonodynamic therapy. [ABSTRACT FROM AUTHOR]

Photosensitizers (PSs) with effective reactive oxygen species generation ability against hypoxia are of great potential for clinical treatment of malignant tumors. However, complex tumor microenvironment, such as antioxidative responses and immunosuppression, would ineluctably limit the efficiency of photodynamic therapy (PDT). Herein, a molecular‐targeting photosensitizer QTANHOH is rationally designed for histone deacetylases (HDACs‐targeting photo‐immunotherapy application. The PS QTANHOH displays excellent type‐I/II PDT performance, exhibiting significant phototoxicity toward cancer cells with half maximal inhibitory concentration (IC50) less than 10 nm in both normoxia and hypoxia conditions under blue laser irradiation. Moreover, the bioactive compound could inhibit HDACs and activate the immune microenvironment to boost PDT efficacy on the immunocompetent BALB/c mice with breast cancer, leading to the eradication of solid tumor and inhibition of metastasis. Notably, the molecular‐targeting photosensitizer introduces an alternative strategy to achieve superior phototherapy for cancer therapy. [ABSTRACT FROM AUTHOR]

Triple‐negative breast cancer (TNBC) is endowed with a highly aggressive nature that results in distant metastases and high recurrence rates, yet limited success is realized in traditional chemotherapy. Activatable photosensitizers (PSs) may provide an effective and non‐invasive strategy to induce TNBC cell death in a precise way by offering stimuli‐responsive reactive oxygen species (ROS). However, the toxicity of ROS is often mitigated and even devitalized by the instinctive behavior of ROS resistance in TNBC cells. To address this issue, herein a small molecular self‐assembly nano‐prodrug is presented to co‐deliver an activatable PS and ROS resistance inhibitor. In TNBC cells, the overexpressed glutathione can disassemble the nano‐prodrug, thereby releasing ROS resistance inhibitor and activating the PS for photodynamic therapy and fluorescence imaging. A hybrid membrane coating‐assisted nanoparticle formation strategy is further demonstrated for efficient inhibition of tumor growth and distant metastases on both subcutaneous and orthotopic TNBC mice models. [ABSTRACT FROM AUTHOR]

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 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]

Endo/lysosomal escape of gene vectors and the subsequent unpacking of nucleic acids in cytosol are two major challenges for efficient gene delivery. Herein, we report a polymeric gene delivery vector, which consists of a photosensitizer (PS) with aggregation-induced emission (AIE) characteristics and oligoethylenimine (OEI) conjugated via an aminoacrylate (AA) linker that can be cleaved by reactive oxygen species (ROS). In aqueous media, the polymer could self-assemble into bright red fluorescent nanoparticles (NPs), which can efficiently bind to DNA through electrostatic interaction for gene delivery. Upon visible light irradiation, the generated ROS can break the endo/lysosomal membrane and the polymer, resulting in light-controlled endo/lysosomal escape and unpacking of DNA for efficient gene delivery. The smart polymer represents the first successful gene vector to simultaneously address both challenges with a single light excitation process. [ABSTRACT FROM AUTHOR]

Ferroptosis regulates cell death through reactive oxygen species (ROS)‐associated lipid peroxide accumulation, which is expected to affect the structure and polarity of lipid droplets (LDs), but with no clear evidence. Herein, we report the first example of an LD/nucleus dual‐targeted ratiometric fluorescent probe, CQPP, for monitoring polarity changes in the cellular microenvironment. Due to the donor–acceptor structure of CQPP, it offers ratiometric fluorescence emission and fluorescence lifetime signals that reflect polarity variations. Using nucleus imaging as a reference, CQPP was applied to report the increase in LD polarity and the homogenization of polarity between LDs and cytoplasm in the ferroptosis model. This LD/nucleus dual‐targeted fluorescent probe shows the great potential of using fluorescence imaging to study ferroptosis and ferroptosis‐related diseases. [ABSTRACT FROM AUTHOR]

Ferroptosis regulates cell death through reactive oxygen species (ROS)‐associated lipid peroxide accumulation, which is expected to affect the structure and polarity of lipid droplets (LDs), but with no clear evidence. Herein, we report the first example of an LD/nucleus dual‐targeted ratiometric fluorescent probe, CQPP, for monitoring polarity changes in the cellular microenvironment. Due to the donor–acceptor structure of CQPP, it offers ratiometric fluorescence emission and fluorescence lifetime signals that reflect polarity variations. Using nucleus imaging as a reference, CQPP was applied to report the increase in LD polarity and the homogenization of polarity between LDs and cytoplasm in the ferroptosis model. This LD/nucleus dual‐targeted fluorescent probe shows the great potential of using fluorescence imaging to study ferroptosis and ferroptosis‐related diseases. [ABSTRACT FROM AUTHOR]

Intraplaque hemorrhage (IPH) plays a major role in the aggressive progression of vulnerable plaque, leading to acute cardiovascular events. We previously demonstrated that sonodynamic therapy (SDT) inhibits atherosclerotic plaque progression. In this study, we investigated whether SDT could also be applied to treat more advanced hemorrhagic plaque and addressed the underlying mechanism. SDT decreased atherosclerotic burden, positively altered atherosclerotic lesion composition, and alleviated iron retention in rabbit hemorrhagic plaques. Furthermore, SDT reduced iron retention by stimulating ferroportin 1 (Fpn1) expression in apolipoprotein E (ApoE)−/− mouse plaques with high susceptibility to IPH. Subsequently, SDT inhibited iron‐overload‐induced foam‐cell formation and pro‐inflammatory cytokines secretion in vitro. Moreover, SDT reduced levels of the labile iron pool and ferritin expression via the reactive oxygen species (ROS)‐nuclear factor erythroid 2‐related factor 2 (Nrf2)‐FPN1 pathway. SDT exerted therapeutic effects on hemorrhagic plaques and reduced iron retention via the ROS‐Nrf2‐FPN1 pathway in macrophages, thereby suggesting that it is a potential translational strategy for patients with advanced atherosclerosis in clinical practice. [ABSTRACT FROM AUTHOR]

To date, the mortality of tongue squamous cell carcinoma (TSCC) is still high, COX‐2 is highly expressed in the head and neck cancers, and targeting COX‐2 is a potential treatment for TSCC. Herein, a series of novel carborane compounds based on COX‐2 inhibitors have been developed for the effective treatment of TSCC by boron neutron capture therapy (BNCT). Notably, the compound 1 had high COX‐2 selectivity and low cytotoxicity against CAL27 cells. Meanwhile, the compound 1 had higher selectivity and uptake of CAL27 cells compared to the positive control group sodium borocaptate (BSH). The apoptosis of CAL27 cells treated with the compound 1 during BNCT was significantly induced by breaking DNA double strands and generating excess reactive oxygen species, and the proliferation of cancer cells was inhibited by down‐regulating the expression of cytokines associated with phosphatidylinositide 3‐kinases/protein kinase B (PI3K/Akt) and mitogen‐activated protein kinases (MAPKs) signaling pathways in BNCT. Thus, the carborane compounds based on COX‐2 inhibitors have the potential to effectively treat tongue squamous cell carcinoma through BNCT. [ABSTRACT FROM AUTHOR]

The recognition and inactivation of specific pathogenic bacteria remain an enormous scientific challenge and an important therapeutic goal. Therefore, materials that can selectively target and kill specific pathogenic bacteria, without harming beneficial strains are highly desirable. Here, a material platform is reported that exploits bacteria as a template to synthesize polymers with aggregation‐induced emission (AIE) characteristic by copper‐catalyzed atom transfer radical polymerization for self‐selective killing of the bacteria that templates them with no antimicrobial resistance. The bacteria‐templated polymers show very weak fluorescence in aqueous media, however, the fluorescence is turned on upon recognition of the bacteria used as the template to synthesize the polymer even at a low concentration of 600 ng mL−1. Moreover, the incorporated AIE fluorogens (AIEgens) can act as an efficient photosensitizer for reactive oxygen species (ROS) generation after bacteria surface binding, which endows the templated polymers with the capability for selective bacterial killing. The bacterium‐templated synthesis is generally applicable to a wide range of bacteria, including clinically isolated multidrug‐resistant bacterial strains. It is envisioned that the bacterium‐templated method provides a new strategy for bacteria‐specific diagnostic and therapeutic applications. [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]

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]

The complex tumor microenvironment (TME) and nonspecific drug targeting limit the clinical efficacy of photodynamic therapy in combination with chemotherapy. Herein, a metal–organic framework (MOF) assisted strategy is reported that modulates TME by reducing tumor hypoxia and intracellular glutathione (GSH) and offers targeted delivery and controlled release of the trapped chemodrug. Platinum(IV)‐diazido complex (Pt(IV)) is loaded inside a Cu(II) carboxylate‐based MOF, MOF‐199, and an aggregation‐induced‐emission photosensitizer, TBD, is conjugated to polyethylene glycol for encapsulating Pt(IV)‐loaded MOF‐199. Once the fabricated TBD‐Pt(IV)@MOF‐199 nanoparticles are internalized by cancer cells, MOF‐199 consumes intracellular GSH and decomposes to fragments to release Pt(IV). Upon light irradiation, the released Pt(IV) generates O2 that relieves hypoxia and produces Pt(II)‐based chemodrug inside cancer cells. Concomitantly, efficient reactive oxygen species generation and bright emission are afforded by TBD, resulting in synergistic image‐guided photo‐chemo therapy with enhanced efficacies and mitigated side effects. [ABSTRACT FROM AUTHOR]

Disrupted mitochondrial function and reactive oxygen species (ROS) generation cause cellular damage and oxidative stress‐induced macrophage inflammatory cell death. It remains unclear how mitochondrial dysfunction relates to inflammasome activation and pyroptotic cell death. In this study, we demonstrated that tumor necrosis factor receptor‐associated factor 3 (TRAF3) regulates mitochondrial ROS production and promotes TLR agonist LPS plus nigericin (LPS/Ng)‐induced inflammasome and pyroptosis in mouse primary macrophages and human monocyte THP‐1 cells. Co‐IP assays confirmed that TRAF3 forms a complex with TRAF2 and cIAP1 and mediates ubiquitin and degradation of Unc‐51 like autophagy activating kinase 1 (ULK1). Moreover, knockdown of ULK1 in THP‐1 cells significantly promoted LPS/Ng‐induced inflammasome by activating caspase 1 and mature IL‐1β. Apoptosis inducing factor (AIF) translocation from mitochondrial to nuclear was observed in ULK1‐deficient THP‐1 cells under LPS/Ng stimulation, which mediates LPS/Ng‐induced cell death in ULK1 deficient macrophages. In conclusion, this study identified a novel role of TRAF3 in regulation of ULK1 ubiquitination and inflammasome signaling and provided molecular mechanisms by which ubiquitination of ULK1 controls mitochondrial ROS production, inflammasome activity, and AIF‐dependent pyroptosis. [ABSTRACT FROM AUTHOR]

Nowadays various inorganic nanoparticles that generate highly reactive hydroxyl radical (·OH) on the basis of Fenton‐like catalytic activity of metal ions have been designed for chemodynamic therapy. However, the high level of adaptive antioxidants [glutathione (GSH)] in cancer cells could effectively consume ·OH to compromise the treatment efficiency and biosafety of these inorganic nanoparticles, and this is a general concern in chemodynamic therapy. Herein, a new biodegradable nanoscale coordination polymer (NCP) is developed by integration of cisplatin prodrug (DSCP) and iron (III) ions through a reverse microemulsion method. The DSCP in the NCPs could react with GSH to release free cisplatin, while the iron (III) ions could be reduced by GSH into iron (II) to enable Fenton reaction, subsequently leading to amplified intracellular oxidative stress. After surface modification of polyethylene glycol (PEG) and cyclo[Arg‐Gly‐Asp‐D‐Phe‐Lys(mpa)] peptide (cRGD), Fe‐DSCP‐PEG‐cRGD shows an excellent targeting effect against αvβ3‐integrin overexpressed tumor cells. Furthermore, Fe‐DSCP‐PEG‐cRGD enables significant chemo and chemodynamic therapy with dramatically enhanced therapeutic efficiency in comparison to relative monotherapies. Importantly, Fe‐DSCP‐PEG‐cRGD could be efficiently cleared out from mice through feces and urine postinjection 7 days. The NCP presented in this work is simple and economical, which shows great biodegradability and biosafety for potential clinical translation. [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]

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]

The detection and elimination of intracellular bacteria remain a major challenge. In this work, we report an aggregation‐induced emission (AIE) bioprobe that can detect bacterial infection and kill bacteria surviving inside macrophages through a dynamic process, notably specific molecular tailoring of the probe by caspase‐1 activation in infected macrophages and accumulation of the residue on phagosomes containing bacteria, leading to light‐up fluorescent signals. Moreover, the AIEgen can serve as a photosensitizer for generation of reactive oxygen species (ROS); and the average ROS indicator fluorescent signal intensity per unit area in the bacterial phagosomes is approximately 2.7‐fold higher than that in the cytoplasm. This, in turn, induces bacteria killing with high efficiency and minimal cytotoxicity towards macrophages. We envision that this specific light‐up bioprobe may provide a new approach for selective and sensitive detection and eradication of intracellular bacterial infections. [ABSTRACT FROM AUTHOR]

Integrated systems that offer traceable cancer therapy are highly desirable for personalized medicine. Herein, a probe is reported that is composed of a red-emissive photosensitizer (PS) with aggregation-induced emission characteristics and a built-in apoptosis sensor with activatable green emission for targeted cancer cell ablation and real-time monitoring of PS activation and therapeutic response. The probe is nonemissive in aqueous media and can be selectively uptaken by αv β3 integrin overexpressed cancer cells. Cleavage of the probe by intracellular glutathione leads to release of the apoptosis sensor and red fluorescence turn-on to report the PS activation. Upon light irradiation, the PS can generate reactive oxygen species to induce cell apoptosis and activate caspase-3/-7, which will cleave the apoptosis sensor to yield intense green fluorescence. Both the red and green emission can be obtained through a single wavelength excitation, which makes the probe very convenient for therapeutic protocol development. [ABSTRACT FROM AUTHOR]

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria-targeting probe (AIE-mito-TPP) by conjugating a triphenylphosphine (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). Owing to the more negative mitochondrial membrane potential of cancer cells than normal cells, the AIE-mito-TPP probe can selectively accumulate in cancer-cell mitochondria and light up its fluorescence. More importantly, the probe exhibits selective cytotoxicity for studied cancer cells over normal cells. The high potency of AIE-mito-TPP correlates with its strong ability to aggregate in mitochondria, which can efficiently decrease the mitochondria membrane potential and increase the level of intracellular reactive oxygen species (ROS) in cancer cells. The mitochondrial light-up probe provides a unique strategy for potential image-guided therapy of cancer cells. [ABSTRACT FROM AUTHOR]

Subcellular organelle-specific reagents for simultaneous tumor targeting, imaging, and treatment are of enormous interest in cancer therapy. Herein, we present a mitochondria-targeting probe (AIE-mito-TPP) by conjugating a triphenylphosphine (TPP) with a fluorogen which can undergo aggregation-induced emission (AIE). Owing to the more negative mitochondrial membrane potential of cancer cells than normal cells, the AIE-mito-TPP probe can selectively accumulate in cancer-cell mitochondria and light up its fluorescence. More importantly, the probe exhibits selective cytotoxicity for studied cancer cells over normal cells. The high potency of AIE-mito-TPP correlates with its strong ability to aggregate in mitochondria, which can efficiently decrease the mitochondria membrane potential and increase the level of intracellular reactive oxygen species (ROS) in cancer cells. The mitochondrial light-up probe provides a unique strategy for potential image-guided therapy of cancer cells. [ABSTRACT FROM AUTHOR]

Inside Back Cover: A Carbonic Anhydrase IX (CAIX)-Anchored Rhenium(I) Photosensitizer Evokes Pyroptosis for Enhanced Anti-Tumor Immunity (Angew. CA-Re is the first metal-complex-based pyroptosis inducer, and this work provides a promising avenue for cancer metalloimmunotherapy. Keywords: anti-tumor immunity; carbonic anhydrase IX targeting; metallodrugs; photodynamic therapy; pyroptosis EN anti-tumor immunity carbonic anhydrase IX targeting metallodrugs photodynamic therapy pyroptosis 1 1 1 02/09/22 20220214 NES 220214 B Pyroptosis b is a unique form of programmed cell death that is essentially proinflammatory and critical for immunity. [Extracted from the article]

J. Neurochem. (2012) 122, 752-763. Abstract Factors released from injured dopaminergic (DA) neurons may trigger microglial activation and set in motion a vicious cycle of neuronal injury and inflammation that fuels progressive DA neurodegeneration in Parkinson's disease. In this study, using proteomic and immunoblotting analysis, we detected elevated levels of cystatin C in conditioned media (CM) from 1-methyl-4-phenylpyridinium and dieldrin-injured rat DA neuronal cells. Immunodepletion of cystatin C significantly reduced the ability of DA neuronal CM to induce activation of rat microglial cells as determined by up-regulation of inducible nitric oxide synthase, production of free radicals and release of proinflammatory cytokines as well as activated microglia-mediated DA neurotoxicity. Treatment of the cystatin C-containing CM with enzymes that remove O- and sialic acid-, but not N-linked carbohydrate moieties markedly reduced the ability of the DA neuronal CM to activate microglia. Taken together, these results suggest that DA neuronal cystatin C plays a role in the neuronal injury-induced microglial activation and neurotoxicity. These findings from the rat DA neuron-microglia in vitro model may help guide continued investigation to define the precise role of cystatin C in the complex interplay among neurons and glia in the pathogenesis of Parkinson's disease. [ABSTRACT FROM AUTHOR]

Owing to efficient singlet oxygen (1O2) generation in aggregate state, photosensitizers (PSs) with aggregation‐induced emission (AIE) have attracted much research interests in photodynamic therapy (PDT). In addition to high 1O2 generation efficiency, strong molar absorption in long‐wavelength range and near‐infrared (NIR) emission are also highly desirable, but difficult to achieve for AIE PSs since the twisted structures in AIE moieties usually lead to absorption and emission in short‐wavelength range. In this contribution, through acceptor engineering, a new AIE PS of TBT is designed to show aggregation‐induced NIR emission centered at 810 nm, broad absorption in the range between 300 and 700 nm with a large molar absorption coefficient and a high 1O2 generation efficiency under white light irradiation. Further, donor engineering by attaching two branched flexible chains to TBT yielded TBTC8, which circumvented the strong intermolecular interactions of TBT in nanoparticles (NPs), yielding TBTC8 NPs with optimized overall performance in 1O2 generation, absorption, and emission. Subsequent PDT results in both in vitro and in vivo studies indicate that TBTC8 NPs are promising candidates in practical application. [ABSTRACT FROM AUTHOR]