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Designing nanomedicines with low toxicity, high targeting, excellent therapeutic effects, and precise release is always the major challenges in clinical cancer treatment. Here, we report a light‐enhanced tandem‐responsive nano delivery platform COF‐B@X‐03 for amplified anti‐tumor efficiency. Biotin‐loaded COF‐B@X‐03 could precisely target tumor cells, and the azo and hydrazone bonds in it would be depolymerized by the overexpressed azoreductase and acidic microenvironment in hypoxic tumors. In vitro experimental results indicate mitochondrial and endoplasmic reticulum stress caused by COF‐B@X‐03 under light is the direct cause of tumor cell death. In vivo experimental data prove COF‐B@X‐03 achieves low oxygen dependent phototherapy, and the maintenance of intratumoral hypoxia provides the possibility for the continuous degradation of COF‐B@X‐03 to generate more reactive oxygen species for tumor photodynamic therapy by released X‐03. In the end, COF‐B@X‐03 phototherapy group achieves higher tumor inhibition rate than X‐03 phototherapy group, which is 81.37 %. Meanwhile, COF‐B@X‐03 significantly eliminates the risk of tumor metastasis. In summary, the construction of this tandem‐responsive nano delivery platform provides a new direction for achieving efficient removal of solid tumors in clinical practice. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) exerts its therapeutic effects by inducing apoptosis, necrosis, and microvascular damage in tumor cells, but it also causes inflammation and induces the expression of angiogenic factors, accelerating tumor metastasis and proliferation. In this study, aggregation-induced emission (AIE) photosensitizer (PS) for PDT was combined with the cyclooxygenase-2 (COX-2) inhibitor indomethacin (IMC) for cancer-selective imaging and more efficiency in inducing apoptosis in cancer cells. In detail, inhibition of COX-2-mediated AIE PS effectively targeted the Golgi apparatus (GA) of cancer cells to generate large amounts of reactive oxygen species (ROS) in situ, thereby exerting a PDT effect. Specifically, COX-2 and other key enzymes that trigger inflammation and metastasis were significantly inhibited. It had more potent anti-tumor activity (tumor inhibition rate of 64.32 %), as well as anti-metastatic and anti-proliferative effects compared to the use of usual AIE PS. [Display omitted] • TTPI was obtained by combining AIE-PS with the COX-2 inhibitor indomethacin. • TTPI precisely targeted COX-2 in the Golgi with high co-location coefficient. • PDT while inhibiting enzymes that trigger inflammation and metastasis such as COX-2. • The inhibition rate of TTPI in vivo was significantly increased to 64.32 %. [ABSTRACT FROM AUTHOR]

[Display omitted] • TCN-2 has excellent viscosity response characteristics. • TCN-2 could achieve lipid droplets targeting and induce tumor cell death. • TCN-2 induced the generation of large amounts of non-oxygen consuming ROS. A dual donor–acceptor photosensitizer TCN-2 prepared based on single donor–acceptor could fulfil lipid droplets targeting to trigger apoptosis and tumor growth arrest. Meanwhile, all of experiments both in phosphate buffer solution and intracellular surroundings have demonstrated that TCN-2 catalyzed the production of type I as well as type II reactive oxygen species, forming a hybrid reactive oxygen species pattern, indicating that TCN-2 could be applied to initiate a series of biological responses triggered by oxidative stress within most high-viscosity solid tumors. In addition, TCN-2 also has the capability of fluorescence imaging, which could perfectly combine therapeutic imaging to achieve therapeutic effects while identifying cancerous lesions. Due to the structural design of double electron-absorbing groups, TCN-2 retained excellent lipophilicity while enhancing solubility in the biological environment. Terrific biocompatibility, minimal phototoxic damage to normal cells and tissues, and specific driving to prescriptive organelles to maximize therapeutic effects were used to enhance the therapeutic effect of photodynamic therapy to cease disease progression. [ABSTRACT FROM AUTHOR]

Aggregation-induced emission photosensitizers (AIE-PSs) targeting different subcellular organelles with time-dependent manner are highly promising for clinical applications but rarely reported. Herein, we designed and synthesized the near-infrared (NIR) emission AIE-PS (CTQ-S) with broad absorption and excellent type I reactive oxygen species (ROS) generation efficiency that was superior to the widely used PS (Rose Bengal and Chlorine 6). With short-term incubation, CTQ-S anchored on the cell membrane (Rr: 0.843, Rr is for Pearson correlation coefficient) and gradually entered the mitochondria (Rr: 0.937) of cancer cells, showing excellent time-dependent fluorescence fluorescent imaging effect. Furthermore, CTQ-S realized the selective photodynamic therapy (PDT) effect in a time-dependent manner under white light irradiation. This work provided a new way for cancer cells fluorescence imaging and PDT. [Display omitted] • A NIR emission AIE-PS with wide absorption bands and large Stokes shifts. • CTQ-S displayed remarkable type I ROS generation efficiency. • Time-dependent targeting of the cell membrane or mitochondria of cancer cells. • Superior colocalization effect on cell membrane (0.843) and mitochondrial (0.937). • It exhibited a potent selective PDT effect by inducing mitochondrial damage. [ABSTRACT FROM AUTHOR]

[Display omitted] • Optimized molecular side-chain has facilitated photosensitizers from type II to type I PDT. • BOTTQ can target dynamic lipid droplets with high fidelity. • BOTTQ NPs containing MAL moiety can effectively deplete GSH to promote ferroptosis. • Ferroptosis induced by BOTTQ NPs can stimulate cascade responses in other organelles. • BOTTQ NPs can efficaciously inhibit and ablate tumors in hypoxic conditions. Severe ferroptosis is a non-apoptotic iron-dependent cell death pathway, and extreme hypoxia and anomalous iron metabolism in tumors critically suppress the efficacy of ferroptosis therapy. Overcoming tumor hypoxia while facilitating ferroptosis is an extremely challenging task. Herein, the photosensitizer named BOTTQ with specific targeting of lipid droplet (LD) was synthesized by increasing the tail chain length of triphenylamine. The addition of alkoxy chains optimized the molecular structure and fostered inter-system crossing and type I reactive oxygen species (ROS) generation. Besides, BOTTQ yielded large amounts of type I ROS under light excitation oxidize efficiently polyunsaturated fatty acids in lipid monolayer of LD and contribute to the formation of ferroptosis substrate. Meanwhile, the generation of type I ROS accelerated the Fenton reaction, thus effectively boosting the occurrences of ferroptosis. Furthermore, the successful encapsulation of BOTTQ into DSPE-PEG-MAL material not only elevates the stable type of nanoparticle colloids, but the MAL moiety can deplete the functional thiols of glutathione in a mild environment, which leads to glutathione failure and facilitates ferroptosis. Thus tumor-specific ferroptosis-inducing strategy offers a universally applicable therapy with the capacity to enhance type I ROS production and effectively contain tumorigenesis. [ABSTRACT FROM AUTHOR]

A family of near-infrared (NIR) aggregation-induced emission (AIE) photosensitizers (PSs) were designed and synthesized to modulate the spectroscopic and photochemical properties of the contained donor-acceptor (D-A) units. Stronger intermolecular charge transfer (ICT) states were promoted by the synergistic action of benzothiadiazoles and quinolines, which accelerates intersystem crossing (ISC). The best NIR AIE-PS, BTQ , showed an extremely high 1O 2 generation rate (5.6-fold of Rose Bengal) and highly efficient photodynamic killing of cancer cells. Furthermore, the mechanism by which mitochondria-targeted PSs produce large amounts of reactive oxygen species (ROS) triggering calcium ion (Ca2+) overload and opening of the mitochondrial permeability transition pore (mPTP), thereby disrupting mitochondria and leading to apoptosis, was demonstrated for the first time. This work provides an exciting benchmark for the molecular engineering of AIE-PSs targeting mitochondria and presented new insights of the development of fluorescence imaging guided photodynamic therapy (FL-G-PDT). [Display omitted] • Simple Molecular engineering to synthesize mitochondrial targeting NIR AIE photosensitizers (BTQ). • BTQ can efficiently generated singlet oxygen and precisely target mitochondria. • BTQ can open the transition pore of mitochondrial membrane permeability and reduce the mitochondrial membrane potential. • BTQ has excellent photodynamic effect on HepG2 cells under light irradiation. [ABSTRACT FROM AUTHOR]

Organic AIE nanostructures are extremely important fluorescent dyes for imaging-guided photosensitizing therapy, which are capable of imaging organelles and producing ROS well, however, it remains difficulties nowadays. Here we disclose the development and assembly of a NIR AIE nanoparticle (MeTTSN) by multiple assembling chemical engineering for utilization in cellular LDs, with accurate dynamic monitoring (Pearson's coefficient of 0.981) and suitable particle size distribution (267.04 nm) in PBS solution, effective Stokes shifts (91 nm), valuable quantum yield (5.88%) in water and high bioactivity and stability, superior self-assembly and incredibly 1O 2 and ROS generation. Moreover, under white light irradiation, the MeTTSN , as an ideal PS, displayed superior photosensitivity for active HepG2 cells. Furthermore, the end up living cells' co-staining imaging and flow cytometry revealed that MeTTSN could actively suppress cell growth and cause or lead to cell death. Overall, the current study presents a feasible method for LDs targeting chemical bioengineering and highlights the importance of organic AIE materials PSs medication throughout the healthcare and fluorescent imaging-guided PDT area. • MeTTSN was applied to glow brightly and high-fidelity monitoring lipids droplets. • MeTTSN has suitable particle size distribution in PBS. • MeTTSN has excellent bioactivity and photostability. • MeTTS N has been utilized effectively for the photodynamic etching of cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • A Novel NIR AIEgen (MTOQS) synthesized for efficient ROS production. • MTOQS has a killing effect on cancer cells with less damage to normal cells. • Induces endoplasmic reticulum-mitochondria dual oxidative stress. • MTOQS could affect energy metabolism and alter the tumor microenvironment. • MTOQS switches on apoptotic pathways in multiple ways. Organelle-targeted photodynamic therapy has been increasingly investigated in recent decades, but little attention has been paid to the damage caused to other non-primary target organelles during the course of action, even though these non-primary target organelles may play a substantial role in inhibiting the growth of cancer cells. In this contribution, we report an AIE-type strong endoplasmic reticulum-targeted luminogen (MTOQS) with a distorted structure, which is efficient in producing ROS both in cellular and non-cellular environment, causing an effective reduction of high levels of GSH and MDA in cancer cells through the efficient accumulation of intracellular ROS, and the levels of ATP, l -lactic acid, anti-apoptotic factor Bcl-2 and apoptotic protein caspase-3 were determined. Through the identification of these markers, it was evidenced that MTOQS -induced dual organelle oxidative stress could diminish the degree of oxidative phosphorylation and glycolysis in cancer cells and trigger an alteration in the culture environment of cancer cells, while causing damage to the endoplasmic reticulum and mitochondria through multiorganelle oxidative stress, turning on the pathway of apoptosis and consequently driving cancer cells to apoptosis. [ABSTRACT FROM AUTHOR]

The aggregation-induced emission photosensitizers (AIE-PSs) manifest a multitude of notable superiorities in terms of high specificity to organelles, high-efficient singlet oxygen (1O 2) generation as well as enhanced fluorescence intensity, which provides a feasible approach to overcome the problems such as the insufficient generation of reactive oxygen species (ROS) caused by grave aggregation-induced quenching (ACQ) and the lack of specific targeting existing in traditional PSs, but extremely challenging. Herein, a series of near-infrared (NIR) AIE luminogens (AIEgens) for targeting mitochondrial was devised and synthesized by regulating the D-A intensity assembly molecular engineering, which fabricating a progressively stronger intermolecular charge transfer (ICT) state to accelerate highly effective intersystem crossing (ISC) of excited electrons by the synergistic effect of thiophene and quinolinium. Impressively, the optimal NIR AIE-PS (DTTVQ-OH) revealed excellent photostability, biocompatibility, precise mitochondria targeting, extremely high generation yield of 1O 2 (4.9-fold that of Rose Bengal) and superior phototoxicity in living HepG2 cells. Furthermore, apoptosis assay and cell migration experiment further demonstrated that DTTVQ-OH could efficaciously restrain cell proliferation and induce/speed up cancer cell death. Moreover, DTTVQ-OH can selectively distinguish cancer cells and normal cells by difference of fluorescence intensity in high resolution without the assist of any extra targeting ligands. As a consequence, this work provides a rational and practicable strategy for the specific targeted molecular engineering of AIE-PSs, which gives impetus to the development of fluorescence imaging-guided photodynamic therapy fields. Multifunctional nano-photosensitizer was used for mitochondrial-targeting photodynamic ablation of liver cancer cells. [Display omitted] • A mitochondria targeted NIR AIE nanomaterial (DTTVQ-OH) was synthesized by a simple three-part fragment assembly molecular engineering. • DTTVQ-OH possesses desirable merits especially precise mitochondrial targeting and efficient 1O 2 generation. • DTTVQ-OH could selectively accumulate in cancer cells rather than normal cells without the aid of any additional targeting ligands. • As a nanoparticle PS, DTTVQ-OH was successfully used for photodynamic ablation in living HepG2 cells under white light irradiation. [ABSTRACT FROM AUTHOR]

Multifunctional nano-photosensitizer was used for high-fidelity imaging of lipid droplets and photodynamic ablation of liver cancer cells. • A lipophilic NIR AIE nanomaterial (TTI) was designed and prepared. • TTI was applied to specifically 'light up' and high-fidelity dynamic tracking LDs. • In the PBS solution, TTI exhibited extremely efficient 1O 2 quantum yield. • TTI was successfully used for photodynamic ablation cancer cells. Near-infrared (NIR) aggregation-induced emission (AIE) nanomaterials, with organelles targeted-imaging ability and effective reactive oxygen species (ROS) generation nature, are highly desirable photosensitizers (PSs) for fluorescence imaging-guided photodynamic therapy (PDT), but it remains challenging. Herein, a NIR AIE luminogens (AIEgens, TTI) was designed and synthesized using three-fragmentary assembly molecular engineering, which was used for intracellular lipid droplets (LDs) high-fidelity dynamic tracking (Pearson's coefficient of 0.95) due to its strong lipophilic nature (ClogP of 8.34), large Stokes shifts (170 nm), excellent photostability and good biocompatibility. Meanwhile, TTI self-assembled nanoparticles with an average diameter of 196.57 nm exhibited extremely high-efficient singlet oxygen (1O 2) generation efficiency (with up to 85.16% of quantum yield) in PBS solution. In addition, the TTI as a desired PS revealed good phototoxicity for living HepG2 cells under white light irradiation. Moreover, the live/dead cells co-staining image, flow cytometry and scratch wound healing assays indicated that TTI could effectively inhibit the proliferation and cause/induce cells apoptosis, which eventually led to the death of HepG2 cells. Therefore, this work provides a useful strategy for LDs-targeting molecular engineering and highlights the potential of organic nanoparticles PSs drug in biomedical and fluorescence imaging-guided PDT fields. [ABSTRACT FROM AUTHOR]

• O 2 self-sufficient enhanced PDT efficiency anti-hypoxia effect. • Wide-spectrum cancer cell discrimination without the aid of any extra cancer cell-specific targeting ligands. • Mitochondria-specific targeting enhances therapeutic efficiency of PDT. The severe hypoxia in solid tumor and the accurate discrimination between cancer and normal cells gravely restrict the application of fluorescence imaging-guided photodynamic therapy (PDT), although this cancer-therapy modality has significant superiorities in terms of precise visualization of the location of photosensitizers (PSs) in tumor tissue as well as noninvasive and reliable treatment. A convenient and universal fluorescence system featuring Type I reactive oxygen species (ROS) based on free radicals, wide-spectrum cancer cell discrimination and distinctive aggregation-induced emission (AIE) characteristics could offer a feasible approach to resolve the problems above, which is yet extremely challenging. Herein, we propose a series of electron-rich anion-π+ AIE-active luminogens (AIEgens) fabricating increasingly stronger intermolecular charge transfer (ICT) state to promote highly efficient intersystem crossing for boosting Type I ROS generation. Moreover, MeOTPPM has priority to enter cancer cells with better plasma membrane permeability due to the strongest binding force with water molecules. This work serves as a pioneering reference for rationally constructing Type I-based purely organic PSs to overcome tumor hypoxia defects in PDT and selectively targeting and ablating cancer cells over normal cells without the aid of any extra cancer cell-specific targeting ligands. [ABSTRACT FROM AUTHOR]