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Neutrophil extracellular traps (NETs) are web-like complexes of DNA and proteins that are extruded by activated neutrophils and play critical roles as major components of the innate immune response against pathogen invasion. However, some microbes have developed strategies to evade NET attacks, leading to impaired immune defenses and persistent infections. In this study, an engineered neutrophil strategy for enhancing the antibacterial activity of NETs is developed. A nucleus-targeting photosensitizer (NCP) with strong reactive oxygen species production and a strong DNA-binding capacity is synthesized. NCP-loaded neutrophils are subsequently constructed via direct incubation of NCP with neutrophils, and the NCP is closely inserted into the nucleus DNA. Upon activation by bacteria-related toxins, NCP-coupled NETs can be released rapidly, actively trapping bacteria and providing a high local concentration of NCP around them. Both in vitro and in vivo results revealed that NCP-coupled NETs can effectively eradicate various multidrug-resistant bacteria and biofilms through photodynamic therapy, overcome bacterial immune evasion, and promote tissue recovery from severe wound infections. This design can significantly strengthen NET function, providing a non-antibiotic alternative platform for treating bacterial infectious diseases., (© 2024 Wiley‐VCH GmbH.)

The efficacy of imaging-guided photodynamic therapy (PDT) is compromised by the attenuation of fluorescence and decline in reactive oxygen species (ROS) generation efficiency in the physiological environment of conventional photosensitizers, limited near-infrared (NIR) absorption, and high systemic cytotoxicity. This paper presents the synthesis of two cyclometalated Ir (III) complexes (Ir-thpy and Ir-ppy) by using a triphenylamine derivative (DPTPA) as the primary ligand and their encapsulation into an amphiphilic phospholipid to form nanoparticles (NPs). These complexes exhibit aggregation-induced emission features and remarkably enhanced ROS generation compared to Chlorin e6 (Ce6). Moreover, Ir-thpy NPs possess the unique ability to selectively target mitochondria, leading to depolarization of the mitochondrial membrane potential and ultimately triggering apoptosis. Notably, Ir-thpy NPs exhibit exceptional photocytotoxicity even towards cisplatin-resistant A549/DDP tumor cells. In vivo two-photon imaging verified the robust tumor-targeting efficacy of Ir-thpy NPs. The in vivo results unequivocally demonstrate that Ir-thpy NPs exhibit excellent tumor ablation along with remarkable biocompatibility. This study presents a promising approach for the development of multifunctional Ir-NPs for two-photon imaging-guided PDT and provides novel insights for potential clinical applications in oncology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Imaging-guided photodynamic therapy (PDT) holds great potential for tumor therapy. However, achieving the synergistic enhancement of the reactive oxygen species (ROS) generation efficiency and fluorescence emission of photosensitizers (PSs) remains a challenge, resulting in suboptimal image guidance and theranostic efficacy. The hypoxic tumor microenvironment also hinders the efficacy of PDT. Herein, we propose a "two-stage rocket-propelled" photosensitive system for tumor cell ablation. This system utilizes MitoS, a mitochondria-targeted PS, to ablate tumor cells. Importantly, MitoS can react with HClO to generate a more efficient PS, MitoSO, with a significantly improved fluorescence quantum yield. Both MitoS and MitoSO exhibit less O 2 -dependent type I ROS generation capability, inducing apoptosis and ferroptosis. In vivo PDT results confirm that this mitochondrial-specific type I-II cascade phototherapeutic strategy is a potent intervention for tumor downstaging. This study not only sheds light on the correlation between the PS structure and the ROS generation pathway but also proposes a novel and effective strategy for tumor downstaging intervention.

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., (© 2022 Wiley-VCH GmbH.)

Inflammation exists in the microenvironment of most, if not virtually all, tumors, which greatly exacerbates the difficulty of cancer treatment. Considering the superiority of activatable photosensitizers (PSs), a novel strategy of 'making friends with the enemy' for tumor treatment was proposed. In this strategy, the "enemy" refers to inflammatory cytokines and the tumor site is targeted by detecting the enemy. Upon detection, a dichromatic fluorescence signal is released and the PS is activated specifically by the inflammatory cytokines. In this study, a multifunctional PS (TPE-PTZ-Py) was rationally designed, which can be activated specifically under the synergistic action of hypochlorous acid (HClO) (one kind of inflammatory cytokines) and acid (one typical marker of tumor), and output a ratiometric fluorescence signal simultaneously. The sulfoxide analogue (TPE-PTZO-PyH) as the response product effectively produced 1 O 2 (1.8-fold higher than that obtained with Rose Bengal) and showed high phototoxicity (IC 50 < 7.6 μM). More importantly, imaging analyses confirmed that TPE-PTZ-Py could be activated in human cervical cancer tissue. To date, several phenothiazine (PTZ)-based fluorescent probes have been developed for the selective sensing and imaging of HClO in subcellular organelles; however, this is the first phenothiazine-based nanodrug designed for the treatment of inflammation-associated tumors with a few side effects.

Developing novel photosensitizers for deep tissue imaging and efficient photodynamic therapy (PDT) remains a challenge because of the poor water solubility, low reactive oxygen species (ROS) generation efficiency, serve dark cytotoxicity, and weak absorption in the NIR region of conventional photosensitizers. Herein, cyclometalated iridium (III) complexes (Ir) with aggregation-induced emission (AIE) feature, high photoinduced ROS generation efficiency, two-photon excitation, and mitochondria-targeting capability were designed and further encapsulated into biocompatible nanoparticles (NPs). The Ir-NPs can be used to disturb redox homeostasis in vitro, result in mitochondrial dysfunction and cell apoptosis. Importantly, in vivo experiments demonstrated that the Ir-NPs presented obviously tumor-targeting ability, excellent antitumor effect, and low systematic dark-toxicity. Moreover, the Ir-NPs could serve as a two-photon imaging agent for deep tissue bioimaging with a penetration depth of up to 300 μm. This work presents a promising strategy for designing a clinical application of multifunctional Ir-NPs toward bioimaging and PDT., (© 2021. The Author(s).)

Nuclei and mitochondria are the only cellular organelles containing genes, which are specific targets for efficient cancer therapy. So far, several photosensitizers have been reported for mitochondria targeting, and another few have been reported for nuclei targeting. However, none have been reported for photosensitization in both mitochondria and nucleus, especially in cascade mode, which can significantly reduce the photosensitizers needed for maximal treatment effect. Herein, a light-driven, mitochondria-to-nucleus cascade dual organelle cancer cell ablation strategy is reported. A functionalized iridium complex, named BT-Ir, is designed as a photosensitizer, which targets mitochondria first for photosensitization and subsequently is translocated to a cell nucleus for continuous photodynamic cancer cell ablation. This strategy opens new opportunities for efficient photodynamic therapy., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Metal N-Heterocyclic carbene (NHC) complexes are expected to be new opportunities for the development of anticancer metallodrugs. In this work, two near-infrared (NIR) emitting iridium(III)-NHC complexes Ir1 and Ir2 have been explored as mitochondria-targeted anticancer and photodynamic agents. These complexes are more cytotoxic than cisplatin against the cancer cells screened, and display higher cytotoxicity in the presence of 450 nm and 630 nm LED light. Colocalization and quantitative studies indicated that these complexes could specially localize to mitochondria. Mechanism studies show that these complexes increase intracellular reactive oxygen species (ROS) level, reduce mitochondrial membrane potential (MMP) and induce some degree of early apoptosis. Further studies found that Ir1could induce mitophagy at dark and necrocytosis under the irradiation of 630 nm LED light. The in vitro and in vivo photoxicity studies revealed that Ir1 is a promising photodynamic therapy (PDT) agent and could significantly inhibit tumor growth., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A mitochondria-targeted photodynamic therapy (PDT) agent was designed and synthesized. Upon light irradiation, it can produce photoacid and its photolysis products can further sensitize 1O2 generation, causing dual-mode (oxygen-independent and oxygen-dependent) photodynamic damage in mitochondria and killing cancer cells effectively even under hypoxic conditions.