Photodynamic therapy (PDT), with its advantages of high targeting, minimally invasive, and low toxicity side effects, has been widely used in the clinical therapy of various tumors, especially superficial tumors. However, the tumor microenvironment (TME) presents hypoxia due to the low oxygen (O2 ) supply caused by abnormal vascularization in neoplastic tissues and high O2 consumption induced by the rapid proliferation of tumor cells. The PDT process generally relies on the presence of O2 , so the efficacy of PDT can be hampered by a hypoxic TME. To address this problem, researchers have been developing advanced nanoplatforms and strategies to enhance the therapeutic effect of PDT in tumor treatment. This review summarizes recent advanced PDT therapeutic strategies to against the hypoxic TME during the PDT treatment, thus enhancing PDT efficacy, including increasing O2 content in TME through delivering O2 to the tumors and in situ generations of O2 ; decreasing the O2 consumption during PDT by design of type I photosensitizers. To boost the PDT therapeutic effect, recent synergistically combination therapy of PDT and other therapeutic methods such as chemotherapy, photothermal therapy (PTT), immunotherapy, gas therapy is accounted by addressing the challenging problems of mono PDT in hypoxic environments, including tumor resistance, proliferation, and metastasis. Finally, we provide perspectives of the opportunities and challenges of PDT in future clinical research and translations. This article is protected by copyright. All rights reserved.

Strategic Design of Conquering Hypoxia in Tumor for Advanced Photodynamic Therapy.

Microwave thermotherapy (MWT) has shown great potential in cancer treatment due to its deep tissue penetration and minimally invasive nature. However, the poor microwave absorption (MA) properties of the microwave thermal sensitizer in the medical frequency band significantly limit the thermal effect of MWT and then weaken the therapeutic efficacy. In this paper, a Ni-based multilayer heterointerface nanomissile of MOFs-Ni-Ru@COFs (MNRC) with improved MA performance in the desired frequency band via introducing magnetic loss and dielectric loss is developed for MWT-based treatment. The loading of the Ni nanoparticle in MNRC mediates the magnetic loss, introducing the MA in the medical frequency band. The heterointerface formed in the MNRC by nanoengineering induces significant interfacial polarization, increasing the dielectric loss and then enhancing the generated MA performance. Moreover, MNRC with the strong MA performance in the desired frequency range not only enhances the MW thermal effect of MWT but also facilitates the electron and energy transfer, generating reactive oxygen species (ROS) at tumor sites to mediate microwave dynamic therapy (MDT). The strategy of strengthening the MA performance of the sensitizer in the medical frequency band to improve MWT-MDT provides a direction for expanding the clinical application of MWT in tumor treatment.

Magnetic Bimetallic Heterointerface Nanomissiles with Enhanced Microwave Absorption for Microwave Thermal/Dynamics Therapy of Breast Cancer.

The induction of regulated cell death (RCD) through photo/ultrasound sensitization therapeutic agents has gained significant attention as a vital approach to combat drug resistance in tumors. Aggregation‐induced emission (AIE) therapeutic agents generate reactive oxygen species through photo/ultrasound activation, which can synergize with RCD inducers or directly induce RCD, ultimately resulting in the death of tumor cells. The presented comprehensive review delves into recent advancements in AIE therapeutic agents designed to trigger RCD or synergize with RCD inducers, encompassing apoptosis, necroptosis, pyroptosis, immunogenic cell death, autophagy, ferroptosis, and cuproptosis. Additionally, the intricate regulatory mechanisms through which activatory‐AIE therapeutics influence distinct RCD pathways are examined. A forward‐looking perspective on future developments and pertinent challenges within this exciting realm is presented, anticipating the continued evolution of activatable AIE therapeutics as a transformative approach to enhance tumor therapy.

Activated aggregation‐induced emission therapeutics agents for triggering regulated cell death

Rational design of organelle targeted therapeutic platform in where the drug can be targeted to destroy tumor cells as much as possible, is one of the effective ways to improve the therapeutic outcomes and minimize the cytotoxicity to normal cells. Here, photosensitizer TSPy-B with aggregation-induced emission (AIE) feature, biotin receptor and mitochondria dual-targeted capability, and high reactive oxygen species (ROS) generation efficiency was designed for fluorescence imaging guided photodynamic therapy (PDT) by linking biotin group to D-π-A type AIE dyes via ester bonds. Notably, cell imaging experiments showed that TSPy-B could selectively target tumor cells with biotin receptor overexpression and further exhibit mitochondria targeting ability. The in vitro anticancer mechanism confirmed that after cell internalization, TSPy-B localized in the mitochondrial site and produced ROS resulting in mitochondrial dysfunction and cell death. ROS generation experiments showed that TSPy-B could simultaneously produce 1O2 and highly toxic free radicals which not depended on the oxygen level of solid tumor. The cell killing effect of TSPy-B was also confirmed in hypoxic culture model. In vivo photodynamic therapy experiments demonstrated that TSPy-B could effectively inhibit tumor growth and had good biological safety. This work provides a choice for development of highly targeted photosensitizers for clinical fluorescence imaging guided PDT. 

Biotin Receptor and Mitochondria Dual Targeted AIE Photosensitizer for Fluorescence Imaging Guided Photodynamic Anticancer Therapy

Abstract Mitochondrial transplantation and transfer are being explored as therapeutic options in acute and chronic diseases to restore cellular function in injured tissues. To limit potential immune responses and rejection of donor mitochondria, current clinical applications have focused on delivery of autologous mitochondria. We recently convened a Mitochondrial Transplant Convergent Working Group (CWG), to explore three key issues that limit clinical translation: (1) storage of mitochondria, (2) biomaterials to enhance mitochondrial uptake, and (3) dynamic models to mimic the complex recipient tissue environment. In this review, we present a summary of CWG conclusions related to these three issues and provide an overview of pre-clinical studies aimed at building a more robust toolkit for translational trials. 

pdf/bridging-the-gap-between-in-vitro-and-in-vivo-models-a-way-144qbqv0sm.pdf

Bridging the gap between in vitro and in vivo models: a way forward to clinical translation of mitochondrial transplantation in acute disease states

A yellow-green-emitting graphitic-C3N4 derivative consisting of 1,4-phenylene-inserted heptazine units: Preparation and application as a metal-free phosphor for white LEDs

Improving luminescent properties of graphitic-C3N4 via embedding 2,4,6-triphenyl-1,3,5-triazine groups for application in white LEDs

A cationic iridium(III) complex using 2-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol as its ancillary ligand: ESIPT-capability and application for “turn-off” chemiluminescent detection of Ni2+

Aggregation‐induced emission luminogens (AIEgens) are widely used as photosensitizers for image‐guided photodynamic therapy (PDT). Due to the limited penetration depth of light in biological tissues, the treatments of deep‐seated tumors by visible‐light‐sensitized aggregation‐induced emission (AIE) photosensitizers are severely hampered. Microwave dynamic therapy attracts much attention because microwave irradiation can penetrate very deep tissues and sensitize the photosensitizers to generate reactive oxygen species (ROS). In this work, a mitochondrial‐targeting AIEgen (DCPy) is integrated with living mitochondria to form a bioactive AIE nanohybrid. This nanohybrid can not only generate ROS under microwave irradiation to induce apoptosis of deep‐seated cancer cells but also reprogram the metabolism pathway of cancer cells through retrieving oxidative phosphorylation (OXPHOS) instead of glycolysis to enhance the efficiency of microwave dynamic therapy. This work demonstrates an effective strategy to integrate synthetic AIEgens and natural living organelles, which would inspire more researchers to develop advanced bioactive nanohybrids for cancer synergistic therapy.

AIEgens/Mitochondria Nanohybrids as Bioactive Microwave Sensitizers for Non‐Thermal Microwave Cancer Therapy

A highly luminescent 3-phenylfluoranthene-modified g-C3N4 derivative used as a metal-free phosphor in white light-emitting diodes

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