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Given the scarcity of novel antibiotics, the eradication of bacterial biofilm infections poses formidable challenges. Upon bacterial infection, the host restricts Fe ions, which are crucial for bacterial growth and maintenance. Having coevolved with the host, bacteria developed adaptive pathways like the hemin‐uptake system to avoid iron deficiency. Inspired by this, we propose a novel strategy, termed iron nutritional immunity therapy (INIT), utilizing Ga‐CT@P nanocomposites constructed with gallium, copper‐doped tetrakis (4‐carboxyphenyl) porphyrin (TCPP) metal–organic framework, and polyamine‐amine polymer dots, to target bacterial iron intakes and starve them. Owing to the similarity between iron/hemin and gallium/TCPP, gallium‐incorporated porphyrin potentially deceives bacteria into uptaking gallium ions and concurrently extracts iron ions from the surrounding bacteria milieu through the porphyrin ring. This strategy orchestrates a "give and take" approach for Ga3+/Fe3+ exchange. Simultaneously, polymer dots can impede bacterial iron metabolism and serve as real‐time fluorescent iron‐sensing probes to continuously monitor dynamic iron restriction status. INIT based on Ga‐CT@P nanocomposites induced long‐term iron starvation, which affected iron‐sulfur cluster biogenesis and carbohydrate metabolism, ultimately facilitating biofilm eradication and tissue regeneration. Therefore, this study presents an innovative antibacterial strategy from a nutritional perspective that sheds light on refractory bacterial infection treatment and its future clinical application. [ABSTRACT FROM AUTHOR]

The development of efficient drug delivery systems is essential for improving the efficacy and safety of cancer drugs, particularly for aggressive and difficult‐to‐treat cancers. Covalent organic frameworks (COFs) are emerging as innovative porous nanomaterials in drug delivery systems (DDS), due to their unique properties, including the metal‐free organic skeleton, predetermined structures and pore geometries, high porosity, large surface area, facile surface modification potential, and good biocompatibility. These characteristics make COFs excellent candidates for improving drug delivery by enhancing drug loading capacity and enabling precise encapsulation. This review emphasizes the importance of donor‐acceptor‐based COFs, which provide channels for charge transportation, and we also explore how the π‐conjugated skeleton of COFs enhances its long‐acting fluorescent properties and facilitates drug uptake via cell endocytosis. While this review primarily focuses on recent advancements in COF‐based targeted DDS, it also acknowledges the challenges posed by the diverse pore geometries in porous materials and discusses potential solutions. Further, it underlines the potential of developing future drug carriers that can successfully and specifically target cancer cells, improving treatment efficiency while reducing adverse side effects. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has received extensive attention as a promising cancer treatment approach. Still, challenges to in vivo photodynamic therapy have existed for decades. First, the "always on" nature of conventional photosensitizers will cause damage to normal tissues thereby limiting the treatment efficiency of PDT. Second, the hypoxic TME protects cancer stem cells (CSCs) deeply harbored in the center of tumors from PDT administration, thus contributing to the recrudescence and metastasis of tumors. Herein, a ROS‐triggered self‐immolative therapeutic prodrug (Mu‐PS) is reported, comprising of an activatable photosensitizer, an indomethacin (IMC) part, and a ROS‐responsive trigger, for the anti‐stemness chemical and photodynamic therapy of tumors. Intriguingly, Mu‐PS can target the tumor and selectively release the photosensitizer and IMC upon the activation of TME‐related ROS, generating massive phototoxic 1O2 to kill most non‐CSCs tumor cells under the action of PDT and block the growth of CSCs by IMC, hence, it multiplies the therapeutic index. Noteworthy, the anti‐stemness mechanism of IMC in tumors is confirmed and elucidated for the first time. Overall, this study introduces a self‐immolatative prodrug for combined CSCs‐involved chemical therapy and activatable PDT for tumors and provides a design paradigm of prodrug for the precise prognosis and treatment of tumors. [ABSTRACT FROM AUTHOR]

A simple yet powerful D–A type-based NIR-II fluorophore (MTF) with mitochondria targeting was constructed. This mitochondrial targeting dye MTF exhibited not only a photothermal effect but also photodynamic performance, and was further fabricated with DSPE-mPEG to generate nanodots for in vivo experiments, achieving strong NIR-II fluorescence tracing of tumors and impressive NIR-II image-guided photodynamic therapy (PDT) and photothermal therapy (PTT). [ABSTRACT FROM AUTHOR]

Cancer remains as one of the most significant health problems, with approximately 19 million people diagnosed worldwide each year. Chemotherapy is a routinely used method to treat cancer patients. However, current treatment options lack the appropriate selectivity for cancer cells, are prone to resistance mechanisms, and are plagued with dose-limiting toxicities. As such, researchers have devoted their attention to developing prodrug-based strategies that have the potential to overcome these limitations. This tutorial review highlights recently developed prodrug strategies for cancer therapy. Prodrug examples that provide an integrated diagnostic (fluorescent, photoacoustic, and magnetic resonance imaging) response, which are referred to as theranostics, are also discussed. Owing to the non-invasive nature of light (and X-rays), we have discussed external excitation prodrug strategies as well as examples of activatable photosensitizers that enhance the precision of photodynamic therapy/photothermal therapy. Activatable photosensitizers/photothermal agents can be seen as analogous to prodrugs, with their phototherapeutic properties at a specific wavelength activated in the presence of disease-related biomarkers. We discuss each design strategy and illustrate the importance of targeting biomarkers specific to the tumour microenvironment and biomarkers that are known to be overexpressed within cancer cells. Moreover, we discuss the advantages of each approach and highlight their inherent limitations. We hope in doing so, the reader will appreciate the current challenges and available opportunities in the field and inspire subsequent generations to pursue this crucial area of cancer research. [ABSTRACT FROM AUTHOR]

Light-based phototherapy has been developed for cancer treatment owing to its non-invasiveness and spatiotemporal control. Despite the unique merits of phototherapy, one critical disadvantage of light is its limited penetration depth, which restricts its application in cancer treatment. Although many researchers have developed various strategies to deliver light into deep-seated tumors with two-photon and near-infrared light irradiation, phototherapy encounters the peculiar limitations of light. In addition, high oxygen dependency is another limitation of photodynamic therapy to treat hypoxic tumors. To overcome the drawbacks of conventional treatments, various energy sources have been developed for cancer treatment. Generally, most energy sources, such as ultrasound, chemiluminescence, radiation, microwave, electricity, and magnetic field, are relatively free from the restraint of penetration depth. Combining other strategies or therapies with other energy-source-based therapies improves the strength and compensates for the weakness. This tutorial review focuses on recent advances in the diverse energy sources utilized in cancer treatment and their future perspectives. [ABSTRACT FROM AUTHOR]

Despite significant advances, the therapeutic impact of photodynamic therapy is still substantially hampered by the restricted penetration depth of light and the reactive oxygen species (ROS)-mediated toxicity, which is impeded by the shorter effective half-life and radius of ROS produced during treatment. Sonodynamic therapy (SDT), on the other hand, provides unrivalled benefits in deep-seated tumour ablation due to its deep penetration depth and not totally ROS-dependent toxicity, exhibiting enormous preclinical and clinical potential. In this tutorial review, we highlight imaging-guided precise SDT, which allows choosing the best treatment option and monitoring the therapy response in real-time, as well as recent clinical trials based on SDT. Aside from that, the subtle design strategies of sonosensitizers based on tumour environment shaping and rational structure modification, as well as SDT combination treatment (chemotherapy, chemodynamic therapy, photodynamic therapy, photothermal therapy, gas therapy and immunotherapy), aimed at a more effective treatment outcome, are summarized. Finally, we discussed the future of SDT for personalized cancer and other disease treatments. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed. [ABSTRACT FROM AUTHOR]

Despite being a clinically approved intervention for cancer, photodynamic therapy (PDT) still suffers from limitations. Prime among these is a therapeutic response that is mostly oxygen dependent. This limits the utility of PDT in treating hypoxic tumors since lower levels of cytotoxic reactive oxygen species (ROS) are generated in regions of low oxygen tension. Glutathione‐pi (GST‐pi) is a key enzyme that militates against ROS‐mediated apoptosis. We report herein a new construct, EA‐BPS, that contains both a brominated BODIPY photosensitizer (BPS) and an ethacrynic acid (EA) GST‐pi inhibitor. Photoirradiation of EA‐BPS induces a synergistic antitumor effect that results from the combination of ROS production and GST‐pi inhibition. Relative to BPS alone, an enhanced cell‐killing effect is seen under hypoxic conditions both in vitro and in vivo. We conclude that by making better use of the available oxygen in tumor environments, improved therapeutic PDT outcomes should be achievable even under hypoxic conditions. [ABSTRACT FROM AUTHOR]

Optical techniques using developed laser and optical devices have made a profound impact on modern medicine, with "biomedical optics" becoming an emerging field. Sophisticated technologies have been developed in cancer nanomedicine, such as photothermal therapy and photodynamic therapy, among others. However, single-mode phototherapy cannot completely treat persistent tumors, with the challenges of relapse or metastasis remaining; therefore, combinatorial strategies are being developed. In this review, the role of light in cancer therapy and the challenges of phototherapy are discussed. The development of combinatorial strategies with other therapeutic methods, including chemotherapy, immunotherapy, gene therapy, and radiotherapy, is presented and future directions are further discussed. This review aims to highlight the significance of light in cancer therapy and discuss the combinatorial strategies that show promise in addressing the challenges of phototherapy. [ABSTRACT FROM AUTHOR]

A novel ferrocene decorated vinyl pyridinium-substituted tetraphenylethylene (TPEPY-S-Fc) linked by a disulfide bond was designed as a GSH activatable photosensitizer by aggregation-induced emission for imaging-guided photodynamic therapy of cancer cells. [ABSTRACT FROM AUTHOR]

Phototherapy, including photodynamic therapy and photothermal therapy, has the potential to treat several types of cancer. However, to be an effective anticancer treatment, it has to overcome limitations, such as low penetration depth, low target specificity, and resistance conferred by the local tumor microenvironment. As a non-invasive technique, low-intensity ultrasound has been widely used in clinical diagnosis as it exhibits deeper penetration into the body compared to light. Recently, sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a chemotherapeutic agent (sonosensitizer), has been explored as a promising alternative for cancer therapy. As all known cancer treatments such as chemotherapy, photodynamic therapy, photothermal therapy, immunotherapy, and drug delivery have been advanced independently enough to complement others substantially, the combination of these therapeutic modalities with SDT is opportune. This review article highlights the recent advances in SDT in terms of sonosensitizers and their formulations and anticancer therapeutic efficacy. Also discussed is the potential of SDT in combination with other modalities to address unmet needs in precision medicine. [ABSTRACT FROM AUTHOR]

Phosphorene, also known as single- or few-layer black phosphorus (FLBP), is a new member of the two-dimensional (2D) material family and has attracted significant attention in recent years for applications in optoelectronics, energy storage and biomedicine due to its unique physicochemical properties and excellent biocompatibility. FLBP is regarded as a potential biological imaging agent for cancer diagnosis due to its intrinsic fluorescence (FL) and photoacoustic (PA) properties and negligible cytotoxicity. FLBP-based photothermal and photodynamic therapies have emerged with excellent anti-tumour therapeutic efficacies due to their unique physical properties, such as near-infrared (NIR) optical absorbance, large extinction coefficients, biodegradability and reactive oxygen species (ROS) or heat generation upon light irradiation. Furthermore, FLBP is a promising drug delivery platform because of its high drug-loading capacity due to its puckered layer structure with an ultralarge surface area, and FLBP is size-controllable with facile surface chemical modification. Because of the marked advantages of FLBP nanomaterials in biomedical applications, an overview of the latest progress and paradigms of FLBP-based nanoplatforms for multidisciplinary biomedical applications is presented in this tutorial review. [ABSTRACT FROM AUTHOR]

A major challenge in photodynamic cancer therapy (PDT) is avoiding PDT-induced hypoxia, which can lead to cancer recurrence and progression through activation of various angiogenic factors and significantly reduce treatment outcomes. Reported here is an acetazolamide (AZ)-conjugated BODIPY photosensitizer (AZ-BPS) designed to mitigate the effects of PDT-based hypoxia by combining the benefits of anti-angiogenesis therapy with PDT. AZ-BPS showed specific affinity to aggressive cancer cells (MDA-MB-231 cells) that overexpress carbonic anhydrase IX (CAIX). It displayed enhanced photocytotoxicity compared to a reference compound, BPS, which is an analogous PDT agent that lacks an acetazolamide unit. AZ-BPS also displayed an enhanced in vivo efficacy in a xenograft mouse tumor regrowth model relative to BPS, an effect attributed to inhibition of tumor angiogenesis by both PDT-induced ROS generation and CAIX knockdown. AZ-BPS was evaluated successfully in clinical samples collected from breast cancer patients. We thus believe that the combined approach described here represents an attractive therapeutic approach to targeting CAIX-overexpressing tumors. [ABSTRACT FROM AUTHOR]

This review explores the advanced strategies using COFs for improving the treatment of hypoxic tumors, including oxygen-boosting COFs, drug-delivery COFs, type-I photodynamic therapy, thermo and sonodynamic therapies, immune responses, and combination therapy. We also discussed the current challenges and prospects for therapies that use COFs to target low-oxygen tumors specifically. [Display omitted] • COFs can enhance oxygen levels in hypoxic tumors and deliver anticancer drugs, prodrugs, and immune therapies through modifications. • COFs have the potential for efficient photodynamic, photothermal, and chemodynamic therapies for hypoxic tumors. • The engineering principle for tumor hypoxia-associative nano COFs is elaborated. • Limitations and prospects of COFs for hypoxia-based cancer therapy are discussed. Hypoxia, or low oxygen levels, is a common feature of the tumor microenvironment. It is caused by the aggressive proliferation of cancer cells, which consume more oxygen than healthy cells. Hypoxia not only activates several signaling pathways that promote tumor growth, and metastasis but also increases resistance to conventional cancer treatments. The introduction of covalent organic frameworks (COFs), with their porous structure, high stability, tunable properties, large surface area, and unrivaled biocompatibility, has offered promising prospects for resolving hypoxia-specific challenges. This write-up critically explores the COFs in enhancing oxygen delivery, reactive oxygen species (ROS) generation, optimized drug delivery, and enabling hypoxia-specific imaging. Furthermore, it outlines how COFs facilitate various hypoxia-targeting therapeutic modalities such as chemotherapy, type-I and type-II photodynamic therapy, photothermal therapy, sonodynamic therapy, and immunotherapy. By evaluating the latest research findings and their implications, this review offers insights into the potent role of COFs in curtailing hypoxia and bolstering cancer treatment efficiency. The overarching goal of this assessment is to enrich our understanding of hypoxia-specific cancer therapy strategies, crediting the pivotal role of COFs. It is hoped that this greater comprehension of the abilities and constraints of COFs will pave the way to conceive more potent and targeted therapeutic interventions, thereby enhancing patient outcomes in the complex terrain of cancer therapeutics. [ABSTRACT FROM AUTHOR]

[Display omitted] • BODIPY-based theranostics has good and tunable imaging and therapeutic modalities. • Molecular/nanoparticle engineering of BODIPY-based theranostics is elaborated. • Strategies to balance the imaging and therapy of the theranostics are summarized. • The review offers a guide to designing BODIPY-based theranostics in cancer therapy. In recent years, BODIPY-based theranostics have increasingly been used in cancer therapy and have achieved significant success. According to photochemical theories, the optical imaging (e.g., fluorescence [FLI]/photoacoustic [PAI]/photothermal imaging [PTI]) and phototherapy properties (photodynamic therapy [PDT] and photothermal therapy [PTT]) of BODIPY-based dyes can be well-tuned and balanced by chemical structural modifications. Furthermore, with the benefits of molecular/nanoparticle engineering, BODIPY-based theranostics can be endowed with versatile functionalities, including other cutting-edge therapeutic modalities, commendable tumor-targeting ability, and a delicate balance between imaging and therapy performance in a molecular/nano-entity, further enhancing its synergetic therapeutic potency and minimizing the undesirable side effects. In this review, we focus on BODIPY-based theranostics for tumor therapy and describe and discuss BODIPY-based FLI-guided chemotherapy, FLI-guided PDT, FLI-guided phototherapies, FLI-guided multi-modal therapies, and PAI-guided phototherapies, as well as multi-modal imaging-guided multi-modal therapies, particularly those that have become available in the last 3 years. The progress and bottlenecks of recent BODIPY-based theranostics are also itemized and discussed, describing the general design principles of BODIPY-based theranostics, with the aim of promoting the use of the theranostics in the clinical transformation of cancer therapy. [ABSTRACT FROM AUTHOR]

Photodynamic therapy combined with immunogenic cell death has been proposed to overcome the unsolvable problems of single therapy, such as high levels of tumor recurrence and treatment resistance of tumors. Previous works on this theme have mostly concentrated on endoplasmic reticulum (ER)-stressed damage-associated molecular patterns (DAMPs), ignoring the secretion and function of mitochondria-related DAMPs. Herein, our work reports two intersystem crossing photosensitizers based on well-designed multiarylpyrrole structures and draws valuable attention to mitochondria-related DAMP-TFAM (mitochondrial transcription factor) when cancer cells are under forceful oxidative stress. The tumors vanished, and immunogenic experiments were applied to illuminate the advantages of double treatment. Our discovery of new mitochondria-related DAMPs compensates for the lack of ER-stressed DAMPs and offers an innovative target for immunity therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Mitochondrial targeted theranostic are important for simultaneous diagnosis and therapeutic evaluation in cancer therapy. • Several strategies for delivering cytotoxins preferentially to mitochondria are summarized. • Feasibility of currently used strategies for translation in clinical practices is analyzed. Mitochondria, an eukaryotic organelle, is regarded as the most critical target since it regulates several vital functions in cell physiology. It is the hub of metabolic activity and a source of fascination due to its role in a variety of diseases like cardiovascular, cancer and neurological disorders. Because of the structural and functional discrepancies between normal and cancerous mitochondria (respiratory rate, membrane potential, genetic mutations and energy-producing pathway), mitochondria have garnered substantial attention in cancer therapy. For delivering cytotoxins exclusively to mitochondria, several synthetic strategies are used for mitochondrial dysfunction and cell apoptosis/necrosis. Covalent binding of lipophilic cations (triphenylphosphonium ion, rhodamine, peptides etc) to the molecular-based pharmacophore is the most effective process. Significant mitochondrial accumulations (>1000 folds) can be accomplished by proper selection of cell types, their mitochondrial membrane potential and targeting unit. In this review article, we address various strategies for targeting small molecule-based theranostics to cancerous mitochondria for diagnostic and potential therapeutic purposes that have been published since 2015. Particularly, conventional chemotherapeutic drugs, photosensitizers for photodynamic and photothermal treatment, drug-free agents, intra-mitochondrial aggregation agents and their combination are among the molecular-based agents discussed. [ABSTRACT FROM AUTHOR]

This tutorial review summarizes the strategies for improving the efficacy of PDT in hypoxic tumor therapy. The advantages of combining PDT with other therapeutics, such as chemotherapy, chemodynamic therapy, gas therapy, immunotherapy and gene therapy, are also demonstrated. Finally, the existing challenges and future perspectives on clinical PDT for hypoxic tumors are discussed. [Display omitted] • Advanced materials and strategies for PDT to overcome hypoxia are classified. • Novel nano-systems in enhancing anti-tumor effects are summarized. • Combining PDT with other therapeutics to achieve synergetic effects are reported. • The current challenges and further opportunities are discussed. Photodynamic therapy (PDT) has been a preferred clinical technology for treating superficial tumors due to its advantages of high selectivity, non-invasiveness and negligible drug resistance. However, the hypoxic tumor microenvironment weakens the efficiency of O 2 -dependent PDT. Moreover, the PDT process consumes a large amount of O 2 and destroys the tumor blood vessels and further blocks the O 2 supply to tumor sites. Therefore, developing more advanced materials and methods for PDT of the hypoxic tumor is an essential scientific significance. This tutorial review summarizes the strategies for improving the efficacy of PDT in hypoxic tumor therapy, which is categorized into three sections: (I) enhancing O 2 concentration in the tumor; (II) disregarding hypoxia; and (III) exploiting hypoxia. The advantages of combining PDT with other therapeutics, such as chemotherapy, chemo-dynamic therapy, gas therapy, immunotherapy and gene therapy, are also demonstrated. Finally, the existing challenges and future perspectives on clinical PDT for hypoxic tumors are discussed. [ABSTRACT FROM AUTHOR]

Despite the wide application of the traditional NIR-I phototheranostic platforms in basic research and clinical studies, problems such as tissue scattering, auto-fluorescence combined with aggregation caused quenching hamper precise image-guided phototherapy. Herein, we developed a multifunctional NIR-II phototheranostic platform using a novel AIE-based dye (ZSY-TPE) for single laser-activated imaging-guided combined photothermal and photodynamic therapies of tumors and pathogens. As confirmed through in vivo studies, the ZSY-TPE dots displayed precise and efficient high-performance NIR-II imaging-guided combination phototherapy against 4T1 tumor as well as S. aureus-infected mice models without any noticeable side effects. The current study demonstrates ZSY-TPE as a powerful phototheranostic platform for precise NIR-II fluorescence/PA imaging and synergistic photodynamic/photothermal therapy of tumors and bacterial infections. Image 1 [ABSTRACT FROM AUTHOR]