The rapid development of nanomedicine has significantly improved the targeting and biosafety of cancer therapy. However, most current nanotherapeutics require 4-24 h of intracellular delivery and signaling responses, leading to delayed responses, increased risks of resistance and metastasis. Achieving efficient tumor cell killing within minutes holds promise for overcoming these limitations and enabling more thorough tumor elimination. In this study, we synthesized a nanosheet material, Bi2Fe4O9@Au (BFO@Au NSs), which integrates membrane thiol-targeting recognition with potent oxidative-damage capability. By efficiently depleting sulfhydryl groups on the surface of tumor cell membranes and disrupting membrane functional proteins within minutes, BFO@Au NSs rapidly induces membrane dysfunction, triggering metabolic disorders, mitochondrial membrane potential collapse, and redox imbalance, ultimately leading to irreversible necrosis of tumor cells, thereby successfully achieving 'membrane necrotherapy'. This process simultaneously induces an immunogenic cell death (ICD)-like response, effectively promoting the dendritic cell maturation and the M1 polarization of macrophages, enhancing antitumor immune responses and suppressing distant metastasis. Importantly, the oxidative activity of BFO@Au NSs decays rapidly after reacting with tumor membranes, significantly reducing toxicity to biological tissues. This study proposes a new synergistic anti-tumor strategy based on membrane function disruption, providing a theoretical basis and application prospects for efficient and safe nanotherapeutic systems.

To address the urgent clinical need for more effective and selective cancer treatments, increasing attention has been directed toward metallodrugs that act beyond classical nuclear DNA damage and exploit mitochondrial vulnerabilities in cancer cells. This review critically evaluates recent progress reported from 2020 to 2026 in mitochondria-targeted palladium(II), platinum(II/IV), copper(I/II), and gold(I/III) complexes for cancer therapy. Particular emphasis is placed on how metal identity, oxidation state, ligand architecture, charge, lipophilicity, redox behavior, and subcellular localization collectively influence mitochondrial accumulation and anticancer activity. These complexes can induce mitochondrial dysfunction through multiple pathways, including disruption of mitochondrial membrane potential, overproduction of reactive oxygen species, cytochrome c release, inhibition of thioredoxin reductase, disruption of mitochondrial metabolism, and activation of intrinsic or non-apoptotic cell death pathways. In addition to summarizing recent advances, this review develops a comparative perspective on how the intrinsic chemical features of Pd(II), Pt(II/IV), Cu(I/II), and Au(I/III) complexes shape their mitochondrial behavior, therapeutic potential, and translational challenges. While Pd(II) systems illustrate the value of ligand-tunable dual DNA/mitochondrial targeting, Pt(II/IV) complexes connect mitochondrial intervention with clinically established platinum pharmacology and prodrug design. In contrast, Cu(I/II) complexes introduce redox-driven and cuproptosis-related mechanisms, whereas Au(I/III) compounds emphasize mitochondrial redox disruption and TrxR inhibition. Together, these comparisons highlight that the therapeutic promise of each metal class depends not only on cytotoxic potency but also on stability, selectivity, drug resistance-overcoming capability, pharmacokinetics, biodistribution, and long-term safety. Overall, this review systematically explores both therapeutic advantages and current limitations of mitochondria-targeted metallodrugs and provides design principles for the development of next-generation metal-based anticancer agents.

Photodynamic therapy (PDT) has emerged as a promising strategy for cancer treatment due to its non-invasive nature and high specificity toward malignant tissues. In recent years, a variety of protocols have been proposed to improve the PDT efficacy, of which organelle-targeted PDT strategy is supposed to be quite promising. Particularly, lipid droplets (LDs)-localized PDT attracts a lot of interest due to the inherent advantages such as abundant LDs in cancer cells and their close relation with ferroptosis. This review provides a comprehensive summary of the advancements of LDs-localized photosensitizers (PSs) according to their chemical structures and functions. Especially, these PSs are featured with fluorescence emission, thereby facilitating an imaging-guided phototherapy. The review highlights the cytocidal actions of these PSs, such as the cell death pathway and their cytotoxicity. Finally, some unresolved issues and challenges in this domain will be discussed.

Drug resistance is one of the greatest challenges in cancer treatment. Mitochondria play a crucial role in cell survival and death through the generation of reactive oxygen species (ROS). Recent research has shown that targeting mitochondria can promote tumor elimination, enhancing the effectiveness of strategies to combat drug resistance. In this context, we introduced a mitochondria-targeted antibiotic, compound 1 (CFX-TPP+). We found that 1 with its amide functional unit is much more stable in blood plasma than the compound with an ester group. Compound 1 also showed significant cytotoxicity toward drug resistant triple-negative breast cancer (TNBC) cells (MDA-MB-231). It enhances ROS generation, leading to increased mitochondrial oxidative stress and triggering a cascade of anticancer effects. These effects include the activation of mitochondria-mediated apoptotic cell signaling, upregulation of pro-apoptotic factors such as BAX, and downregulation of genes associated with mitochondrial biogenesis. This approach has the potential to overcome drug resistance in TNBC and possibly cure the disease without relapse.

Immunogenic cell death (ICD) is a form of regulated cell death that engages the immune system by releasing damage-associated molecular patterns, making it a promising target for cancer immunotherapy. Presented here is the synthesis and evaluation of a series of asymmetric redox-active water-soluble Au(I) bis-N-heterocyclic carbenes (Au(I) bis-NHCs). We explore the structure-activity relationships between redox activity, water solubility and ICD induction, building on our previous work with a redox-active Au(I) bis-NHC (1) that effectively induced ICD but suffered from poor water solubility. To overcome this limitation, we synthesized several water-soluble redox-active Au(I) bis-NHCs, derivatives 2-4, by modifying the imidazole moiety. Compound 2 was identified as the lead, balancing water solubility and ICD induction efficacy. This compound, featuring a naphthoquinone moiety, and was found to generate reactive oxygen species (ROS) and trigger key ICD biomarkers, including calreticulin (CRT) translocation, ATP release, and high mobility group box 1 (HMGB1) secretion. A control compound lacking the redox active naphthoquinone failed to elicit these ICD markers or promote ROS production. Across the series 1-4 a correlation was observed between ROS generation and ICD biomarker expression. In vivo studies in syngeneic immunocompetent mice demonstrated that compound 2 not only prevents CT26 colorectal cancer tumor growth upon challenge with live cancer cells but also elicits a long-lived immune response upon rechallenge 12 months later.

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.

The global prevalence of cancer presents a formidable challenge to medical systems, compelling the pursuit of novel and effective therapeutic modalities to improve patient survival rates. In this context, cancer phototherapy, encompassing both photodynamic (PDT) and photothermal (PTT) therapies, stands out as a targeted, minimally invasive modality to trigger the selective ablation of cancer cells. Covalent organic frameworks (COFs), with their distinct crystalline and porous nature, excellent biocompatibility, and chemical robustness, are increasingly recognized as outstanding materials to propel cancer phototherapy forward. In this review, we focus on examining the application of COF nanoparticles in the domain of PDT and PTT, demonstrating their potent anti-cancer capabilities. We pay special attention to combination therapies that exploit COFs, particularly those that elicit immunogenic cell death. These synergistic approaches offer considerable promise for the enhancement of cancer therapy efficiency. Additionally, we address the prevalent hurdles associated with COF-based cancer phototherapy, such as toxicity concerns, in vivo stability issues, and the complexities of photo agent delivery. We also discuss potential methods to overcome these barriers, especially through surface modifications of COFs. The review concludes by charting prospective research paths and the urgent need for the establishment of standardized procedures to fast-track the clinical adoption of COF-based phototherapy. By offering a detailed yet succinct outline of the capabilities of COFs in advancing cancer phototherapy, this article provides valuable insights for investigators in this vibrant field.

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 Ga 3+ /Fe 3+ 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.

The rising flexible and intelligent electronics greatly facilitate the noninvasive and timely tracking of physiological information in telemedicine healthcare. Meticulously building bionic-sensitive moieties is vital for designing efficient electronic skin with advanced cognitive functionalities to pluralistically capture external stimuli. However, realistic mimesis, both in the skin's three-dimensional interlocked hierarchical structures and synchronous encoding multistimuli information capacities, remains a challenging yet vital need for simplifying the design of flexible logic circuits. Herein, we construct an artificial epidermal device by in situ growing Cu3(HHTP)2 particles onto the hollow spherical Ti3C2Tx surface, aiming to concurrently emulate the spinous and granular layers of the skin's epidermis. The bionic Ti3C2Tx@Cu3(HHTP)2 exhibits independent NO2 and pressure response, as well as novel functionalities such as acoustic signature perception and Morse code-encrypted message communication. Ultimately, a wearable alarming system with a mobile application terminal is self-developed by integrating the bimodular senor into flexible printed circuits. This system can assess risk factors related with asthmatic, such as stimulation of external NO2 gas, abnormal expiratory behavior and exertion degrees of fingers, achieving a recognition accuracy of 97.6% as assisted by a machine learning algorithm. Our work provides a feasible routine to develop intelligent multifunctional healthcare equipment for burgeoning transformative telemedicine diagnosis.

Fluorescence imaging in the second near-infrared window (NIR-II) is crucial for accurate tumor diagnosis, offering superior resolution and penetration capabilities. Current NIR-II probes are limited by either being "always on" or responding to one stimulus, leading to low signal-to-noise ratios and potential false positives. We introduced a dual-lock-controlled probe, HN-PBA, activated by both H2O2 and tumor acidic environment. This dual response ensures bright fluorescence at tumor sites, leading to higher tumor-to-normal tissue ratios (T/NT) compared to conventional "always on" probes and probes activated only by H2O2. This strategy allows precise tumor identification and removal of primary and metastatic tumors, achieving superior T/NT ratios (24.3/6.4 for orthotopic and lung metastasis, respectively). Our probe also effectively detected lung metastatic foci as small as≤0.7 mm and showed the capability for accurate lesion localization in clinical breast cancer specimens. This dual-stimuli-responsive strategy could aid future diagnostic probe design.

Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(ii), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalysed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(ii) was evident from the enhanced affinity of CA9-BPS-Cu(ii) towards CD133-positive MDA-MB-231 cells where CA9 is overexpressed vs. CD133-negative cells. Moreover, the efficacy of CA9-BPS-Cu(ii) was successfully demonstrated in a xenograft mouse tumour model.

Mechanical stimulation utilizing deep tissue-penetrating and focusable energy sources, such as ultrasound and magnetic fields, is regarded as an emerging patient-friendly and effective therapeutic strategy to overcome the limitations of conventional cancer therapies based on fundamental external stimuli such as light, heat, electricity, radiation, or microwaves. Recent efforts have suggested that mechanical stimuli-driven cancer therapy (henceforth referred to as "mechanical cancer therapy") could provide a direct therapeutic effect and intelligent control to augment other anti-cancer systems as a synergistic combinational cancer treatment. This review article highlights the latest advances in mechanical cancer therapy to present a novel perspective on the fundamental principles of ultrasound- and magnetic field-mediated mechanical forces, including compression, tension, shear force, and torque, that can be generated in a cellular microenvironment using mechanical stimuli-activated functional materials. Additionally, this article will shed light on mechanical cancer therapy and inspire future research to pursue the development of ultrasound- and magnetic-field-activated materials and their applications in this field.

Cancer stem cells (CSCs) are associated with the invasion and metastatic relapse of various cancers. However, current cancer therapies are limited to targeting the bulk of primary tumor cells while remaining the CSCs untouched. Here, we report a new proton (H+) modulation approach to selectively eradicate CSCs via cutting off the H+ leaks on the inner mitochondrial membrane (IMM). Based on the fruit extract of Gardenia jasminoides, a multimodal molecule channel blocker with high biosafety, namely, Bo-Mt-Ge, is developed. Importantly, in this study, we successfully identify that mitochondrial uncoupling protein UCP2 is closely correlated with the stemness of CSCs, which may offer a new perspective for selective CSC drug discovery. Mechanistic studies show that Bo-Mt-Ge can specifically inhibit the UCP2 activities, decrease the H+ influx in the matrix, regulate the electrochemical gradient, and deplete the endogenous GSH, which synergistically constitute a unique MoA to active apoptotic CSC death. Intriguingly, Bo-Mt-Ge also counteracts the therapeutic resistance via a two-pronged tactic: drug efflux pump P-glycoprotein downregulation and antiapoptotic factor (e.g., Bcl-2) inhibition. With these merits, Bo-Mt-Ge proved to be one of the safest and most efficacious anti-CSC agents, with ca. 100-fold more potent than genipin alone in vitro and in vivo. This study offers new insights and promising solutions for future CSC therapies in the clinic.

The RNA splicing process which removes introns from nascent transcripts is an indispensable step in gene expression. The life processes of organisms are composed of a range of different mRNA variants that are translated into proteins with various functions as a result of alternative splicing. Monitoring and control-ling RNA splicing can successfully repair the dangerous mutant genes that underlie various diseases. However, attempts to uncover specific elements in the regulation of splicing are hampered by the absence of appropriate tools. Traditional RNA splicing detection technology frequently focuses on the identification and analysis of post-splicing products, which is often accompanied by irreversible damage to the detected objects. It cannot provide dynamic and detailed descriptions of regulatory factors, func-tional elements, and spatiotemporal distributions during the splicing process. It is still difficult to identify and measure aberrant RNA splicing in living cells and in vivo. New technical tools have sprung up, pro-viding fresh motivation and guidance for the identification of RNA splicing. Here, based on the genetically encoded reporter gene system, we cover in detail the monitoring, imaging and biomedical applications of RNA splicing process using different types of reporter gene systems.(c) 2022 Elsevier B.V. All rights reserved.

The development of superior photoelectrochemical (PEC) sensors for biosensing has become a major objective of PEC research. However, conventional PEC-active materials are typically constrained by a weak photocurrent response owing to their limited surface-active sites and high electron-hole recombination rate. Here, a boron and graphene quantum dots codoped g-C3N4 (named GBCN) as PEC sensor for highly sensitive dopamine (DA) detection was fabricated. GBCN exhibited the greatest photocurrent response and PEC activity compared to free g-C3N4 and g-C3N4 doped with boron. The proposed PEC sensor for DA determination exhibited a broad linear range (0.001-800 mu M) and a low detection limit (0.96 nM). In particular, a sensitivity up to 10.3771 mu A/mu M/cm2 was seen in the case of GBCN. The high PEC activity can be attributed to the following factors: (1) the boron and graphene quantum dots co-doping significantly increased the specific surface area of g-C3N4, providing more adsorption sites for DA; (2) the dopants extended the absorption intensity of g-C3N4, red-shifting the absorption from 470 to 540 nm; and (3) the synergism of boron and graphene quantum dots efficiently boosted the photogenerated electrons migration from the conduction band of g-C3N4 to graphene quantum dots, facilitating charge separation. In addition, GBCN also exhibited good anti-interference ability and stability. This research may shed light on the creation of a highly sensitive and selective PEC platform for detecting biomolecules.

Synergistic strategies by combining nanoreactors and prodrugs hold tremendous potential in anticancer treatment. However, precise death of target cancer cells remains a significant challenge due to the absence of an elaborate cancer targeting strategy. Here, a dual-targeting approach that combines the action of H2O2-producing folate receptor-targeted nanoreactors with a cyclooxygenase-2 (COX-2) targeted prodrug is reported. A folate-modified silica nanoreactor encapsulating glucose oxidase (GOX) is prepared to generate H2O2, which induces oxidative stress and allows the activation of the prodrug by targeted intracellular delivery. A novel prodrug bearing both COX-2 targeting Celecoxib and SN-38 anticancer agent with an H2O2-cleavable thioketal linker to activate the drug is presented. By dual-targeting, the generated H2O2 from GOX triggers the cleavage of a thioketal linker in the prodrug to produce the active form of the SN-38 anticancer drug in cancer cells inducing synergistic cell death. This dual-targeting strategy with a synergistic potency can aid in developing selective and effective anticancer therapeutics.

Abstract Chemoresistance originating from cancer stem cells (CSCs) is a major cause of cancer treatment failure and highlights the need to develop CSC-targeting therapies. Although enormous progress in both photodynamic therapy (PDT) and chemodynamic therapy (CDT) has been made in recent decades, the efficacy of these modalities against CSC remains limited. Here, we report a new generation photosensitizer, CA9-BPS-Cu(II), a system that combines three subunits within a single molecule, namely a copper catalyst for CDT, a boron dipyrromethene photosensitizer for PDT, and acetazolamide for CSC targeting via carbonic anhydrase-9 (CA9) binding. A therapeutic effect in MDA-MB-231 cells was observed that is ascribed to elevated oxidative stress mediated by a combined CDT/PDT effect, as well as through copper-catalyzed glutathione oxidation. The CSC targeting ability of CA9-BPS-Cu(II) was evident from its specific affinity for CD133-positive MDA-MB-231 cells. Moreover, its efficacy was successfully demonstrated in a xenograft mouse tumor model.

Cancer is the deadliest disease in the world behind heart disease. Sadly, this remains true even as we suffer the ravages of the Covid-19 pandemic. Whilst current chemo- and radiotherapeutic treatment strategies have significantly improved the patient survival rate, disease reoccurrence continues to pose a deadly risk for all too many patients. Incomplete removal of tumour cells from the body increases the chances of metastasis and developing resistance against current treatments. Immunotherapy represents a therapeutic modality that has helped to overcome these limitations in recent decades. However, further progress is needed. So-called immunogenic cell death (ICD) is a recently discovered and unique mode of cell death that could trigger this necessary further progress. ICD involves stimulation of a tumour-specific immune response as a downstream effect. Facilitated by certain treatment modalities, cells undergoing ICD can trigger the IFN-γ mediated immune response involving cytotoxic T cells (CTLs) and γδ T cells that eradicate residual tumour cells. In recent years, there has been a significant increase in the number of small-molecules being tested as potential ICD inducers. A large number of these ICD inducers are metal-based complexes. In fact, anticancer metal drugs based on Pt, Ru, Ir, Cu, and Au are now known to give rise to an immune response against tumour cells as the result of ICD. Advances have also been made in terms of exploiting combinatorial and delivery strategies. In favourable cases, these approaches have been shown to increase the efficacy of otherwise ICD "silent" metal complexes. Taken in concert, rationally designed novel anticancer metal complexes that can act as ICD inducers show promise as potential new immunotherapies for neoplastic disease. This Tutorial Review will allow the readers to assess the progress in this fast-evolving field thus setting the stage for future advances.

Non-invasive dynamic tracking of lysosomes and their interactions with other organelles is important for the study of lysosomal function and related diseases. However, many fluorescent dyes developed so far to target lysosomes cannot be used to monitor these processes due to the high concentrations required for imaging, long cell penetration times, and non-ideal photostability. In this regard, we synthesized three lysosomal targeting probes with large Stokes shifts, good stability, and high brightness. The Q-P-ARh dye, developed by us for the first time, can stain lysosomes at ultra-low concentrations (1.0 nM) without affecting the physiological functions of the lysosomes. More importantly, its excellent anti-interference ability and ultrafast lysosomal staining ability (within 1.0 min) clearly monitored the entire dynamic process of lipophagy. Ultimately, this method can greatly contribute to the study of autophagy pathways. This novel fluorescence platform shows great promise for the development of biological probes for application in pathological environments.