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Abstract The blockade of cytoprotective autophagy has been demonstrated to effectively enhance the efficacy of sonodynamic therapy (SDT). However, the limited recognition of antiautophagy agents for autophagosomes impedes the clinical application of autophagy inhibition. To efficiently deliver hydroxychloroquine (HCQ), an autophagy inhibitor, to autophagosomes, we utilized a strategy based on in situ click chemistry between sulfhydryl (‐SH) and maleimide (Mal) groups to trigger autophagosomes tracking and suppress tumor growth synergistically. A cascade nanoreactor was synthesized by encapsulating Mal‐modified HCQ (MHCQ) into a manganese porphyrin‐based metal‐organic framework with sonosensitizer properties, followed by poly(ethylene glycol)ylated liposomal membrane coating. After ultrasound irradiation, SDT‐induced apoptotic cells released damaged proteins with free ‐SH groups, which MHCQ rapidly captured in situ via a Mal‐thiol click reaction. When autophagosomes actively wrapped damaged proteins for detoxification, they simultaneously internalized HCQ anchored on proteins. In this scenario, antiautophagy drugs could actively track intracellular autophagosomes instead of undergoing passive diffusion in the cytosol. The interaction between HCQ and autophagic vesicles was greatly enhanced, which strengthened the blocking efficiency of autophagy and resulted in complete cell death. Overall, this study with smart design provides a promising strategy for improving intracellular targeted delivery to autophagosomes, thereby enhancing antitumor therapy.

Abstract Background Breast cancer ranks first among malignant tumors, of which triple-negative breast cancer (TNBC) is characterized by its highly invasive behavior and the worst prognosis. Timely diagnosis and precise treatment of TNBC are substantially challenging. Abnormal tumor vessels play a crucial role in TNBC progression and treatment. Nitric oxide (NO) regulates angiogenesis and maintains vascular homeostasis, while effective NO delivery can normalize the tumor vasculature. Accordingly, we have proposed here a tumor vascular microenvironment remodeling strategy based on NO-induced vessel normalization and extracellular matrix collagen degradation with multimodality imaging-guided nanoparticles against TNBC called DNMF/PLGA. Results Nanoparticles were synthesized using a chemotherapeutic agent doxorubicin (DOX), a NO donor L-arginine (L-Arg), ultrasmall spinel ferrites (MnFe2O4), and a poly (lactic-co-glycolic acid) (PLGA) shell. Nanoparticle distribution in the tumor was accurately monitored in real-time through highly enhanced magnetic resonance imaging and photoacoustic imaging. Near-infrared irradiation of tumor cells revealed that MnFe2O4 catalyzes the production of a large amount of reactive oxygen species (ROS) from H2O2, resulting in a cascade catalysis of L-Arg to trigger NO production in the presence of ROS. In addition, DOX activates niacinamide adenine dinucleotide phosphate oxidase to generate and supply H2O2. The generated NO improves the vascular endothelial cell integrity and pericellular contractility to promote vessel normalization and induces the activation of endogenous matrix metalloproteinases (mainly MMP-1 and MMP-2) so as to promote extravascular collagen degradation, thereby providing an auxiliary mechanism for efficient nanoparticle delivery and DOX penetration. Moreover, the chemotherapeutic effect of DOX and the photothermal effect of MnFe2O4 served as a chemo-hyperthermia synergistic therapy against TNBC. Conclusion The two therapeutic mechanisms, along with an auxiliary mechanism, were perfectly combined to enhance the therapeutic effects. Briefly, multimodality image-guided nanoparticles provide a reliable strategy for the potential application in the fight against TNBC. Graphical Abstract

Abstract Background The prognosis for hepatocellular carcinoma (HCC) remains suboptimal, characterized by high recurrence and metastasis rates. Although metalloimmunotherapy has shown potential in combating tumor proliferation, recurrence and metastasis, current apoptosis-based metalloimmunotherapy fails to elicit sufficient immune response for HCC. Results A smart responsive bimetallic nanovaccine was constructed to induce immunogenic cell death (ICD) through pyroptosis and enhance the efficacy of the cGAS-STING pathway. The nanovaccine was composed of manganese-doped mesoporous silica as a carrier, loaded with sorafenib (SOR) and modified with MIL-100 (Fe), where Fe3+, SOR, and Mn2+ were synchronized and released into the tumor with the help of the tumor microenvironment (TME). Afterward, Fe3+ worked synergistically with SOR-induced immunogenic pyroptosis (via both the classical and nonclassical signaling pathways), causing the outflow of abundant immunogenic factors, which contributes to dendritic cell (DC) maturation, and the exposure of double-stranded DNA (dsDNA). Subsequently, the exposed dsDNA and Mn2+ jointly activated the cGAS-STING pathway and induced the release of type I interferons, which further led to DC maturation. Moreover, Mn2+-related T1 magnetic resonance imaging (MRI) was used to visually evaluate the smart response functionality of the nanovaccine. Conclusion The utilization of metallic nanovaccines to induce pyroptosis-mediated immune activation provides a promising paradigm for HCC treatment.

Abstract Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria‐mediated cell death. However, the highly adaptive nature and damage‐repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self‐reinforced bimetallic Mito‐Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO2) into hyaluronic acid (HA) ‐modified metal‐organic frameworks (MOF). After cellular, Mito‐Jammer dissociates into CaO2 and Cu2+ in the tumor microenvironment. The exposed CaO2 further yields hydrogen peroxide (H2O2) and Ca2+ in a weakly acidic environment to strengthen the Cu2+‐based Fenton‐like reaction. Furthermore, the combination of chemodynamic therapy and Ca2+ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu‐ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

This paper describes the development and application of a systematic methodology to identify and quantify risks in drinking water and recreational catchments. The methodology assesses microbial and chemical contaminants from both diffuse and point sources within a catchment using Escherichia coli, protozoan pathogens and chemicals (including fuel and pesticides) as index contaminants. Hazard source information is gathered by a defined sanitary survey process involving use of a software tool which groups hazards into six types: sewage infrastructure, on-site sewage systems, industrial, stormwater, agriculture and recreational sites. The survey estimates the likelihood of the site affecting catchment water quality, and the potential consequences, enabling the calculation of risk for individual sites. These risks are integrated to calculate a cumulative risk for each sub-catchment and the whole catchment. The cumulative risks process accounts for the proportion of potential input sources surveyed and for transfer of contaminants from upstream to downstream sub-catchments. The output risk matrices show the relative risk sources for each of the index contaminants, highlighting those with the greatest impact on water quality at a sub-catchment and catchment level. Verification of the sanitary survey assessments and prioritisation is achieved by comparison with water quality data and microbial source tracking. [ABSTRACT FROM AUTHOR]