High Toxicity Research Articles

Evaluating Fitness in Older Acute Myeloid Leukemia Patients: Balancing Therapy and Treatment Risks.

Assessing the suitability of older adults with acute myeloid leukemia (AML) for intensive chemotherapy or stem cell transplantation remains a long-standing challenge. Geriatric assessment, which involves the evaluation of multiple dimensions of health, may influence a patient's ability to tolerate intensive or mild-intensity approaches, including treatment-related mortality. Prospective studies are required to validate different fitness criteria, in addition to making it possible to compare the effectiveness of geriatric assessment-based fitness against other criteria, in order to identify which aspects of geriatric assessment are linked to treatment tolerance. It is hoped that validation studies will include different groups of patients receiving either intensive or lower-intensity chemotherapy. At a minimum, geriatric assessment should involve the measurement of the comorbidity burden, cognition, physical function, and emotional health-factors previously associated with mortality in AML. These assessments should be conducted before starting chemotherapy in order to minimize the treatment's impact on the results. While treatment tolerance has traditionally been evaluated through toxicity rates in solid tumor patients, AML treatment often results in high toxicity rates regardless of the intensity. Therefore, early mortality should be the primary endpoint for assessing treatment tolerance, given its significant and clear implications. Other important endpoints might include declines in functional status and quality of life and treatment adjustments or discontinuation due to toxicity. Validating these fitness criteria is essential for guiding treatment choices, improving supportive care, determining trial eligibility, interpreting study outcomes, and informing drug labeling.

Synthesis and stability of one-dimensional red-emitting manganese-based Organic–inorganic halide

Pb-based halides are a highly promising class of materials due to their exceptional optoelectronic and magnetic properties. However, lead-based halides’ high toxicity and instability have detrimentally affected their actual applications. To address these issues, we investigated a lead-free one-dimensional manganese (Mn)-based organic–inorganic halide (TZI)MnCl3 (TZI = thiazolidin-3-ium). The red-emitting (TZI)MnCl3 demonstrated photoluminescence quantum yields of up to 46.4 % and 30.6 % when excited by light at wavelengths of 373 nm and 446 nm, respectively. Furthermore, (TZI)MnCl3 exhibited high stability under various conditions, highlighting its potential for optoelectronic applications.

On the lifespan of Enchytraeus crypticus - impact of iron (nanomaterial and salt) on aging.

Iron oxide nanomaterials (Fe3O4 NMs) have important biomedical and environmental applications, e.g. drug delivery, chemotherapy, magnetic resonance imaging contrast agents, etc. However, the environmental risks of such Fe3O4 are not fully assessed, particularly for soil living invertebrates, which are among the ones in the first line of exposure. Research has showed that longer-term exposure time is required to assess hazards of NMs, not predicted when based on shorter time and are therefore recommended. Thus, in the present study the effects of Fe3O4 NMs and FeCl3 were assessed in the terrestrial environment, using the soil model species Enchytraeus crypticus (Oligochaeta), throughout its entire lifespan (202 days). Two animals' density were used: 1 (D1) and 40 (D40) animals per replicate, in LUFA 2.2 soil. The endpoints were survival and reproduction monitored over-time, up to 202 days. Results showed that density clearly affected the toxicity response, with higher toxicity and lower lifespan in D1 compared to D40. Overall, FeCl3 was more toxic than Fe3O4 NM in terms of reproduction, however, adult animals can be at higher (long-term) risk when exposed to Fe3O4 NM. Differences might be linked to slower Fe kinetics for the Fe3O4 NMs, i.e., slower Fe dissolution and release of ions.

Toxicity and Repellency of (E/Z)-3-Butylidenephthalide: A Natural Compound Isolated from Ligusticum porteri Root Extract Evaluated Against Imported Fire Ants (Hymenoptera: Formicidae)

Imported fire ants are pests of significant importance, especially in the southern United States. We tested (E/Z)-3-butylidenephthalide, a natural compound that was isolated from the ethanolic extract of Ligusticum porteri roots, as a repellent and toxicant against workers of imported fire ants. A series of serial concentrations, starting from 156 µg/g until failure, were tested using digging bioassays. Workers removed significantly less sand from the vials treated with (E/Z)-3-butylidenephthalide as compared to the ethanol control. Based on sand removal data, (E/Z)-3-butylidenephthalide treatment resulted in a more significant digging suppression against red imported fire ant workers at concentrations ranging between 19.5 and 0.6 µg/g than the solvent control whereas sand removal at 0.3 µg/g was similar with the solvent control. Black imported fire ants showed repellency at serial concentrations ranging between 19.5 and 0.15 µg/g whereas the hybrid imported fire ants showed repellency between 19.5 and 4.9 µg/g. In DEET treatments, red and black imported fire ants showed repellency at dosages of 125 to 62.5 µg/g, whereas the treatment failed at the dose of 15.6 µg/g in hybrid fire ants. (E/Z)-3-butylidenephthalide with LC50 values of 11 and 16.4 µg/g was toxic against red and black imported fire ants, respectively, followed by hybrid imported fire ants (LC50 = 104.7 µg/g). Fipronil with LC50 values of 0.49, 0.33, and 0.53 µg/g against red, black, and hybrid fire ants, respectively, was more toxic than (E/Z)-3-butylidenephthalide. In residual bioassay, toxic activity lasted for 3 weeks at dosages of 250 and 500 μg/g against HIFA. In residual bioassay, toxic activity lasted for 3 weeks at dosages of 250 and 500 μg/g against HIFA. The high repellency and toxicity of (E/Z)-3-butylidenephthalide against imported fire ants makes it a natural compound of interest for further evaluation under natural field conditions.

Cytotoxicity of Orthodontic Archwires Used in Clinical Practice: In Vitro Study

This study investigates the cytotoxicity of various orthodontic archwires, which are essential in directing tooth movement through biomechanical forces. With advancements in material science, different archwire materials have been developed to balance mechanical performance with aesthetic and biological considerations. The study focuses on evaluating the biocompatibility and mechanical properties of stainless steel, nickel–titanium, and chromium–cobalt archwires, particularly their cytotoxic effects on oral cavity cells. In vitro cell culture experiments with fibroblasts, combined with scanning electron microscopy (SEM) analysis, were conducted to assess cell viability and morphology. The results revealed significant differences in cytotoxicity, with copper wires showing high toxicity and causing extensive cell death, while nickel–titanium and chromium–cobalt wires supported better cell viability and healthier cell morphology. These findings highlight the importance of selecting archwire materials that ensure mechanical efficiency without compromising cellular health, emphasizing the need for ongoing assessment of material biocompatibility in the oral environment.

A Critical Review of Deep Oxidation of Gaseous Volatile Organic Compounds via Aqueous Advanced Oxidation Processes.

Volatile organic compounds (VOCs) are considered to be the most recalcitrant gaseous pollutants due to their high toxicity, diversity, complexity, and stability. Gas-solid catalytic oxidation methods have been intensively studied for VOC treatment while being greatly hampered by energy consumption, catalyst deactivation, and byproduct formation. Recently, aqueous advanced oxidation processes (AOPs) have attracted increasing interest for the deep oxidation of VOCs at room temperature, owing to the generation of abundant reactive oxygen species (ROS). However, current reviews mainly focus on VOC degradation performance and have not clarified the specific reaction process, degradation products, and paths of VOCs in different AOPs. This study systematically reviews recent advances in the application of aqueous AOPs for gaseous VOC removal. First, the VOC gas-liquid mass transfer and chemical oxidation processes are presented. Second, the latest research progress of VOC removal by various ROS is reviewed to study their degradation performances, pathways, and mechanisms. Finally, the current challenges and future strategies are discussed from the perspectives of synergistic oxidation of VOC mixtures, accurate oxidation, and resource utilization of target VOCs via aqueous AOPs. This perspective provides the latest information and research inspiration for the future industrial application of aqueous AOPs for VOC waste gas treatment.

Construction of α-Fe2O3 Nanorods/UiO-66-NH2 by in-situ Growth with Photocatalytic Reduction of Cr (VI)

Abstract Cr (VI) is widely used in industry but its high toxicity causes environmental pollution that needs addressing. The growth of photosensitive materials on semiconductor surfaces can successfully stop photogenerated electron-hole pair recombination, increasing photocatalytic efficiency. Herein, α-Fe2O3 nanorods/UiO-66-NH2 compounds were successfully obtained through the in-situ solvothermal approach. By using 2-aminoterephthalic acid in the solvothermal treatment of Zr4+ adsorbed α-Fe2O3 nanorods, the UiO-66-NH2 nanocrystals were evenly distributed on the nanorods. In addition, the reduction efficiency of wastewater reached 93% after 150 min of light exposure, much higher than uncompounded materials. Moreover, the α-Fe2O3/UiO-66-NH2 crystals had good regeneration ability, retaining 73% of Cr (VI) removal capacity after four cycles. In this process, α-Fe2O3 and UiO-66-NH2 effectively complexed to form a heterojunction, which effectively suppressed the complexation of electrons (e-) and holes (h+). This efficient complex facilitates the photocatalytic degradation of highly noxious Cr (VI) to Cr (III) under visible light. The efficient Cr (VI) elimination ability comes from the photocatalytic reduction mechanism where they form a special interface to promote the movement of electrons and holes for efficient removal. This work provides both a new approach for in-situ synthesis and a reference for efficient Cr (VI) elimination.

In-Silico Perspectives on the Potential Therapeutic Aids of Hesperetin Derivatives for Lung Cancer

Background: Lung carcinoma has become one of the most noteworthy and dangerous health problems discovered today. The disease is mainly caused by smoking and becomes among the leading causes of death spread by growing the cancerous cells into the lining of the lungs and nearby lobes. The FDA has given clearance to numerous drugs and chemotherapy agents; nevertheless, they can be exceedingly costly as well as frequently fall short of entirely addressing the ailment. In the medical management of lung cancer, new medicines or active leads with high efficacy and minimal toxicity are required in this era.Methods: The study has been conducted with the intent to uncover a prospective approach to treating lung cancer through structural modification of Hesperetin by creating its analogs to enhance its efficacy compared to its parent compound with the computational drug design. The analysis has been conducted with various approaches followed by PASS prediction, ADME, toxicity profile, molecular docking, data filtration, and anticancer activity.Results: All the compounds showed satisfactory criteria in each parameter that was assessed. The data mining was done carefully by pointing out the compounds that had the greatest value among all the compounds in each investigation, which resulted in a total of 3 compounds out of 50. Conclusions: Finally, the selected compounds were further analyzed for MD simulation studies. Afterward, PCA analysis was also conducted in order to get the lead compound with this additional investigation.Keywords: Lung cancer; Anti-cancer lead; Hesperetin; Drug designing; Molecular docking; MD simulation; PCA

A Tumor Homing Peptide-Linked Arsenic Compound Inhibits Pancreatic Cancer Growth and Enhances the Inhibitory Effect of Gemcitabine.

Arsenic trioxide (ATO) has been shown to inhibit pancreatic cancer (PC) cell growth in vitro and to promote the inhibitory effects of gemcitabine (Gem) on PC in vivo. However, the high toxicity of ATO associated with the required high doses and indiscriminate targeting has limited its clinical application. This study aimed to determine whether coupling arsenic to a tumor homing peptide would increase the inhibitory potency against PC cells. The effects of this peptide-linked arsenic compound (PhAs-LHP), the analogous non-targeting arsenic compound (phenylarsine oxide, PAO), and marketed ATO on PC growth were tested in vitro and in a mouse model. The data demonstrated that PhAs-LHP inhibited PC cell growth in vitro more potently, with IC50 values 10 times lower than ATO. Like ATO, PhAs-LHP induced cell death and cell cycle arrest. This cytotoxic effect of PhAs-LHP was mediated via a macropinocytosis-linked uptake pathway as amiloride (a macropinocytosis inhibitor) reduced the inhibitory effect of PhAs-LHP. More importantly, PhAs-LHP inhibited PC growth in mice and enhanced the inhibitory effect of Gem on PC growth at 2 times lower molar concentration than PAO. These results indicate that PhAs-LHP inhibited PC more potently than ATO/PAO and suggest a potential clinical use for the combination of Gem with the peptide-linked arsenic compound for the treatment of pancreatic cancer.

A pH-Sensitive cRGD-PEG-siRNA Conjugated Compound Targeting Glioblastoma.

Glioblastoma ranks among the most prevalent primary intracranial tumors, characterized by high mortality and poor prognosis. Chemotherapy remains a key treatment strategy for gliomas, though most current drugs suffer from limited efficacy and significant toxicity. This study focuses on a cRGD-siEGFR coupling compound synthesized in a previous stage. Prior research indicated that cRGD-siEGFR molecules exhibited certain targeting and antitumor properties but faced issues of inadequate targeting, low efficacy, and high renal toxicity. To enhance antitumor efficacy and mitigate side effects, a pH-responsive, long-circulating, and highly targeted siRNA delivery system, the cRGD-PEG-siEGFR conjugate, was developed. The targeting, antitumor effects, and biological distribution of cRGD-PEG-siEGFR were examined. The results demonstrated that cRGD-PEG-siEGFR was effectively taken up by αvβ3-positive U87MG cells, specifically silenced EGFR gene expression, and exhibited antitumor effects. In normal physiological conditions, it avoided uptake by normal cells, thereby reducing side effects. Furthermore, in vivo biodistribution experiments revealed that cRGD-PEG-siEGFR, compared to cRGD-siEGFR, significantly decreased renal accumulation and exhibited prolonged circulation. Consequently, cRGD-PEG-siRNA emerges as a promising drug candidate with attributes of long circulation, high targeting, pH responsiveness, and substantial antitumor efficacy.

Design, synthesis, and biological evaluation of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives as orally bioavailable PI3K inhibitors.

Phosphoinositide-3-kinase (PI3K) is overexpressed in many tumors and is, thus, an ideal target for cancer treatments. Accordingly, there is an urgent need for the development of PI3K inhibitors with high potency and low toxicity. In this study, we designed and synthesized a series of 2,4-dimorpholinopyrimidine-5-carbonitrile derivatives, which were evaluated for their PI3K inhibitory potency. Compound 17p demonstrated comparable PI3Kα inhibitory activity (IC50: 31.8 ± 4.1nM) to the positive control, BKM-120 (IC50: 44.6 ± 3.6nM). In addition, 17p showed significant inhibitory activity against PI3Kδ (IC50: 15.4 ± 1.9nM) and significant isoform selectivity against PI3Kβ, PI3Kγ, and mTOR. Furthermore, 17p exhibited good antiproliferative activities against cancer cell activity and good safety in the Ames and hERG tests while having outstanding liver microsomal stability in vitro, with half-lives of 38.5min in rats and 127.9min in humans. In addition, in an apoptosis assay, 17p could induce dose-dependent cytotoxicity in the ovarian cancer cell line A2780. In a pharmacokinetic study, 17p was stable (T ½: 2.03h) and showed high bioavailability (46.2%). Collectively, these results indicate that 17p could be a promising PI3K agent for cancer treatment.

Toxicity of nuclear-localized GFP in reporter mice

Various techniques using fluorescent reporter probes have been developed, such as GFP transgenic mouse lines that are used to detect spatial–temporal expression levels of genes. Although GFP expression is largely considered non-toxic, recent reports have indicated that under certain conditions GFP can display cellular toxicity. We hereby report the nuclear toxicity of H2B-GFP using a K14 specific Tet-on reporter mouse system. Using this system, GFP accumulates in the nucleus of all K14 expressing cells, such as the ocular surface epithelia and ocular adnexa. Expression of high levels of nuclear GFP during embryonic stages led to an eye open-at-birth (EOB) phenotype and abnormal ocular adnexa development and during adult and aging stages showed notable toxicity to ocular tissues. Other tissues, such as skin, also presented multiple defects associated with H2B-GFP expression. This toxicity was found to be concentration dependent, with homozygous mice presenting extremely high toxicity, while heterozygous mice presented limited toxicity. Upon induction, the accumulation of H2B-GFP in the nucleus of homozygous mice led to apoptosis within 2 weeks. This study therefore shows that although the use of nuclear GFP reporter mice is a valuable tool, at high levels, nuclear GFP can be toxic, leading to cell death and affecting tissue function.

Development of polyfunctionalized biochar modified with manganese oxide and sulfur for immobilizing Hg(II) and Pb(II) in water and soil and improving soil health

Mercury (Hg) and lead (Pb) pose significant risks to human health due to their high toxicity and bioaccumulative properties. This study aimed to develop a novel biochar composite (HMB-S), polyfunctionalized with manganese dioxide (α-MnO2) and sulfur functional groups, for the effective immobilization of Hg(II) and Pb(II) from contaminated environments. HMB-S demonstrated superior adsorption capacities of 190.1 mg/g for Hg(II) and 259.9 mg/g for Pb(II), which significantly surpasses the capacities of unmodified biochar (HB) and biochar functionalized solely with Mn (HMB). Mechanistic studies revealed that the immobilization of these metals by HMB-S involved ion exchange, mineral precipitation, surface complexation, and electrostatic interactions. In soil incubation experiments, HMB-S significantly decreased the levels of extractable Hg(II) and Pb(II) compared to the control, reducing the mobility of these metals and converting 17 % of Hg(II) and 26 % of Pb(II) into less bioavailable residual forms. Pot experiments confirmed that all tested biochar materials (HB, HMB, and HMB-S) promoted spinach growth in contaminated soils, with HMB-S being the most effective at lowering Hg(II) and Pb(II) uptake by plants. Additionally, analysis of soil microbial communities indicated that HMB-S altered community composition and increased the relative abundance of metal-resistant bacteria. These findings highlight the potential of polyfunctionalized biochar HMB-S as an effective remediation strategy for Hg and Pb contamination in soil and aqueous environments.

Monocrotaline-mediated autophagy via inhibiting PI3K/AKT/mTOR pathway induces apoptosis in rat hepatocytes.

Monocrotaline (MCT), a major pyrrolizidine alkaloid, is well-known for its high liver toxicity. Dysregulation of autophagy induced apoptosis can lead to various liver diseases, including those induced by chemical compounds. Therefore, we aim to explore whether autophagy might serve as a potential strategy for addressing liver apoptosis caused by MCT. In primary rat hepatocytes (PRHs), MCT significantly increased the number of autophagosomes and the expression levels of LC3II, Becline-1, and Atg5, while it decreased the expression of p62 in a concentration-dependent manner at doses of 100, 200, 300, and 400μM. Western blot assays revealed MCT inhibited the phosphorylation levels of the PI3K/AKT/mTOR pathway. To elucidate the role of autophagy in mediating MCT-induced apoptosis, we further pretreated PRHs with the autophagy agonist Rapamycin and the inhibitors Bafilomycin A1 and Chloroquine, respectively, and assessed the apoptosis of PRHs induced by MCT. The results displayed that Rapamycin increased the apoptosis rate and the expression of cleaved caspase-3, whereas Bafilomycin A1 and Chloroquine reduced the apoptosis and the expression of cleaved caspase-3 in PRHs. This study confirms that autophagy enhances PRHs apoptosis induced by MCT. In summary, this study demonstrates that MCT-induced autophagy via inhibition of the PI3K/AKT/mTOR pathway can lead to apoptosis in PRHs.

SMCVdb: a database of experimental cellular toxicity information for drug candidate molecules.

Many drug discovery exercises fail because small molecules that are effective inhibitors of target proteins exhibit high cellular toxicity. Early and effective assessment of toxicity and pharmacokinetics is essential to accelerate the drug discovery process. Conventional methods for toxicity profiling, including in vitro and in vivo assays, are laborious and resource-intensive. In response, we introduce the Small Molecule Cell Viability Database (SMCVdb), a comprehensive resource containing toxicity data for over 24 000 compounds obtained through high-content imaging (HCI). SMCVdb seamlessly integrates chemical descriptions and molecular weight data, offering researchers a holistic platform for toxicity data aiding compound prioritization and selection based on biological and economic considerations. Data collection for SMCVdb involved a systematic approach combining HCI toxicity profiling with chemical information and quality control measures ensured data accuracy and consistency. The user-friendly web interface of SMCVdb provides multiple search and filter options, allowing users to query the database based on compound name, molecular weight range, or viability percentage. SMCVdb empowers users to access toxicity profiles, molecular weights, compound names, and chemical descriptions, facilitating the exploration of relationships between compound properties and their effects on cell viability. In summary, the database provides experimentally derived cellular toxicity information for over 24 000 drug candidate molecules to academic researchers, and pharmaceutical companies. The SMCVdb will keep growing and will prove to be a pivotal resource to expedite research in drug discovery and compound evaluation. Database URL: http://smcvdb.rcb.ac.in:4321/.

Nano-pesticide delivery system based on UiO-66 with pH sensitivity for precise control of Spodoptera frugiperda.

Metal-organic frameworks have the advantages of easy synthesis, high loading capacity and good biocompatibility, making them essential materials for constructing pesticide nano-delivery systems. In this study, a pH-responsive nano-controlled-release formulation Chl@UiO-66 was prepared using UiO-66 as the nano-scale carrier for adsorbing chlorantraniliprole (Chl). The appearance, pesticide loading, release behaviour, insecticidal activity, long-term control efficacy and safety of Chl@UiO-66 for non-target organisms were extensively evaluated. The results showed that the prepared Chl@UiO-66 was a regular octahedron with a uniform particle size of 230 nm and pesticide loading of 15.62%. The release of pesticides under alkaline conditions was superior to that under acidic and neutral conditions, which showed pH-responsive performance. Chl@UiO-66 had an excellent ability to protect pesticides from ultraviolet degradation. Compared with chlorantraniliprole suspension concentrate, Chl@UiO-66 had a better control effect against Spodoptera frugiperda and long-term control efficacy. The prepared nano-controlled-release formulation had low toxicity to zebrafish, earthworms and human BEAS-2B cells. Chl@UiO-66 is a new pesticide formulation with high efficacy and low toxicity that provides a smart controlled-release solution. © 2024 Society of Chemical Industry.

Management and Performance Analysis of Textile Effluent Treatment Plants in Laundries of The Local Productive Arrangement of Pernambuco

Objective: The present study aimed to assess 10 laundries for compliance with Brazilian legislation Theoretical Framework: The Local Productive Arrangement (APL) of Pernambuco plays a crucial role in job creation and economic growth in the state. However, the jeans beneficiation process consumes a significant amount of water and involves the use of various chemicals, which generate effluents with high organic loads, color, and toxicity. This has caused serious environmental problems. The issue is exacerbated during prolonged drought periods and by intermittent river flows, which reduce the natural self-purification capacity of the rivers. Method: A total of 334 influent and effluent samples were collected. All the laundries studied employed physicochemical treatment processes (flocculation followed by sedimentation). Results and Discussion: The WWTPs proved to be efficient in the removal of settleable solids, demonstrating that the coagulation and flocculation processes are effective for this purpose, even in scenarios with management deficiencies. On the other hand, poor operation of the treatment plants has resulted in other parameters, such as pH, oils, and greases, being out of compliance with current legislation. The efficiency in reducing BOD was highly inconsistent, with fluctuations ranging from over 90% efficiency to negative values, indicating significant operational issues. High concentrations of organic matter can compromise oxygen levels in the receiving bodies. It is essential to intensify monitoring and improve treatment processes to mitigate negative environmental impacts.

Covalent Self-Assembly of Bio-HCP Nanoparticles for Shell-Programmed Encapsulation of Microbial Cells.

Modifying the bacterial surface through grafting functional nanoparticles is a common strategy for programing bacteria. At this moment, the targeted nanoparticles face a dilemma of no multifunctional structure, high toxicity, and weak chemical driving forces, which restrict the broad practical applications. Like a multistage booster of a rocket, we propose a multistage covalent self-assembly strategy to protect, expand, and control the encapsulated shells of microbial cells via biocompatible hyper-cross-linked polymer nanoparticles (Bio-HCP NPs) with internal porosity and surface functional groups. The bacterial surface is enhanced with rich amino groups up to 1010 per cell for specifically grafting nanoparticles. The arming bacteria after first-stage assembly can complete biocatalysis in a highly toxic environment, and as-prepared polymer aggregates (6-20 μm) after third-stage assembly can be accurately counted in an aerosol environment. This nanoparticle encapsulation exhibits strong cell viability from pollutants and specificity from impurity particles, holding promise for various complex application scenarios.

More than a mutagenic Aflatoxin B1 precursor: The multiple cellular targets of Versicolorin A revealed by global gene expression analysis

Versicolorin A (VerA), a precursor of the potent carcinogen Aflatoxin B1 (AFB1), is an emerging mycotoxin. Recent research has highlighted the mutagenic and genotoxic properties of VerA, yet several facets of its pronounced toxicity remain unexplored. In the present study, we investigated early (6 h) transcriptomic changes induced by VerA in differentiated intestinal cells in non-cytotoxic conditions (1 and 3 μM) and compared its effects to those of AFB1 at 1 μM. Our findings indicated that VerA led to substantial alterations in global gene expression profiles, while AFB1 did not exhibit the same effects. As expected, both toxins caused alterations in gene expression associated with well-known aspects of their toxicity, including mutagenicity, genotoxicity, oxidative stress, and apoptosis. However, we also observed novel features of VerA toxicity, including the ability to cause mitochondrial dysfunction and to trigger a type-1 interferon response, at least partially mediated by cGAS-STING. VerA also induced changes in the expression of genes involved in the regulation of cell shape and adhesion, transcription/translation as well as genes associated with tumor biology. Our results provide new evidence of the high toxicity of VerA and underscore the importance of further assessing the risks associated with its presence in food.

Programmable Circular Multivalent Nanobody‐Targeting Chimeras (mNbTACs) for Multireceptor‐Mediated Protein Degradation and Targeted Drug Delivery

Multispecific therapeutics hold significant promise in drug delivery, protein degradation, and cell recruitment to address clinical issues of tumor heterogeneity, resistance, and immune evasion. However, their modular engineering remains challenging. We developed a targeted degradation platform, termed multivalent nanobody‐targeting chimeras (mNbTACs), by encoding diverse nanobody codons on a circular template using DNA printing technology. The homo‐ or hetero‐ mNbTACs specifically recognized membrane targets in a multivalent manner and simultaneously recruited scavenger receptors to favor clathrin‐/caveolae‐dependent endocytosis and lysosomal degradation of multiple proteins with high efficiency and selectivity. We demonstrated that a bispecific doxorubicin‐loaded mNbTAC, named Doxo‐mvNbsPPH, passively accumulated at tumor sites, specifically interacted with PD‐L1 and HER2 targets, and was rapidly transported into lysosome, inducing potent immunogenic cell death and alleviating immune checkpoint evasion. The synergistic boosting of innate and adaptive immunity promoted the infiltration and proliferation of CD8+ T cells in tumor microenvironment (an 11‐fold increase) with high toxicity and low exhaustion, eventually enhancing antitumor efficacy. Our mNbTAC platform provides multispecific therapeutics with variable valences and programmed species, whereas it induces targeted protein degradation through multireceptor‐mediated endocytosis and lysosomal degradation without the need for lysosome‐targeting receptors, representing a general and modular tool to harness extracellular proteome for disease treatment.