Orthogonal multimodality integration and clustering in single-cell data.

Multimodal integration combines information from different sources or modalities to gain a more comprehensive understanding of a phenomenon. The challenges in multi-omics data analysis lie in the complexity, high dimensionality, and heterogeneity of the data, which demands sophisticated computational tools and visualization methods for proper interpretation and visualization of multi-omics data. In this paper, we propose a novel method, termed Orthogonal Multimodality Integration and Clustering (OMIC), for analyzing CITE-seq. Our approach enables researchers to integrate multiple sources of information while accounting for the dependence among them. We demonstrate the effectiveness of our approach using CITE-seq data sets for cell clustering. Our results show that our approach outperforms existing methods in terms of accuracy, computational efficiency, and interpretability. We conclude that our proposed OMIC method provides a powerful tool for multimodal data analysis that greatly improves the feasibility and reliability of integrated data.

Rapid Initiation of Antiretroviral Therapy with Coformulated Bictegravir, Emtricitabine, Tenofovir Alafenamide Versus Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate in HIV-positive Men Who Have Sex with Men in China: Week 48 Results of the Multicenter, Randomized Clinical Trial.

BACKGROUND: Most international treatment guidelines recommend rapid initiation of antiretroviral therapy (ART) for people newly diagnosed with HIV-1 infection, but experiences with rapid ART initiation remain limited in China. We aimed to evaluate the efficacy and safety of efavirenz (400-mg) plus lamivudine and tenofovir disoproxil fumarate (EFV + 3TC + TDF) versus coformulated bictegravir, emtricitabine, tenofovir alafenamide (BIC/FTC/TAF) in rapid ART initiation among HIV-positive men who have sex with men (MSM). METHODS: This multicenter, open-label, randomized clinical trial enrolled MSM aged ≥18 years to start ART within 14 days of confirmed HIV diagnosis. The participants were randomly assigned in a 1:1 ratio to receive EFV(400-mg) + 3TC + TDF or BIC/FTC/TAF. The primary end point was viral suppression (<50 copies/ml) at 48 weeks per FDA Snapshot analysis. RESULTS: Between March 2021 and July 2022, 300 participants were enrolled; 154 were assigned to receive EFV + 3TC + TDF (EFV group) and 146 BIC/FTC/TAF (BIC group). At week 48, 118 (79.2%) and 140 (95.9%) participants in the EFV and BIC group, respectively, were retained in care with viral suppression; and 24 (16.1%) and 1 (0.7%) participant in the EFV and BIC group (p < 0.001), respectively, discontinued treatment due to adverse effects, death, or loss to follow-up. The median increase of CD4 count was 181 and 223 cells/µL (p = 0.020), respectively, for the EFV and BIC group, at week 48. The overall incidence of adverse effects was significantly higher for the EFV group (65.8% vs 37.7%, P < 0.001). CONCLUSION: BIC/FTC/TAF was more efficacious and safer than EFV(400-mg) + 3TC + TDF for rapid ART initiation among HIV-positive MSM in China.

Dual Starvations Induce Pyroptosis for Orthotopic Pancreatic Cancer Therapy through Simultaneous Deprivation of Glucose and Glutamine.

Pancreatic cancer is a highly fatal disease, and existing treatment methods are ineffective, so it is urgent to develop new effective treatment strategies. The high dependence of pancreatic cancer cells on glucose and glutamine suggests that disrupting this dependency could serve as an alternative strategy for pancreatic cancer therapy. We identified the vital genes glucose transporter 1 (GLUT1) and alanine-serine-cysteine transporter 2 (ASCT2) through bioinformatics analysis, which regulate glucose and glutamine metabolism in pancreatic cancer, respectively. Human serum albumin nanoparticles (HSA NPs) for delivery of GLUT1 and ASCT2 inhibitors, BAY-876/V-9302@HSA NPs, were prepared by a self-assembly process. This nanodrug inhibits glucose and glutamine uptake of pancreatic cancer cells through the released BAY-876 and V-9302, leading to nutrition deprivation and oxidative stress. The inhibition of glutamine leads to the inhibition of the synthesis of the glutathione, which further aggravates oxidative stress. Both of them lead to a significant increase in reactive oxygen species, activating caspase 1 and GSDMD and finally inducing pyroptosis. This study provides a new effective strategy for orthotopic pancreatic cancer treatment by dual starvation-induced pyroptosis. The study for screening metabolic targets using bioinformatics analysis followed by constructing nanodrugs loaded with inhibitors will inspire future targeted metabolic therapy for pancreatic cancer.

Effects of Skeleton Structure of Mesoporous Silica Nanoadjuvants on Cancer Immunotherapy.

Mesoporous silica nanoparticles (MSNs) have been widely praised as nanoadjuvants in vaccine/tumor immunotherapy thanks to their excellent biocompatibility, easy-to-modify surface, adjustable particle size, and remarkable immuno-enhancing activity. However, the application of MSNs is still greatly limited by some severe challenges including the unclear and complicated relationships of structure and immune effect. Herein, three commonly used MSNs with different skeletons including MSN with tetrasulfide bonds (TMSN), MSN containing ethoxy framework (EMSN), and pure -Si-O-Si- framework of MSN (MSN) are comprehensively compared to study the impact of chemical construction on immune effect. The results fully demonstrate that the three MSNs have great promise in improving cellular immunity for tumor immunotherapy. Moreover, the TMSN performs better than the other two MSNs in antigen loading, cellular uptake, reactive oxygen species (ROS) generation, lymph node targeting, immune activation, and therapeutic efficiency. The findings provide a new paradigm for revealing the structure-function relationship of mesoporous silica nanoadjuvants, paving the way for their future clinical application.

Classical swine fever virus NS5A protein activates autophagy via the PP2A-DAPK3-Beclin 1 axis.

IMPORTANCE: Autophagy is a conserved degradation process that maintains cellular homeostasis and regulates native and adaptive immunity. Viruses have evolved diverse strategies to inhibit or activate autophagy for their benefit. The paper reveals that CSFV NS5A mediates the dissociation of PP2A from Beclin 1 and the association of PP2A with DAPK3 by interaction with PPP2R1A and DAPK3, PP2A dephosphorylates DAPK3 to activate its protein kinase activity, and activated DAPK3 phosphorylates Beclin 1 to trigger autophagy, indicating that NS5A activates autophagy via the PP2A-DAPK3-Beclin 1 axis. These data highlight a novel mechanism by which CSFV activates autophagy to favor its replication, thereby contributing to the development of antiviral strategies.

X-ray irradiation effectively inactivated lymphocytes in transfusion in vivo monitored by the bioluminescence transfusion-associated graft-versus-host disease model.

BACKGROUND AND OBJECTIVES: Transfusion of cold-stored whole blood is the preferred resuscitation method for trauma patients but may cause transfusion-associated graft-versus-host disease (TA-GVHD). Standard clinical practice to prevent this is to irradiate blood components with gamma-rays. X-ray irradiations are also a safe and effective alternative to gamma-ray irradiation. We established a visual mouse model of TA-GVHD to compare the viability and function of lymphocytes exposed to gamma- and x-ray irradiation. MATERIALS AND METHODS: A haploidentical transplantation mouse model was established to simulate TA-GVHD with Balb/c mice as donors and hybrid F1 CB6 mice (Balb/c × C57) as recipients. Spleen cells from Tg-Fluc+ Balb/c mice were isolated and irradiated with gamma-rays and x-rays. Lymphocyte activation, apoptosis and proliferation post phorbol 1 2-myristate 1 3-acetate (PMA) stimulation were evaluated. After transfusion, we monitored Fluc+ lymphocytes daily by bioluminescence imaging. Recipients were euthanized on day 21, and tissues were examined pathologically and for inflammatory cytokines. RESULTS: The viability of gamma- or x-ray irradiated lymphocytes decreased significantly with slight changes in proliferation in vivo after transfusion. Compared with the non-irradiated group, both the gamma- and x-ray irradiated groups showed significantly decreased clinical scoring and inflammatory cytokine levels. The fluorescence intensity of the body and target organs was reduced after irradiation. CONCLUSION: No recipients acquired TA-GVHD after lymphocyte transfusion subjected to gamma- or x-rays, showing that x-rays inactivate as well as gamma rays and are suitable for irradiating whole blood.

Raman spectroscopy coupled with chemometrics for identification of adulteration and fraud in muscle foods: a review.

Muscle foods, valued for their significant nutrient content such as high-quality protein, vitamins, and minerals, are vulnerable to adulteration and fraud, stemming from dishonest vendor practices and insufficient market oversight. Traditional analytical methods, often limited to laboratory-scale., may not effectively detect adulteration and fraud in complex applications. Raman spectroscopy (RS), encompassing techniques like Surface-enhanced RS (SERS), Dispersive RS (DRS), Fourier transform RS (FTRS), Resonance Raman spectroscopy (RRS), and Spatially offset RS (SORS) combined with chemometrics, presents a potent approach for both qualitative and quantitative analysis of muscle food adulteration. This technology is characterized by its efficiency, rapidity, and noninvasive nature. This paper systematically summarizes and comparatively analyzes RS technology principles, emphasizing its practicality and efficacy in detecting muscle food adulteration and fraud when combined with chemometrics. The paper also discusses the existing challenges and future prospects in this field, providing essential insights for reviews and scientific research in related fields.

8-Br-cGMP suppresses tumor progression through EGFR/PLC γ1 pathway in epithelial ovarian cancer.

BACKGROUND: Cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (PKG-I), a serine/threonine kinase, is important in tumor development. The present study determines that the cGMP/PKG I pathway is essential for promoting cell proliferation and survival in human ovarian cancer cells, whereas cGMP analog has been shown to lead to growth inhibition and apoptosis of various cancer cells. The role of cGMP/PKG I pathway in epithelial ovarian cancer (EOC), therefore, remains controversial. We investigated the effect of cGMP/PKG I pathway and the underlying mechanism in EOC. METHODS AND RESULTS: The results showed that exogenous 8-Bromoguanosine-3', 5'-cyclic monophosphate (8-Br-cGMP) (cGMP analog) could antagonize the effects by EGF, including suppressing proliferation, invasion and migration of EOC cells. In vivo, 8-Br-cGMP hampered the growth of the xenograft tumor. Additionally, the expressions of epidermal growth factor receptor (EGFR), matrix metallopeptidase 9 (MMP9), proliferating cell nuclear antigen and Ki67 in xenograft tumor were decreased after 8-Br-cGMP intervention. Further research demonstrated that 8-Br-cGMP decreased the phosphorylation of EGFR (Y992) and downstream proteins phospholipase Cγ1 (PLC γ1) (Y783), calmodulin kinase II (T286) and inhibited cytoplasmic Ca2+ release as well as PKC transferring to cell membrane. It's worth noting that the inhibition was 8-Br-cGMP dose-dependent and 8-Br-cGMP showed similar inhibitory effect on EOC cells compared with U-73122, a specific inhibitor of PLC γ1. CONCLUSIONS: The activation of endogenous PKG I by addition of exogenous 8-Br-cGMP could inhibit EOC development probably via EGFR/PLCγ1 signaling pathway. 8-Br-cGMP/PKG I provide a new insight and strategy for EOC treatment.

Increased regional body fat is associated with depressive symptoms: a cross-sectional analysis of NHANES data obtained during 2011-2018.

AIMS: The findings from previous epidemiological studies of the association between regional body fat and depressive symptoms have been unclear. We aimed to determine the association between the body fat in different regions and depressive symptoms based on data from the National Health and Nutrition Examination Survey (NHANES). METHODS: This study included 3393 participants aged ≥ 20 years from the NHANES performed during 2011-2018. Depressive symptoms were assessed using the Patient Health Questionnaire-9. The fat mass (FM) was measured in different regions using dual-energy X-ray absorptiometry to determine the total FM, trunk FM, arm FM, and leg FM. The FM index (FMI) was obtained by dividing the FM in kilograms by the square of the body height in meters. Weighted data were calculated in accordance with analytical guidelines. Linear logistic regression models were used to quantify the association between regional FMI and depressive symptoms. Univariate and stratified analyses were also performed. RESULTS: The participants in this study comprised 2066 males and 1327 females. There were 404 (11.91%) participants with depressive symptoms, who were aged 40.89 ± 11.74 years and had a body mass index of 30.07 ± 7.82 kg/m². A significant association was found between total FMI and depressive symptoms. In the fully adjusted multivariate regression model, a higher total FMI (odds ratio = 2.18, 95% confidence interval [CI] = 1.08-4.39) was related to a higher risk of depressive symptoms, while increased total FMI (ß = 1.55, 95% CI = 0.65-2.44, p = 0.001), trunk FMI (ß = 0.57, 95% CI = 0.04-1.10, p = 0.036), and arm FMI (ß = 0.96, 95% CI = 0.33-1.59, p = 0.004) were significantly associated with PHQ-9 (Patient Health Questionnaire-9) scores, whereas the leg FMI was not (p = 0.102). The weighted association between total FMI and depressive symptoms did not differ significantly between most of the subpopulations (all p values for interaction > 0.05). The risk of having depression was higher in individuals who were non-Hispanic Whites, smokers, drinkers, obese, and had diabetes and thyroid problems (p < 0.05). CONCLUSION: These findings suggest that the population with a higher regional FMI is more likely to have depressive symptoms, especially in those who also have an increased total FMI. The association is more pronounced in individuals who are smokers, drinkers, obese, and have diabetes and thyroid problems.

Distinct roles of nuclear basket proteins in directing the passage of mRNA through the nuclear pore.

The in vivo characterization of the exact copy number and the specific function of each composite protein within the nuclear pore complex (NPC) remains both desirable and challenging. Through the implementation of live-cell high-speed super-resolution single-molecule microscopy, we first quantified the native copies of nuclear basket (BSK) proteins (Nup153, Nup50, and Tpr) prior to knocking them down in a highly specific manner via an auxin-inducible degron strategy. Second, we determined the specific roles that BSK proteins play in the nuclear export kinetics of model messenger RNA (mRNA) substrates. Finally, the three-dimensional (3D) nuclear export routes of these mRNA substrates through native NPCs in the absence of specific BSK proteins were obtained and further validated via postlocalization computational simulations. We found that these BSK proteins possess the stoichiometric ratio of 1:1:1 and play distinct roles in the nuclear export of mRNAs within live cells. The absence of Tpr from the NPC predominantly reduces the probability of nuclear mRNAs entering the NPC for export. Complete depletion of Nup153 and Nup50 results in an mRNA nuclear export efficiency decrease of approximately four folds. mRNAs can gain their maximum successful export efficiency as the copy number of Nup153 increased from zero to only half the full complement natively within the NPC. Lastly, the absence of Tpr or Nup153 seems to alter the 3D export routes of mRNAs as they pass through the NPC. However, the removal of Nup50 alone has almost no impact upon mRNA export route and kinetics.

microRNA-3037 targeting CYP6CY2 confers imidacloprid resistance to Sitobion miscanthi (Takahashi).

The wheat aphid Sitobion miscanthi is a dominant and destructive pest in agricultural production. Insecticides are the main substances used for effective control of wheat aphids. However, their extensive application has caused severe resistance of wheat aphids to some insecticides; therefore, exploring resistance mechanisms is essential for wheat aphid management. In the present study, CYP6CY2, a new P450 gene, was isolated and overexpressed in the imidacloprid-resistant strain (SM-R) compared to the imidacloprid-susceptible strain (SM-S). The increased sensitivity of S. miscanthi to imidacloprid after knockdown of CYP6CY2 indicates that it could be associated with imidacloprid resistance. Subsequently, the posttranscriptional regulation of CYP6CY2 in the 3' UTR by miR-3037 was confirmed, and CYP6CY2 participated in imidacloprid resistance. This finding is critical for determining the role of P450 in relation to the resistance of S. miscanthi to imidacloprid. It is of great significance to understand this regulatory mechanism of P450 expression in the resistance of S. miscanthi to neonicotinoids.

Influence of formaldehyde exposure on the molecules of the NO/cGMP-cAMP signaling pathway in different brain regions of Balb/c mice.

This toxicology study was conducted to assess the impact of formaldehyde, a common air pollutant found in Chinese gymnasiums, on the brain function of athletes. In this research, a total of 24 Balb/c male mice of SPF-grade were divided into four groups, each consisting of six mice. The mice were exposed to formaldehyde at different concentrations, including 0 mg/m3, 0.5 mg/m3, 3.0 mg/m3, and 3.0 mg/m3 in combination with an injection of L-NMMA (NG-monomethyl-L-arginine), which is a nitric oxide synthase antagonist. Following a one-week test period (8 h per day, over 7 days), measurements of biomarkers related to the nitric oxide (NO)/cGMP-cAMP signaling pathway were carried out on the experimental animals post-treatment. The study found that: (1) Exposure to formaldehyde can lead to brain cell apoptosis and neurotoxicity; (2) Additionally, formaldehyde exposure was found to alter the biomarkers of the NO/cGMP-cAMP signaling pathway, with some changes being statistically significant (p < 0.05 or p < 0.01); (3) The use of L-NMMA, an antagonist of the NO/cGMP-cAMP signaling pathway, was found to prevent these biomarker changes and had a protective effect on brain cells. The study suggests that the negative impact of formaldehyde on the brain function of mice is linked to the regulation of the NO/cGMP-cAMP signaling pathway.

Sodium Citrate Nanoparticles Induce Dual-Path Pyroptosis for Enhanced Antitumor Immunotherapy through Synergistic Ion Overload and Metabolic Disturbance.

Metabolic reprogramming, as one of the characteristics of cancer, is associated with tumorigenesis, growth, or migration, and the modulation of metabolic pathways has emerged as a novel approach for cancer therapy. However, the conventional metabolism-mediated apoptosis process in tumor cells exhibits limited immunogenicity and inadequate activation of antitumor immunity. Herein, phospholipid-coated sodium citrate nanoparticles (PSCT NPs) are successfully prepared, which dissolve in tumor cells and then release significant amounts of citrate ions and Na+ ions. Massive quantities of ions lead to increased intracellular osmotic pressure, which activates the caspase-1/gasdermin D (GSDMD) mediated pyroptosis pathway. Simultaneously, citrate induces activation of the caspase-8/gasdermin C (GSDMC) pathway. The combined action of these two pathways synergistically causes intense pyroptosis, exhibiting remarkable antitumor immune responses and tumor growth inhibition. This discovery provides new insight into the potential of nanomaterials in modulating metabolism and altering cell death patterns to enhance antitumor immunotherapy.

Efficacy of Community Health Worker-Delivered Family Health History-Based Breast Cancer Education and Services Among Chinese Americans.

Family health history (FHH) is an evidence-based genomics tool used in cancer prevention and education. Chinese Americans, the largest Asian American group, face unique barriers in FHH collection and communication. This study aimed to evaluate the efficacy of culturally and linguistically appropriate community health worker (CHW)-delivered FHH-based breast cancer (BC) education and services to Chinese Americans. A total of 1129 Chinese Americans received FHH-based BC education and service delivered by our trained Chinese American CHWs. Participants responded to evaluation surveys before, immediately after, and 3 months after the education and service. Participating Chinese Americans showed significant increases in rates of collecting FHH of BC, discussing FHH of BC with family members, informing their primary care physicians of their FHH of BC, and discussing their FHH of BC with their primary care physicians at 3 months post-education and service compared to the baseline data (all Ps < 0.01). Attitudes, intention, and self-efficacy related to FHH of BC communication and collection and FHH of BC knowledge were improved both immediately after and 3 months after the delivery of the education and services (all Ps < 0.01). Within 3 months, ~ 14.3% of participants who had a high risk of BC based on FHH reported visiting geneticists for genetic evaluation. Our Chinese American CHW-delivered FHH-based BC education and services showed initial success in increasing knowledge, collection and communication of BC-related FHH, and genetic service utilization among Chinese American participants. This study can serve as a starting point for conducting more robust studies, such as randomized controlled trials, in the future.

Calcifying fibrous tumor and pathological analysis.

A 55-year-old male presented to our outpatient department with complaints of upper abdominal dull pain. Gastroscopy revealed a submucosal eminence at the greater curvature of the gastric body, with smooth surface mucosa, and biopsy pathology indicated inflammation. Physical examination showed no obvious abnormalities, and laboratory results were within the normal range. Computerized tomography (CT) showed thickening of the gastric body. Endoscopic submucosal dissection (ESD) was performed,and representative photomicrographs of histologic sections were shown.

Defect-Repaired g-C3N4 Nanosheets: Elevating the Efficacy of Sonodynamic Cancer Therapy Through Enhanced Charge Carrier Migration.

Sonodynamic therapy (SDT) has garnered growing interest owing to its high tissue penetration depth and minimal side effects. However, the lack of efficient sonosensitizers remains the primary limiting factor for the clinical application of this treatment method. Here, defect-repaired graphene phase carbon nitride (g-C3N4) nanosheets are prepared and utilized for enhanced SDT in anti-tumor treatment. After defect engineering optimization, the bulk defects of g-C3N4 are significantly reduced, resulting in higher crystallinity and exhibiting a polyheptazine imide (PHI) structure. Due to the more extended conjugated structure of PHI, facilitating faster charge transfer on the surface, it exhibits superior SDT performance for inducing apoptosis in tumor cells. This work focuses on introducing a novel carbon nitride nanomaterial as a sonosensitizer and a strategy for optimizing sonosensitizer performance by reducing bulk defects.

Glutathione Induced In situ Synthesis of Cu Single-Atom Nanozymes with Anaerobic Glycolysis Metabolism Interference for Boosting Cuproptosis.

Single-atom nanozyme (SAzyme) has sparked increasing interest for catalytic antitumor treatment due to their more tunable and diverse active sites than natural metalloenzymes in complex physiological conditions. However, it is usually a hard task to precisely conduct catalysis at tumor sites after intravenous injection of those SAzyme with high reactivity. Moreover, the explorations of SAzymes in the anticancer application are still in its infancy and need to be developed. Herein, an in situ synthesis strategy for Cu SAzyme was constructed to convert adsorbed copper ions into isolated atoms anchored by oxygen atoms (Cu-O2/Cu-O4) via GSH-responsive deformability of supports. Our results suggest that the in situ activation process could further facilitate the dissociation of copper ions and the consumption of glutathione, thereby leading to copper deposition in cytoplasm and triggering cuproptosis. Moreover, the in situ synthesis of Cu SAzyme with peroxidase-like activity enabled the intracellular reactive oxygen species production, resulting in specifically disturbance of copper metabolism pathway. Meanwhile, the in situ exposed glucose transporter (GLUT) inhibitor phloretin (Ph) can block the glycose uptake to boost cuproptosis efficacy. Overall, this in situ activation strategy effectively diminished the off-target effects of SACs-induced catalytic therapies and introduced a promising treatment paradigm for advancing cuproptosis-associated therapies.

Heterostructural Nanoadjuvant CuSe/CoSe2 for Potentiating Ferroptosis and Photoimmunotherapy through Intratumoral Blocked Lactate Efflux.

The desirable curative effect in clinical immunotherapy has been challenging due to the immunosuppressive tumor microenvironment (TME) with high lactic acid (LA) metabolism in solid tumors. Although targeting metabolic reprogramming of tumor cells can restore the survival and function of immune cells in the TME, it is also plagued by insufficient immunogenicity. Herein, an activatable immunomodulatory nanoadjuvant CuSe/CoSe2@syrosingopine (CSC@Syro) is constructed for simultaneously relieving immunosuppressive TME and boosting tumor immune response. Specifically, CuSe/CoSe2 (CSC) exhibits TME-activated glutathione (GSH) depletion and hydroxyl radical (•OH) generation for potential ferroptosis. Meanwhile, the remarkable photothermal conversion efficiency and elevated photocatalytic ROS level both promote CSC heterostructures to induce robust immunogenic cell death (ICD). Besides, the loaded syrosingopine inhibitor achieves LA metabolism blockade in cancer cells by downregulating the expression of monocarboxylate transporter 4 (MCT4), which could sensitize ferroptosis by intracellular milieu acidification and neutralize the acidic TME to alleviate immunosuppression. Hence, advanced metabolic modulation confers the potentiated immune infiltration of ICD-stimulated T lymphocytes and further reinforces antitumor therapy. In brief, CSC@Syro-mediated synergistic therapy could elicit potent immunogenicity and suppress tumor proliferation and metastasis effectually by integrating the tumor metabolic regulation and ferroptosis with immunotherapy.

Dendritic Plasmonic CuPt Alloys for Closed-Loop Multimode Cancer Therapy with Remarkably Enhanced Efficacy.

The outcome of laser-triggered plasmons-induced phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is significantly limited by the hypoxic tumor microenvironment and the upregulation of heat shock proteins (HSPs) in response to heat stress. Mitochondria, the biological battery of cells, can serve as an important breakthrough to overcome these obstacles. Herein, dendritic triangular pyramidal plasmonic CuPt alloys loaded with heat-sensitive NO donor N, N'-di-sec-butyl-N, N'-dinitroso-1,4-phenylenediamine (BNN) is developed. Under 808 nm laser irradiation, plasmonic CuPt can generate superoxide anion free radicals (·O2 - ) and heat simultaneously. The heat generated can then trigger the release of NO gas, which not only enables gas therapy but also damages the mitochondrial respiratory chain. Impaired mitochondrial respiration leads to reduced oxygen consumption and insufficient intracellular ATP supply, which effectively alleviates tumor hypoxia and undermines the synthesis of HSPs, in turn boosting plasmonic CuPt-based PDT and mild PTT. Additionally, the generated NO and ·O2 - can react to form more cytotoxic peroxynitrite (ONOO- ). This work describes a plasmonic CuPt@BNN (CPB) triggered closed-loop NO gas, free radicals, and mild photothermal therapy strategy that is highly effective at reciprocally promoting antitumor outcomes.

Fe(III)-Naphthazarin Metal-Phenolic Networks for Glutathione-Depleting Enhanced Ferroptosis-Apoptosis Combined Cancer Therapy.

Nowadays, Fenton chemistry-based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H2 O2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one-step strategy for the construction of Fe3+ -naphthazarin metal-phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH2 -PEG-NH2 , is developed. The carrier-free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe3+ , which is further reduced to Fe2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)-triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe2+ as a T1 -weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.