Spatially Confined in Situ Formed Sodiophilic-Conductive Network for High-Performance Sodium Metal Batteries.

The sodium (Na) metal anode encounters issues such as volume expansion and dendrite growth during cycling. Herein, a novel three-dimensional flexible composite Na metal anode was constructed through the conversion-alloying reaction between Na and ultrafine Sb2S3 nanoparticles encapsulated within the electrospun carbon nanofibers (Sb2S3@CNFs). The formed sodiophilic Na3Sb sites and the high Na+-conducting Na2S matrix, coupled with CNFs, establish a spatially confined "sodiophilic-conductive" network, which effectively reduces the Na nucleation barrier, improves the Na+ diffusion kinetics, and suppresses the volume expansion, thereby inhibiting the Na dendrite growth. Consequently, the Na/Sb2S3@CNFs electrode exhibits a high Coulombic efficiency (99.94%), exceptional lifespan (up to 2800 h) at high current densities (up to 5 mA cm-2), and high areal capacities (up to 5 mAh cm-2) in symmetric cells. The coin-type full cells assembled with a Na3V2(PO4)3/C cathode demonstrate significant enhancement in electrochemical performance. The flexible pouch cell achieves an excellent energy density of 301 Wh kg-1.

Esketamine inhibits the c-Jun N-terminal kinase pathway in the spinal dorsal horn to relieve bone cancer pain in rats.

Cancer-induced bone pain (CIBP) is one of the most common and feared symptoms in patients with advanced tumors. The X-C motif chemokine ligand 12 (CXCL12) and the CXCR4 receptor have been associated with glial cell activation in bone cancer pain. Moreover, mitogen-activated protein kinases (MAPKs), as downstream CXCL12/CXCR4 signals, and c-Jun, as activator protein AP-1 components, contribute to the development of various types of pain. However, the specific CIBP mechanisms remain unknown. Esketamine is a non-selective N-methyl-d-aspartic acid receptor (NMDA) inhibitor commonly used as an analgesic in the clinic, but its analgesic mechanism in bone cancer pain remains unclear. We used a tumor cell implantation (TCI) model and explored that CXCL12/CXCR4, p-MAPKs, and p-c-Jun were stably up-regulated in the spinal cord. Immunofluorescence images showed activated microglia in the spinal cord on day 14 after TCI and co-expression of CXCL12/CXCR4, p-MAPKs (p-JNK, p-ERK, p-p38 MAPK), and p-c-Jun in microglia. Intrathecal injection of the CXCR4 inhibitor AMD3100 reduced JNK and c-Jun phosphorylations, and intrathecal injection of the JNK inhibitor SP600125 and esketamine also alleviated TCI-induced pain and reduced the expression of p-JNK and p-c-Jun in microglia. Overall, our data suggest that the CXCL12/CXCR4-JNK-c-Jun signaling pathway of microglia in the spinal cord mediates neuronal sensitization and pain hypersensitivity in cancer-induced bone pain and that esketamine exerts its analgesic effect by inhibiting the JNK-c-Jun pathway.

Periostin-TGF-ß feedforward loop contributes to tumour-stroma crosstalk in liver metastatic outgrowth of colorectal cancer.

BACKGROUND: This study aimed to investigate the underlying mechanisms of matricellular protein periostin (POSTN) on tumour-stroma crosstalk in the liver metastatic microenvironment of colorectal cancer (CRC). METHODS: Postn-knockout mice and hepatic Postn-overexpressing mice were used to investigate the functions of POSTN on the formation of fibrotic microenvironment and the tumour-stroma crosstalk in the liver metastatic microenvironment of CRC. Clinical samples and database were analyzed to show the correlation between POSTN expression and fibrotic features and TGF-ß signalling in metastatic livers of CRC. RESULTS: POSTN deficiency reduced hepatic stellate cell (HSC) activation and liver metastasis, whereas POSTN overexpression in the liver significantly augmented the formation of a fibrotic microenvironment to support the liver metastatic growth of CRC cells in mice. Moreover, HSC-derived POSTN promoted TGF-ß1 expression in CRC cells through the integrin/FAK/ERK/STAT3 pathway; conversely, tumour cell-derived TGF-ß1 induced POSTN expression in HSCs via the Smad pathway. POSTN levels correlated with fibrotic features and TGF-ß signalling in metastatic liver tissues of CRC patients. CONCLUSIONS: POSTN and TGF-ß1 cooperatively contribute to the tumour-stroma crosstalk by forming a supporting fibrotic microenvironment to promote liver metastasis of CRC cells via the POSTN/integrin/FAK/ERK/STAT3/TGF-ß axis in tumour cells and TGF-ß/Smad/POSTN signalling in activated HSCs.

Periodic Defect Engineering of Iron-Nitrogen-Carbon Catalysts for Nitrate Electroreduction to Ammonia.

Iron-nitrogen-carbon single atom catalyst (SAC) is regarded as one of the promising electrocatalysts for NO3 - reduction reaction (NO3 RR) to NH3 due to its high activity and selectivity. However, synergistic effects of topological defects and FeN4 active moiety in Fe-N-C SAC have rarely been investigated. By performing density functional theory (DFT) calculations, 13 defective graphene FeN4 with 585, 484, and 5775 topological line defects are constructed, yielding 585-68-FeN4 with optimal NO3 RR catalytic activity, high selectivity, as well as robust anti-dissolution stability. The high NO3 RR activity on 585-68-FeN4 is well explained by the high valence state of Fe center as well as asymmetric charge distribution on FeN4 moiety influenced by 5- and 8-member rings. This DFT work provides theoretical guidance for engineering NO3 RR performance of iron-nitrogen-carbon catalysts by modulating periodic topological defects.

ANGPTL4 regulates ovarian cancer progression by activating the ERK1/2 pathway.

BACKGROUND: Ovarian cancer (OC) has the highest mortality rate among all gynecological malignancies. A hypoxic microenvironment is a common feature of solid tumors, including ovarian cancer, and an important driving factor of tumor cell survival and chemo- and radiotherapy resistance. Previous research identified the hypoxia-associated gene angiopoietin-like 4 (ANGPTL4) as both a pro-angiogenic and pro-metastatic factor in tumors. Hence, this work aimed to further elucidate the contribution of ANGPTL4 to OC progression. METHODS: The expression of hypoxia-associated ANGPTL4 in human ovarian cancer was examined by bioinformatics analysis of TCGA and GEO datasets. The CIBERSORT tool was used to analyze the distribution of tumor-infiltrating immune cells in ovarian cancer cases in TCGA. The effect of ANGPTL4 silencing and overexpression on the proliferation and migration of OVCAR3 and A2780 OC cells was studied in vitro, using CCK-8, colony formation, and Transwell assays, and in vivo, through subcutaneous tumorigenesis assays in nude mice. GO enrichment analysis and WGCNA were performed to explore biological processes and genetic networks associated with ANGPTL4. The results obtained were corroborated in OC cells in vitro by western blotting. RESULTS: Screening of hypoxia-associated genes in OC-related TCGA and GEO datasets revealed a significant negative association between ANGPTL4 expression and patient survival. Based on CIBERSORT analysis, differential representation of 14 distinct tumor-infiltrating immune cell types was detected between low- and high-risk patient groups. Silencing of ANGPTL4 inhibited OVCAR3 and A2780 cell proliferation and migration in vitro and reduced the growth rate of xenografted OVCAR3 cells in vivo. Based on results from WGCNA and previous studies, western blot assays in cultured OC cells demonstrated that ANGPTL4 activates the Extracellular signal-related kinases 1 and 2 (ERK1/2) pathway and this results in upregulation of c-Myc, Cyclin D1, and MMP2 expression. Suggesting that the above mechanism mediates the pro-oncogenic actions of ANGPTL4T in OC, the pro-survival effects of ANGPTL4 were largely abolished upon inhibition of ERK1/2 signaling with PD98059. CONCLUSIONS: Our work suggests that the hypoxia-associated gene ANGPTL4 stimulates OC progression through activation of the ERK1/2 pathway. These findings may offer a new prospect for targeted therapies for the treatment of OC.

E3 ubiquitin ligase RNF187 promotes growth of spermatogonia via lysine 48-linked polyubiquitination-mediated degradation of KRT36/KRT84.

Ubiquitination is the most common post-translational modification and is essential for various cellular regulatory processes. RNF187, which is known as RING domain AP1 coactivator-1, is a member of the RING finger family. RNF187 can promote the proliferation and migration of various tumor cells. However, whether it has a similar role in regulating spermatogonia is not clear. This study explored the role and molecular mechanism of RNF187 in a mouse spermatogonia cell line (GC-1). We found that RNF187 knockdown reduced the proliferation and migration of GC-1 cells and promoted their apoptosis. RNF187 overexpression significantly increased the proliferation and migration of GC-1 cells. In addition, we identified Keratin36/Keratin84 (KRT36/KRT84) as interactors with RNF187 by co-immunoprecipitation and mass spectrometry analyses. RNF187 promoted GC-1 cell growth by degrading KRT36/KRT84 via lysine 48-linked polyubiquitination. Subsequently, we found that KRT36 or KRT84 overexpression significantly attenuated proliferation and migration of RNF187-overexpressing GC-1 cells. In summary, our study explored the involvement of RNF187 in regulating the growth of spermatogonia via lysine 48-linked polyubiquitination-mediated degradation of KRT36/KRT84. This may provide a promising new strategy for treating infertility caused by abnormal spermatogonia development.

Assessing the causal association between dietary vitamin intake and lymphoma risk: a Mendelian randomisation study.

Observational studies of diet-related vitamins and lymphoma risk results were inconsistent. Our study aimed to estimate the causality between dietary vitamin intake and lymphoma through a Mendelian randomisation (MR) study. We enrolled dietary-related retinol, vitamin C, vitamin E, vitamin B6 and vitamin B12 as exposures of interest, with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) as the outcome. The causal effects were estimated using inverse variance weighting (IVW), MR-Egger regression analysis and weighted median, supplemented by sensitivity analyses. The results revealed that genetically predicted dietary vitamin B12 intake was associated with a reduced HL risk (OR = 0.22, 95% CI 0.05-0.91, p = 0.036). The Q test did not reveal heterogeneity, the MR-Egger test showed no significant intercepts, and the leave-one-out (LOO) analysis did not discover any SNP that affect the results. No causal relationship about dietary vitamin intake on the NHL risk was observed.

Heat shock protein HvHSP16.9 from wild barley enhances tolerance to salt stress.

Heat shock proteins (HSPs) are known to play a crucial role in the response of plants to environmental stress, particularly heat stress. Nevertheless, the function of HSPs in salt stress tolerance in plants, especially in barley, remains largely unexplored. Here, we aimed to investigate and compare the salt tolerance mechanisms between wild barley EC_S1 and cultivated barley RGT Planet through a comprehensive analysis of physiological parameters and transcriptomic profiles. Results demonstrated that the number of differentially expressed genes (DEGs) in EC_S1 was significantly higher than in RGT Planet, indicating that wild barley gene regulation is more adaptive to salt stress. KEGG enrichment analysis revealed that DEGs were mainly enriched in the processes of photosynthesis, plant hormone signal transduction, and reactive oxygen species metabolism. Furthermore, the application of weighted gene correlation network analysis (WGCNA) enabled the identification of a set of key genes, including small heat shock protein (sHSP), Calmodulin-like proteins (CML), and protein phosphatases 2C (PP2C). Subsequently, a novel sHSP gene, HvHSP16.9 encoding a protein of 16.9 kDa, was cloned from wild barley, and its role in plant response to salt stress was elucidated. In Arabidopsis, overexpression of HvHSP16.9 increased the salt tolerance. Meanwhile, barley stripe mosaic virus-induced gene silencing (BSMV-VIGS) of HvHSP16.9 significantly reduced the salt tolerance in wild barley. Overall, this study offers a new theoretical framework for comprehending the tolerance and adaptation mechanisms of wild barley under salt stress. It provides valuable insights into the salt tolerance function of HSP, and identifies new candidate genes for enhancing cultivated barley varieties. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01455-4.

CO Intermediate-Assisted Dynamic Cu Sintering During Electrocatalytic CO2 Reduction on Cu-N-C Catalysts.

The electrochemical CO2 reduction reaction (eCO2RR) to multicarbon products has been widely recognized for Cu-based catalysts. However, the structural changes in Cu-based catalysts during the eCO2RR pose challenges to achieving an in-depth understanding of the structure-activity relationship, thereby limiting catalyst development. Herein, we employ constant-potential density functional theory calculations to investigate the sintering process of Cu single atoms of Cu-N-C single-atom catalysts into clusters under eCO2RR conditions. Systematic constant-potential ab initio molecular dynamics simulations revealed that the leaching of Cu-(CO)x moieties and subsequent agglomeration into clusters can be facilitated by synergistic adsorption of H and eCO2RR intermediates (e.g., CO). Increasing the Cu2+ concentration or the applied potential can efficiently suppress Cu sintering. Both microkinetic simulations and experimental results further confirm that sintered Cu clusters play a crucial role in generating C2 products. These findings provide significant insights into the dynamic evolution of Cu-based catalysts and the origin of their activity toward C2 products during the eCO2RR.

Activation of E3 ubiquitin ligase WWP2 by non-receptor tyrosine kinase ACK1.

WW domain containing E3 ubiquitin protein ligase 2 (WWP2) is a member of the NEDD4 E3 ubiquitin ligase family. WWP2 ligase activity is regulated by the 2, 3-linker auto-inhibition. Tyrosine phosphorylation of the 2, 3-linker was identified as an activating means for releasing the auto-inhibition of WWP2. However, the tyrosine kinase (TK) for the phosphorylation and activation remains unknown. In this report, we have found that non-receptor TK ACK1 binds to the WW3 domain of WWP2 and phosphorylates WWP2. ACK1 phosphorylates WWP2 at the 2, 3-linker and partially activates the ubiquitination ligase activity. Unexpectedly, tyrosine phosphorylation of the 2, 3-linker seems not a major mode for activation of WWP2, as ACK1 causes much higher activation of the 2, 3-linker tyrosine phosphorylation defective mutants of WWP2 than that of wild-type WWP2. Furthermore, epidermal growth factor (EGF) stimulates tyrosine phosphorylation of WWP2 and this EGF-stimulated phosphorylation of WWP2 is mediated by ACK1. Finally, knockdown of WWP2 by shWWP2 inhibits the EGF-dependent cell proliferation of lung cancer A549 cells, suggesting that WWP2 may function in the EGFR signaling in lung cancer progression. Taken together, our findings have revealed a novel mechanism underlying activation of WWP2.

Theoretical Study on B-doped FeN4 Catalyst for Potential-Dependent Oxygen Reduction Reaction.

Electrochemical reactions mostly take place at a constant potential, but traditional DFT calculations operate at a neutral charge state. In order to really model experimental conditions, we developed a fixed-potential simulation framework via the iterated optimization and self-consistence of the required Fermi level. The B-doped graphene-based FeN4 sites for oxygen reduction reaction were chosen as the model to evaluate the accuracy of the fixed-potential simulation. The results demonstrate that *OH hydrogenation gets facile while O2 adsorption or hydrogenation becomes thermodynamically unfavorable due to the lower d-band center of Fe atoms in the constant potential state than the neutral charge state. The onset potential of ORR over B-doped FeN4 by performing potential-dependent simulations agree well with experimental findings. This work indicates that the fixed-potential simulation can provide a reasonable and accurate description on electrochemical reactions.

Genome sequence analysis of H7N3 subtype avian influenza virus originated from wild birds and its potential infectivity in mice.

In 2021, an H7N3 avian influenza virus (AIV) was isolated from a mallard in Tianhewan Yellow River National Wetland Park, Ningxia Hui Autonomous Region, China. Sequences analysis showed that this strain received its genes from H7, H6, H5, H3, and H1 AIVs of domestic poultry and wild birds in Asia and Europe. It was mild pathogenicity in mice. These results suggest the importance of continued surveillance of the H7N3 virus to better understand the ecology and evolution of the AIVs in poultry and wild birds and the potential threat to humans.

Dengue fever and dengue virus in the People's Republic of China.

Infection with dengue virus (DENV) leads to symptoms variable from dengue fever to severe dengue, which has posed a huge socioeconomic and disease burden to the world population, particularly in tropical and subtropical regions. To date, four serotypes of DENV (DENV-1 to DENV-4) have been identified to sustain the transmission cycle in humans. In the past decades, dengue incidences have become more frequent, and four serotypes and various genotypes have been identified in PR China. Several large-scale dengue outbreaks and frequent local endemics occurred in the southern and coastal provinces, and the imported dengue cases accounted primarily for the initiation of the epidemics. No antiviral drug exists for dengue, and no vaccine has been approved to use in PR China, however strategies including public awareness, national reporting system of infectious diseases and public health emergencies, vector mosquito control, personal protection, and improved environmental sanitation have greatly reduced dengue prevalence. Some new technologies in vector mosquito control are emerging and being applied for dengue control. China's territory spans tropical, subtropical, and temperate climates, hence understanding the dengue status in China will be of beneficial for the global prevention and control of dengue. Here, we review the dengue status in PR China for the past decades and the strategies emerging for dengue control.

The interaction effect of transfusion history and previous stroke history on the risk of venous thromboembolism in stroke patients: a prospective cohort study.

BACKGROUND: Blood transfusion and previous stroke history are two independent risk factors of venous thromboembolism (VTE) in stroke patients. Whether the potential interaction of transfusion history and previous stroke history is associated with a greater risk of VTE remains unclear. This study aims to explore whether the combination of transfusion history and previous stroke history increases the risk of VTE among Chinese stroke patients. METHODS: A total of 1525 participants from the prospective Stroke Cohort of Henan Province were enrolled in our study. Multivariate logistic regression models were used to explore the associations among transfusion history, previous stroke history and VTE. The interaction was evaluated on both multiplicative and additive scales. The odds ratio (95% CI), relative excess risk of interaction (RERI), attributable proportion (AP), and synergy index (S) of interaction terms were used to examine multiplicative and additive interactions. Finally, we divided our population into two subgroups by National Institutes of Health Stroke Scale (NIHSS) score and re-evaluated the interaction effect in both scales. RESULTS: A total of 281 (18.4%) participants of 1525 complicated with VTE. Transfusion and previous stroke history were associated with an increased risk of VTE in our cohort. In the multiplicative scale, the combination of transfusion and previous stroke history was statistically significant on VTE in both unadjusted and adjusted models (P<0.05). For the additive scale, the RERI shrank to 7.016 (95% CI: 1.489 ~ 18.165), with the AP of 0.650 (95% CI: 0.204 ~ 0.797) and the S of 3.529 (95% CI: 1.415 ~ 8.579) after adjusting for covariates, indicating a supra-additive effect. In subgroups, the interaction effect between transfusion history and previous stroke history was pronouncedly associated with the increased risk of VTE in patients with NIHSS score > 5 points (P<0.05). CONCLUSIONS: Our results suggest that there may be a potential synergistic interaction between transfusion history and previous stroke history on the risk of VTE. Besides, the percentage of VTE incidence explained by interaction increased with the severity of stroke. Our findings will provide valuable evidence for thromboprophylaxis in Chinese stroke patients.

Non-hippo kinases: indispensable roles in YAP/TAZ signaling and implications in cancer therapy.

The transcriptional co-activators Yes-associated protein (YAP) and PDZ-binding domain (TAZ) are the known downstream effectors of the Hippo kinase cascade. YAP/TAZ have been shown to play important roles in cellular growth and differentiation, tissue development and carcinogenesis. Recent studies have found that, in addition to the Hippo kinase cascade, multiple non-Hippo kinases also regulate the YAP/TAZ cellular signaling and produce important effects on cellular functions, particularly on tumorigenesis and progression. In this article, we will review the multifaceted regulation of the YAP/TAZ signaling by the non-Hippo kinases and discuss the potential application of the non-Hippo kinase-regulated YAP/TAZ signaling for cancer therapy.

Exosomes derived from stem cells from apical papilla promote angiogenesis via miR-126 under hypoxia.

OBJECTIVES: To explore the effect of exosomal miR-126 derived from stem cells from the apical papilla (SCAPs) under hypoxia on human umbilical vein endothelial cell (HUVEC) angiogenesis. METHODS: miR-126 mimics plasmids were used to upregulate miR-126 in SCAPs. Internalization of PKH26-labeled exosomes was examined by fluorescent microscopy. CCK-8 assay, Transwell assay, scratch assay, tube formation assay, and Matrigel plug assay were performed to detect the effects of exosomes on the angiogenic ability of HUVECs. The luciferase reporter assay and rescue assay were performed to examine the relationship between miR-126 and sprouty-related, EVH1 domain-containing protein 1 (SPRED1). The involvement of SPRED1 and the extracellular signal-regulated kinase (ERK) signaling pathway was evaluated by western blotting. RESULTS: miR-126 expression was upregulated in SCAPs and in SCAP-derived exosomes under hypoxia. miR-126 expression was increased in HUVECs when cocultured with SCAP-derived exosomes. Induced overexpression of miR-126 in hypoxic SCAPs and secreted exosomes resulted in enhanced angiogenesis both in vitro and in vivo. Western blot analysis revealed that miR-126-mediated SPRED1 downregulation induced activation of ERK signaling. CONCLUSIONS: Under hypoxic conditions, exosomes derived from SCAPs can promote HUVEC angiogenesis through expression of miR-126, which subsequently suppresses SPRED1 and activates the ERK signaling pathway.

Effect of curcumin on regulatory B cells in chronic colitis mice involving TLR/MyD88 signaling pathway.

Curcumin (Cur) is a natural active phenolic compound extracted from the root of Curcuma Longa L. It has anti-inflammatory, anti-tumor and other pharmacological activities, and is commonly used to treat ulcerative colitis (UC). However, it is not clear whether curcumin regulates the function and differentiation of Breg cells to treat UC. In this study, mice with chronic colitis were induced by dextran sulfate sodium (DSS), and treated with curcumin for 12 days. Curcumin effectively improved the body weight, colonic weight, colonic length, decreased colonic weight index and pathological injury score under colonoscopy in mice with chronic colitis, and significantly inhibited the production of IL-1ß, IL-6, IL-33, CCL-2, IFN-γ, TNF-α, and promoted the secretion of IL-4, IL-10, IL-13 and IgA. Importantly, curcumin markedly upregulated CD3- CD19+ CD1d+ , CD3- CD19+ CD25+ , CD3- CD19+ Foxp3+ Breg cells level and significantly down-regulated CD3- CD19+ PD-L1+ , CD3- CD19+ tim-1+ , CD3- CD19+ CD27+ Breg cells level. In addition, our results also showed that curcumin observably inhibited TLR2, TLR4, TLR5, MyD88, IRAK4, p-IRAK4, NF-κB P65, IRAK1, TRAF6, TAB1, TAB2, TAK1, MKK3, MKK6, p38MAPK, p-p38MAPK and CREB expression in TLR/MyD88 signaling pathway. These results suggest that curcumin can regulate the differentiation and function of Breg cell to alleviate DSS-induced colitis, which may be realized by inhibiting TLR/MyD88 pathway.

Inhibitory Effects of Corydalis saxicola Bunting Total Alkaloids on Macrophage Pyroptosis.

This study investigated the effect of Corydalis saxicola Bunting total alkaloids (CSBTA) on pyroptosis in macrophages (Mϕ). In the Mϕ pyroptosis model, an inverted fluorescence microscope was used to assess cell pyroptosis, while a scanning electron microscope was used to observe morphological changes in Mϕ. NLR family pyrin domain-containing 3 (NLRP3), caspase-1, and gasdermin D (GSDMD) expression levels were detected by polymerase chain reaction and western blotting, whereas interleukin-1 (IL-1) and interleukin-18 (IL-18) expression levels were measured by an enzyme-linked immunosorbent assay. After pretreatment with CSBTA or the caspase-1 inhibitor, acetyl-tyrosyl-valyl-alanyl-aspartyl-chloromethylketone (Ac-YVAD-cmk), it was discovered that NLRP3, caspase-1, and GSDMD expressions were significantly reduced at both the mRNA and protein levels, as were IL-1 and IL-18 levels. The inhibitory effects of CSBTA and Ac-YVAD-cmk did not differ significantly. These findings indicate that CSBTA blocks Porphyromonas gingivalis-lipopolysaccharide-induced Mϕ pyroptosis.

A DNA Origami-based Bactericide for Efficient Healing of Infected Wounds.

Bacteria infection is a significant obstacle in the clinical treatment of exposed wounds facing widespread pathogens. Herein, we report a DNA origami-based bactericide for efficient anti-infection therapy of infected wounds in vivo. In our design, abundant DNAzymes (G4/hemin) can be precisely organized on the DNA origami for controllable generation of reactive oxygen species (ROS) to break bacterial membranes. After the destruction of the membrane, broad-spectrum antibiotic levofloxacin (LEV, loaded in the DNA origami through interaction with DNA duplex) can be easily delivered into the bacteria for successful sterilization. With the incorporation of DNA aptamer targeting bacterial peptidoglycan, the DNA origami-based bactericide can achieve targeted and combined antibacterial therapy for efficiently promoting the healing of infected wounds. This tailored DNA origami-based nanoplatform provides a new strategy for the treatment of infectious diseases in vivo.

Genetically Encoded Double-Stranded DNA-Based Nanostructure Folded by a Covalently Bivalent CRISPR/dCas System.

DNA nanotechnology has been widely employed in the construction of various functional nanostructures. However, most DNA nanostructures rely on hybridization between multiple single-stranded DNAs. Herein, we report a general strategy for the construction of a double-stranded DNA-ribonucleoprotein (RNP) hybrid nanostructure by folding double-stranded DNA with a covalently bivalent clustered regularly interspaced short palindromic repeats (CRISPR)/nuclease-dead CRISPR-associated protein (dCas) system. In our design, dCas9 and dCas12a can be efficiently fused together through a flexible and stimuli-responsive peptide linker. After activation by guide RNAs, the covalently bivalent dCas9-12a RNPs (staples) can precisely recognize their target sequences in the double-stranded DNA scaffold and pull them together to construct a series of double-stranded DNA-RNP hybrid nanostructures. The genetically encoded hybrid nanostructure can protect genetic information in the folded state, similar to the natural DNA-protein hybrids present in chromosomes, and elicit efficient stimuli-responsive gene transcription in the unfolded form. This rationally developed double-stranded DNA folding and unfolding strategy presents a new avenue for the development of DNA nanotechnology.