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Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy. Radiotherapy has the potential to induce immunogenic cell death (ICD), however radiation-induced immune responses are often limited. Here the authors design gadolinium-based nanoscale coordination polymers to amplify radiation-mediated oxidative stress, promoting ICD and anti-tumor immune responses.

The irradiated tumor itself represents an opportunity to establish endogenous in situ vaccines. However, such in situ cancer vaccination (ISCV) triggered by radiation therapy (RT) alone is very weak and hardly elicits systemic anticancer immunity. In this study, we develop two-dimensional risedronate-manganese nanobelts (RMn-NBs) as an adjuvant for RT to address this issue. RMn-NBs exhibit good T 2 magnetic resonance imaging performance and enhanced Fenton-like catalytic activity, which induces immunogenic cell death. RMn-NBs can inhibit the HIF-1α/VEGF axis to empower RT and synchronously activate the cGAS/STING pathway for promoting the secretion of type I interferon, thereby boosting RT-triggered ISCV and immune checkpoint blockade therapy against primary and metastatic tumors. RMn-NBs as a nano-adjuvant for RT show good biocompatibility and therapeutic efficacy, presenting a promising prospect for cancer radiotherapy and immunotherapy. Radiation therapy (RT) can induce immunogenic cell death and elicit anti-tumor immune responses. Here the authors report the design and characterization of a risedronate-manganese-based nanosystem for in situ vaccination, amplifying RT-mediated anti-tumor immunity in preclinical models.

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8 + T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches. Radiation-induced tumor vaccination is insufficient to elicit robust antitumor immune response. Here they combine chiral vidarabine monophosphate-gadolinium nanowires with immune checkpoint blockade therapy to synergistically induce antitumor immunity. Reviewer recognition:

Nutrient avidity is one of the most distinctive features of tumours. However, nutrient deprivation has yielded limited clinical benefits. In Gaucher disease, an inherited metabolic disorder, cells produce cholesteryl-glucoside which accumulates in lysosomes and causes cell damage. Here we develop a nanoparticle (AbCholB) to emulate natural-lipoprotein-carried cholesterol and initiate Gaucher disease-like damage in cancer cells. AbCholB is composed of a phenylboronic-acid-modified cholesterol (CholB) and albumin. Cancer cells uptake the nanoparticles into lysosomes, where CholB reacts with glucose and generates a cholesteryl-glucoside-like structure that resists degradation and aggregates into microscale crystals, causing Gaucher disease-like damage in a glucose-dependent manner. In addition, the nutrient-sensing function of mTOR is suppressed. It is observed that normal cells escape severe damage due to their inferior ability to compete for nutrients compared with cancer cells. This work provides a bioinspired strategy to selectively impede the metabolic action of cancer cells by taking advantage of their nutrient avidity. Increased nutrient uptake of cancer cells offers a possible therapeutic target. Here, the authors designed a nanoparticle to deliver phenylboronic-acid-modified cholesterol which reacts in cancer cells to trigger Gaucher disease-like metabolic damage to tumour cells, demonstrating potential application.

The resistance of urinary tract pathogenic bacteria to various antibiotics is increasing, which requires the rapid detection of infectious pathogens for accurate and timely antibiotic treatment. Here, we propose a rapid diagnosis strategy for the antibiotic resistance of bacteria in urinary tract infections (UTIs) based on surface-enhanced Raman scattering (SERS) using a positively charged gold nanoparticle planar solid SERS substrate. Then, an intelligent identification model for SERS spectra based on the deep learning technique is constructed to realize the rapid, ultrasensitive, and non-labeled detection of pathogenic bacteria. A total of 54,000 SERS spectra were collected from 18 isolates belonging to 6 species of common UTI bacteria in this work to realize identification of bacterial species, antibiotic sensitivity, and multidrug resistance (MDR) via convolutional neural networks (CNN). This method significantly simplify the Raman data processing processes without background removing and smoothing, however, achieving 96% above classification accuracy, which was significantly greater than the 85% accuracy of the traditional multivariate statistical analysis algorithm principal component analysis combined with the K-nearest neighbor (PCA-KNN). This work clearly elucidated the potential of combining SERS and deep learning technique to realize culture-free identification of pathogenic bacteria and their associated antibiotic sensitivity.

Background Hypervirulent Klebsiella pneumoniae ( hvKP ) is emerging globally and can cause various, severe infections in healthy individuals. However, the clinical manifestations of hvKP infections are nonspecific, and there is no gold standard for differentiating hvKP strains. Our objective was to develop prognostic models for estimating severity of disease and predicting 30-day all-cause mortality in patients with hvKP infections. Methods We enrolled 116 patients diagnosed with hvKP infections and obtained their demographic and clinical data. Taking septic shock and acute respiratory distress syndrome (ARDS) as the primary outcomes for disease severity and 30-day all-cause mortality as the primary outcome for clinical prognosis, we explored the influencing factors and constructed prognostic models. Results The results showed that increased Acute Physiologic and Chronic Health Evaluation (APACHE) II score [odds ratio (OR) = 1.146; 95% confidence interval (CI), 1.059–1.240], decreased albumin (ALB) level (OR = 0.867; 95% CI, 0.758–0.990), diabetes (OR = 9.591; 95% CI, 1.766–52.075) and high procalcitonin (PCT) level (OR = 1.051; 95%CI, 1.005–1.099) were independent risk factors for septic shock. And increased APACHE II score (OR = 1.254; 95% CI, 1.110–1.147), community-acquired pneumonia (CAP) (OR = 11.880; 95% CI, 2.524–55.923), and extrahepatic lesion involved (OR = 14.718; 95% CI, 1.005–215.502) were independent risk factors for ARDS. Prognostic models were constructed for disease severity with these independent risk factors, and the models were significantly correlated with continuous renal replacement therapy (CRRT) duration, vasopressor duration, mechanical ventilator duration and length of ICU stay. The 30-day all-cause mortality rate in our study was 28.4%. Younger age [hazard ratio (HR) = 0.947; 95% CI, 0.923–0.973)], increased APACHE II score (HR = 1.157; 95% CI, 1.110–1.207), and decreased ALB level (HR = 0.924; 95% CI, 0.869–0.983) were the independent risk factors for 30-day all-cause mortality. A prediction model for 30-day mortality was constructed, which had a good validation effect. Conclusions We developed validated models containing routine clinical parameters for estimating disease severity and predicting 30-day mortality in patients with hvKP infections and confirmed their calibration. The models may assist clinicians in assessing disease severity and estimating the 30-day mortality early.

Adenosine deaminase acting on double-stranded RNA 1 (ADAR1) mediates adenosine-to-inosine (A-to-I) RNA editing events. ADAR1 is highly expressed in “septic” macrophages and in small intestinal tissues of mice with sepsis. Overexpression of ADAR1 suppresses inflammation and intestinal damage. However, the specific underlying mechanism is unclear. This study was conducted to explore how microRNA (miRNA) regulates the anti-inflammatory mechanism of macrophages following ADAR1 upregulation. A murine sepsis model was established by cecal ligation and puncture (CLP). Mice were randomly assigned to sham, CLP, and CLP+ADAR1 groups. Hematoxylin and eosin (HE) staining and fluorescence isothiocyanate-dextran were used to evaluate intestinal injury and permeability. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), western blotting, and Luminex assays were performed to detect changes in the expression of inflammatory cytokines. Adenoviruses were used to express ADAR1 in RAW 264.7 cells. Ribonucleoprotein immunoprecipitation analysis was conducted to detect the binding of ADAR1 and miRNAs. A dual-luciferase reporter assay was used to detect the binding of miRNAs and regulatory factors. We observed that ADAR1 significantly increased the expression of suppressor of cytokine signaling 3 (SOCS3) in macrophages and reduced the expression of interleukin-6 in macrophages and the serum, thereby reducing intestinal permeability and mucosal injury in mice with sepsis. The RNA-ribonucleoprotein immunoprecipitation binding assay and qRT-PCR demonstrated a direct interaction between ADAR1 and pri-miR-30a. The luciferase assay demonstrated that SOCS3 was significantly inhibited by miR-30a-5p, the mature product of miR-30a. Thus, ADAR1 exerts a protective effect against sepsis by reducing inflammation and organ damage via the ADAR1-miR-30a-SOCS3 axis.

The emergence of tigecycline-resistant tet(X2/X3/X4/X5) genes poses a new threat to the efficacy of anti-infective therapy and the safety of our food and environment. To control the transfer of such genes, a sensitive and rapid molecular method is warranted to detect tet(X2/X3/X4/X5) genes in clinical isolates. Herein, we established a loop-mediated isothermal amplification (LAMP) assay to rapidly detect tet(X2/X3/X4/X5) genes, and the results were assessed by chromogenic visualization. The specificity and sensitivity of the primers during the LAMP assay for the simultaneous detection of tet(X2/X3/X4/X5) genes were determined in this study. All 48 clinical strains without tet(X2/X3/X4/X5) genes yielded negative results during the LAMP assay, substantiating the high specificity of the LAMP primers. The detection thresholds of this assay were 1.5 × 10 2 CFU/ml and 0.2 fg/uL corresponding to a 10 to 100-fold and 100-fold increase in sensitivity compared to polymerase chain reaction (PCR) assays. Out of 52 bacterial strains tested, using PCR as a reference, our research revealed that the LAMP assay demonstrated a sensitivity and specificity of 100%. To sum up, our novel approach has huge prospects for application in the simultaneous detection of tet(X2/X3/X4/X5) genes and can be applied to detect other drug-resistance genes.

Carbapenem-resistant Enterobacteriaceae (CRE) is a major pathogen that poses a serious threat to human health. Unfortunately, currently, there are no effective measures to curb its rapid development. To address this, an in-depth study on the surface-enhanced Raman spectroscopy (SERS) of 22 strains of 7 categories of CRE using a gold silver composite SERS substrate was conducted. The residual networks with an attention mechanism to classify the SERS spectrum from three perspectives (pathogenic bacteria type, enzyme-producing subtype, and sensitive antibiotic type) were performed. The results show that the SERS spectrum measured by the composite SERS substrate was repeatable and consistent. The SERS spectrum of CRE showed varying degrees of species differences, and the strain difference in the SERS spectrum of CRE was closely related to the type of enzyme-producing subtype. The introduced attention mechanism improved the classification accuracy of the residual network (ResNet) model. The accuracy of CRE classification for different strains and enzyme-producing subtypes reached 94.0% and 96.13%, respectively. The accuracy of CRE classification by pathogen sensitive antibiotic combination reached 93.9%. This study is significant for guiding antibiotic use in CRE infection, as the sensitive antibiotic used in treatment can be predicted directly by measuring CRE spectra. Our study demonstrates the potential of combining SERS with deep learning algorithms to identify CRE without culture labels and classify its sensitive antibiotics. This approach provides a new idea for rapid and accurate clinical detection of CRE and has important significance for alleviating the rapid development of resistance to CRE.

The development of insertion‒deletion (InDel) markers provides a valuable tool for genetic and genomic studies in tea ( Camellia sinensis ) plants. In this study, 4,370,229 InDel markers were identified through genome resequencing of Lingtou Dancong (BY) and Shuixian 7 (SX7). Transcriptome based on RNA sequencing revealed differential expression of 1,125 genes involved in plant-pathogen interaction pathways. Based on genome resequencing of the two tea varieties with a shared genetic background and RNA-seq dataset for post-anthracnose infection, molecular markers for anthracnose resistance in tea plants were developed by identifying specific InDels within the disease resistance-associated interval. The InDel marker linked to anthracnose resistance was located at 123,508,930 bp on chromosome Chr10. Tea plants with DNA bands of 590-bp or heterozygous bands amplified by the primer were resistant to the disease, while those with 431-bp bands were susceptible. When tested across 206 different tea varieties, the Indel marker CsRc demonstrated an 88.59% genotype–phenotype match, confirming its applicability for detecting anthracnose resistance/susceptibility in tea plants. Additionally, the CsRc marker was found to be located within the serine/threonine protein kinase gene, suggesting that ATP plays a critical role in the metabolic processes of tea plants. Taken together, our findings unravel important Indel markers for efficiently distinguishing valuable tea genotpes with desirable resistance to anthracnose, which holds great potential for facilitating disease resistance breeding in the future. Graphical Abstract