The treatment of gram-negative bacterial infections remains a formidable challenge due to their resilient outer membrane and adaptive evasion mechanisms. Herein, we present a multifunctional nanozyme hydrogel, copper telluride@cationic guar gum (Cu_xTe@CG), which acts as a gram-negative-specific bactericidal platform. This hydrogel integrates the unique enzymatic and physical properties of urchin-like Cu_xTe nanozymes with the biocompatible and adhesive cationic guar gum (CG) matrix. The Cu_xTe@CG hydrogel exhibits synergistic oxidase- and glutathione peroxidase-like activities, catalyzing the generation of reactive oxygen species (ROS) while depleting bacterial glutathione, thereby inducing lethal oxidative stress. Crucially, transcriptome sequencing revealed that the platform specifically targets Pseudomonas aeruginosa by down-regulating key genes involved in lipopolysaccharide (LPS) biosynthesis and flagellar assembly, compromising their primary defense and motility structures. This targeted interference with LPS and flagella amplifies the ROS-mediated attack, leading to enhanced and specific killing of gram-negative pathogens (Escherichia coli, P. aeruginosa, and Klebsiella pneumoniae), effective biofilm disruption, and inhibition. In a P. aeruginosa-infected burn wound model, the Cu_xTe@CG hydrogel markedly accelerated healing by eliminating bacteria, promoting angiogenesis, and modulating inflammation, all while demonstrating excellent biosafety. This work establishes the Cu_xTe@CG hydrogel as a robust and targeted therapeutic strategy for combating stubborn gram-negative infections.

Most cancer metastases exhibit mutational profiles similar to those of the primary tumor. However, the nongenetic mechanisms driving metastasis remain poorly understood. Here, we show that lineage trans-differentiation is a hallmark of cancer metastasis. Bioinformatic tools capable of reconstructing cancer phenotypic evolutionary trajectories at single-cell resolution were developed, revealing a progressive loss of transcriptional and epigenomic lineage fidelity in cancer cells as they evolve toward metastasis. During premetastatic evolution, cells undergo de-differentiation into a fetal-like state. The mis-expression of alternative-lineage gene programs during re-differentiation from this fetal-like state leads to the formation of trans-differentiated metastatic cells. This trans-differentiation, rather than fetal-like transcription, constitutes a key feature of metastasis in both humans and mice. In clinical samples, trans-differentiation correlates with histopathological grade, metastatic potential, and patient survival. Additionally, trans-differentiation is associated with gain of oncogenic mitogen-activated protein kinase (MAPK) signaling and can be reversed through MAPK inhibition. These findings offer a detailed account of metastatic cancer evolution driven by epigenetic reprogramming while also uncovering the molecular mechanisms underlying this process.

Lumbar spine diseases substantially impact the patients’ quality of life, necessitating accurate and efficient diagnostic tools. This study presents Lumbar VNet Pro (LVP), the first real-time artificial-intelligence (AI)-assisted system embedded within MRI hardware for lumbar spine analysis, integrating deep learning with MRI. LVP was trained on 2,453 MRI datasets and validated both internally and externally across multiple centers. During the training (1,848 MRI datasets) and validation (605 MRI datasets), LVP exhibited outstanding performance in localization (Dice = 0.93), segmentation (Dice = 0.92), labeling (identification rate = 0.90), and timeliness (average inference time = 1.1 s). Following the successful construction of LVP, we conducted comprehensive testing through both internal and external multicenter evaluations. Internal testing involving 100 patients indicated that the recognition accuracy of LVP was as high as 100%, and the consistency between the LVP assessment and the manual assessment using the gold standard reached 97%. In external testing involving 1,522 patients, LVP’s diagnostic performance was compared to those of manual and human–machine-assisted methods. The AI-assisted approaches demonstrated better performance across multiple spinal pathologies, including lumbar disc herniation, spinal canal stenosis, and lateral recess stenosis, with area under the receiver operating characteristic curve values >0.95 for deep learning/human–machine approaches and >0.90 for the fully manual approach. The real-time integration of LVP with MRI scanning improved positioning accuracy and reduced interobserver variability, supporting its potential as an adjunct tool for enhancing MRI-based spine diagnostics. However, further studies are warranted to assess its generalizability across diverse clinical settings.

RNA has been established as an essential molecule in virtually all cellular processes. Besides its role in cellular modulation via extracellular vesicular release, it has long been thought to only exert its function intracellularly. Recent discoveries have shown evidence of extracellular RNA tethered to the cell surface of different cell types. These cell surface RNAs are predominantly modified with sialylated glycans, denominating them cell surface glycoRNAs. While the expression of cell surface glycoRNAs has been found on a wide array of immune cell and cancer cell types, research on its functional roles has only recently been explored due to challenges in detection, isolation, and sequencing of this new subclass of RNA. In this review, the history, biogenesis, detection and isolation techniques, and functional roles of cell surface RNA to date will be discussed, in addition to commenting on its translational capacity for studying immunomodulation and disease. Acknowledging the presence of cell surface RNAs and propelling our understanding on their function will provide a new avenue to study cellular modulation and cell–cell communication.

Foxtail millet (Setaria italica L.), a C4 cereal crop domesticated in China, exhibits exceptional nitrogen use efficiency (NUtE) with marked genotypic variation; however, the molecular basis remains underexplored. Here, we identified candidate genes through a sequential filtering strategy from genetic linkage (bulked segregant analysis sequencing) to transcriptional response (RNA sequencing) within defined quantitative trait locus intervals to dissect NUtE mechanisms in contrasting genotypes: the low-nitrogen-tolerant variety Yugu28 and the low-nitrogen-sensitive variety Qiyehuang, to identify the genetic regulatory mechanisms. Several candidate genes were screened, such as glutamine synthetase (GS2, Seita.3G024100), glutathione S-transferase (GLUS, Seita.3G386000) and nitrogen regulatory protein P-II (Seita.3G051900). Seita.3G051900 was identified as LOW-NITROGEN REGULATORY GENE (SiLNR1), which is highly expressed in different organs. The functional characterization revealed that SiLNR1 overexpression results in strikingly low-N resilience: Compared with the wild-type controls, the transgenic lines presented 106% longer primary roots, 91.3% greater plant height, and 18.9% greater root nitrogen accumulation under low-nitrogen (LN) conditions and boosted grain yield and NUtE by 29.5% and 24.3%, respectively. By contrast, the silnr1 mutant presented markedly shorter primary roots and plant height and lower shoot N accumulation under LN conditions. Field validation of the SiLNR1 allele in the recombinant inbred line population demonstrated that the SiLNR1 allele from Yugu28 confers a substantial and measurable yield gain under LN field conditions. The functions of SiLNR1 associated with enhanced nitrogen uptake and utilization have been revealed, indicating that SiLNR1 contributes to nitrogen metabolism and NUtE positively, thus providing a theoretical basis and application prospect for resource conservation, environmental protection, and sustainable agricultural development.

Antimicrobial peptides (AMPs), traditionally regarded as innate immune effectors, are increasingly recognized for their structural and functional convergence with pathogenic amyloids. Recent studies—including our own—reveal that AMPs not only exhibit antimicrobial activity but also modulate amyloid aggregation by accelerating, delaying, or redirecting fibril growth, acting at the nexus of protein misfolding, inflammation, and host defense. In this account, we highlight the emerging role of AMPs as cross-seeding modulators that can inhibit or promote amyloid fibrillization depending on structural context. We summarize mechanistic insights into how β-sheet-rich AMPs engage amyloidogenic targets via structural compatibility, directional seeding asymmetry, and surface-mediated catalysis. We also explore how AMP–amyloid cross-seeding contributes to a bidirectional pathogen–amyloid feedback loop, linking microbial infections to chronic inflammation and neurodegeneration. Building on these molecular foundations, we present recent design advances in engineering AMP-derived inhibitors with enhanced amyloid specificity, proteolytic stability, and translational potential. These dual-function peptides—capable of suppressing amyloid aggregation and modulating immune responses—offer a unique therapeutic strategy for diseases such as Alzheimer’s, type 2 diabetes, and systemic amyloidosis. We conclude by outlining current challenges and future directions for data-driven design, delivery optimization, and clinical development of multifunctional AMPs as next-generation therapeutics.

The origin of molecular chirality remains an enigma in chemistry, particularly regarding how single-molecule events overcome intrinsic stochasticity to establish population-level chirality. Here, we present a viable strategy for real-time, from-the-beginning single-molecule trajectory monitoring of asymmetric evolution from a single initial molecule with single-event resolution, allowing direct observation of spontaneous mirror symmetry breaking in a single-molecule Diels–Alder reaction system. We monitor the asymmetric evolution in real time using the chirality-induced spin selectivity effect. This approach enables the capture of initial symmetry breaking at the single-molecule level and the identification of the excess-compensation mechanism. In addition, the introduction of an external electric field to the symmetry-breaking species enables universal asymmetric synthesis without the need for a catalyst. The increase in the number of molecules leads to symmetry breaking, which is also contingent on the coupling with the external environment. This work deepens our understanding of the molecular principles underlying the origin of life and has many implications for precise chiral synthesis and drug design.

Solar-driven carbon dioxide (CO₂) reduction can sustainably produce chemicals and fuels but is often limited by rapid charge recombination and slow CO₂-to-product kinetics, typically necessitating homogeneous photosensitizers and cocatalysts. Here, we reported an integrated photocatalyst, TF-COF-CONH-Au₂₅-Co, constructed by immobilizing atomically precise Au₂₅ nanoclusters (NCs) on a covalent organic framework (COF) incorporating [Co(bpy)₃]²⁺ complex (Co–N₆ coordination). Under visible-light illumination, this hybrid catalyzes CO₂ conversion to syngas without external photosensitizers or cocatalysts, delivering a CO formation rate of 2,321.9 μmol·g⁻¹·h⁻¹ (turnover number of 171.9 and turnover frequency of 7.2 h⁻¹). The Au₂₅ NCs enhance light responsiveness and charge transfer efficiency, thereby enriching long-lived photogenerated electrons, while concurrently modulating the electronic state of Co sites to reduce the energy barrier for CO₂ reduction. This study illustrates a molecular-level strategy to synergistically integrate metal NCs, COFs, and [Co(bpy)₃]²⁺, showing a promising platform for high-performance photocatalytic CO₂ conversion.

Pancreatitis is a complex inflammatory disease with substantial genetic determinants. It progresses from acute to chronic forms and poses substantial clinical challenges due to a lack of disease-modifying therapies. Conventional treatments are largely palliative, highlighting the urgent need for mechanism-based interventions. Gene therapy represents a transformative strategy, directly targeting the root genetic causes. This review comprehensively outlines the current landscape and future directions of gene therapy for pancreatitis. We first delineate the genetic underpinnings of the disease, categorizing susceptibility genes into 4 key pathways involving lipid metabolism, trypsin regulation, ductal secretion, and endoplasmic reticulum stress. We then detail the core therapeutic strategies—gene augmentation, suppression, and editing—highlighting both clinically validated drugs (targeting lipid metabolism) and novel preclinical approaches for pancreatitis. Furthermore, to achieve pancreas-targeted delivery, we thoroughly describe the delivery vectors, including viral and nonviral systems, as well as the administration routes. However, translating these therapies faces considerable hurdles, such as physiological and pathological barriers to pancreatic targeting, the challenge of determining intervention timing, the lack of optimal animal models recapitulating human pancreatitis, and host immune responses. We discuss potential solutions to these hurdles, including innovative vector design, improved models, and immunotherapy. Ultimately, gene therapy holds the promise to fundamentally transform the pancreatitis treatment paradigm, offering a path from palliative care to definitive, precision medicine.

Drug resistance and impaired apoptosis limit durable responses in urological malignancies. Paraptosis is a regulated, nonapoptotic cell death program marked by prominent cytoplasmic vacuolization, typically driven by endoplasmic reticulum (ER) swelling and mitochondrial dysfunction. This perspective synthesizes emerging evidence in prostate, bladder, and renal cancers and proposes a stress-axis framework in which diverse inducers converge into 3 mechanistic classes: (a) proteostasis disruptors that precipitate acute ER stress, (b) ion-handling modulators that trigger lethal mitochondrial Ca²⁺ overload, and (c) redox regulators that amplify reactive-oxygen-species-driven proteotoxic stress. We discuss how natural products, repurposed agents, and delivery platforms can be integrated with chemotherapy, targeted therapy, or immunotherapy to overcome resistance and exploit death-pathway cross talk. Key translational priorities include defining pathway-specific biomarkers, mapping ER–mitochondrion signaling thresholds, and dissecting stress-buffering and cytoprotective autophagy as resistance mechanisms. Clarifying these principles may enable the context-specific exploitation of paraptosis across urological cancers and related diseases, in both primary and therapy-refractory settings.