Establishing physiologically relevant in vitro tumor models is critical for accurately evaluating chemotherapeutic efficacy in ovarian cancer. However, generating high-throughput, uniform, and viable tumor spheroids from primary patient cells remains a major challenge for personalized drug screening. Here, we present an integrated platform that couples hydrogel microencapsulation with organ-on-a-chip culture to achieve biomimetic 3-dimensional tumor growth and dynamic drug assessment. Core–shell hydrogel microcapsules, consisting of a carboxymethyl cellulose core and an alginate shell, create a biocompatible and tunable microenvironment that maintains cell viability, preserves molecular and phenotypic heterogeneity, and enables reproducible spheroid formation. Embedding these spheroids into a microfluidic chip with continuous, precisely regulated drug gradients and perfusion culture facilitates high-resolution, high-throughput evaluation of chemotherapeutic responses. Using this system, clinically relevant agents—including carboplatin, paclitaxel, docetaxel, and pegylated liposomal doxorubicin—were systematically screened, revealing patient-specific variations in drug sensitivity that closely aligned with postoperative clinical outcomes. By integrating hydrogel-based 3-dimensional culture with microscale gradient control, this approach provides a stable, physiologically meaningful, and scalable platform for preclinical pharmacological testing. Collectively, the findings demonstrate its potential as an effective tool for individualized chemotherapy evaluation and precision treatment development in ovarian cancer.

Boron neutron capture therapy (BNCT) enables localized tumor ablation while minimizing damage to surrounding tissues, offering advantages for treating anatomically challenging sites. However, current boron carriers, such as sodium borocaptate (¹⁰BSH), suffer from inadequate tumor specificity. Herein, the present study details the design, synthesis, and preclinical evaluation of a novel small-molecule boron-10-enriched carrier, which was synthesized by covalent bond coupling 4-carboxy-3-fluorophenylboronic acid (FPBA) to ¹⁰BSH (FPBA–BSH), achieving a boron content of approximately 25 wt.%. FPBA–BSH efficiently penetrated the blood–brain barrier and demonstrated pronounced accumulation in orthotopic gliomas, achieving a boron concentration of 75.4 μg-B/g-tumor tissue, which was 4.2- and 3.7-fold higher than those with boronophenylalanine (BPA) and BSH, respectively. Moreover, FPBA–BSH exhibited markedly improved tumor selectivity, with tumor-to-normal tissue (T/N) and tumor-to-blood ratios of 52.0 and 7.2, respectively. The T/N ratio was approximately 19.3- and 14.1-fold greater than those observed for BPA and BSH. In the melanoma model, FPBA–BSH achieved an intratumor boron concentration of 114.4 μg-B/g-tumor tissue, representing 8.4- and 9.9-fold increases compared with BPA and BSH, respectively. Correspondingly, the T/N and tumor-to-blood ratios reached 135.1 and 8.6, indicating substantially enhanced tumor targeting and retention. The T/N ratio achieved with FPBA–BSH was approximately 26.0- and 34.6-fold higher than those obtained with BPA and BSH, respectively. Consistent with its superior tumor selectivity, FPBA–BSH-mediated BNCT induced pronounced tumor-selective cytotoxicity and markedly inhibited tumor growth in both orthotopic glioma and melanoma models compared with BPA, BSH, and untreated controls. These findings demonstrate that FPBA–BSH represents a promising small-molecule boron delivery agent with substantial potential for clinical BNCT applications.

The advancement of porous carbon supercapacitors is constrained by the inability of conventional characterization to probe their dynamic electrode–electrolyte interfaces. In-situ characterization bridges this gap, offering real-time observation of critical processes such as ion adsorption/desorption and surface reactions under operating conditions. This Perspective illustrates how these in-situ techniques are transforming mechanistic understanding, discusses persistent challenges including multimodal integration and spatiotemporal resolution trade-offs, and proposes a roadmap to translate these insights into the design of next-generation devices.

Schistosomiasis, a neglected tropical disease, affects more than 250 million people worldwide. The pathology and transmission of schistosomiasis rely on the parasite’s extended survival and massive egg output. While N⁶-methyladenosine (m⁶A) messenger RNA modification is an important epigenetic regulator, its functional roles in pathogenic helminths remain entirely unexplored. Here, we comprehensively characterize the m⁶A landscape in the human blood fluke Schistosoma japonicum. We generated high-resolution transcriptome-wide m⁶A maps for adult male and female parasites, revealing distinct sex-specific methylation patterns. Functional investigation of the conserved m⁶A writer complex demonstrated that m⁶A methyltransferase-like-3/14 (METTL3/14)-mediated methylation is indispensable for female reproductive development and oviposition. In males, m⁶A modification is essential for maintaining tegumental integrity, metabolic homeostasis, and motility. Mechanistically, integrated methylated RNA immunoprecipitation sequencing and RNA sequencing analyses following METTL3 knockdown identified key m⁶A-modified transcripts, including glutamine synthetase, which underpin the observed phenotypic defects. Our study provides the first functional evidence of m⁶A-mediated epitranscriptomic regulation in a parasitic helminth, establishing it as a master regulator of reproductive and somatic development and revealing the m⁶A pathway as a potentially important target for developing novel strategies against schistosomiasis.

Advancements in biomedical interfaces increasingly demand technologies that can seamlessly bridge the gap between biological tissues and therapeutic systems. Microneedle (MN) technology has emerged as a minimally invasive platform for transdermal drug delivery (TDD) and biosensing, offering tunable geometries, efficient skin penetration, and reduced patient discomfort. However, the inherent limitations of conventional microfabrication techniques in terms of structural complexity, multi-material compatibility, and functional modularization have markedly constrained the development of next-generation biomedical systems. In recent years, 3-dimensional (3D) printing has positioned itself as a highly promising additive manufacturing (AM) technology, offering exceptional design freedom and high-resolution fabrication capabilities for the development of MN platforms with embedded microchannels and integrated multifunctionality. Herein, a comprehensive analysis of recent progress in 3D-printed MNs is provided, with emphasis placed on advances in architectural innovations, intelligent system integration, and their expanding applications in personalized drug delivery and intelligent theranostic platforms. Furthermore, an in-depth examination of the core challenges hindering the clinical translation of 3D-printed MNs, particularly regarding manufacturing processes, material selection, and standardization requirements, is presented, offering a forward-looking perspective on the paradigm shift of MNs from passive delivery terminals to active, closed-loop health platforms.

In middle-aged and older atherosclerotic renal artery stenosis (ARAS), the anatomical severity of stenosis is a poor surrogate for microvascular competence, and the renal benefit of revascularization is unpredictable. We developed Renal-Video-AI, a self-supervised deep learning framework (Video Swin Transformer with VideoMAE pretraining) that extracts spatiotemporal hemodynamic features from contrast-enhanced ultrasound, and applied it to a multi-center Discovery Cohort (N = 1,226), an independent External Validation Cohort (N = 122), a prospective Multimodal Cohort with paired 10x Visium spatial transcriptomics (N = 57), and an aged two-kidney-one-clip (2K1C) murine model. Unsupervised phenomapping identified 3 intrinsic hemodynamic phenotypes—Preserved, Delayed, and Rarefied. The Rarefied phenotype predicted major adverse renal events (MAREs) independently of anatomical stenosis [hazard ratio (HR) 4.82, 95% confidence interval (CI) 3.10 to 6.50; Fine–Gray subdistribution HR (sHR) 5.1], and adding the phenotype to a standard clinical model improved the C-statistic from 0.72 to 0.88. A significant phenotype-by-treatment interaction (P < 0.01) showed that stenting reduced events only in the Delayed phenotype (HR 0.52, 95% CI 0.35 to 0.78), not in the Preserved (HR 0.98) or Rarefied (HR 1.05) phenotypes. In absolute terms, stenting reduced the 3-year cumulative incidence of MARE in the Delayed phenotype from 25.4% to 13.2% (absolute risk reduction 12.2%; number needed to treat = 8, 95% CI 6 to 13), with no benefit in the Preserved (8.4% versus 8.0%) or Rarefied (38.6% versus 39.4%) phenotypes. Spatial transcriptomics localized a hypoxia and pyroptosis signature to rarefied tissue, and the aged 2K1C model revealed a mitochondrial reactive oxygen species (ROS)–NLRP3–pyroptosis axis whose pharmacological inhibition (MCC950) restored microvascular perfusion. AI video-phenomapping thus reframes the revascularization decision around microvascular competence rather than anatomy, identifying both therapeutic futility (Rarefied) and a treatable window (Delayed), and nominates NLRP3-driven pyroptosis as a therapeutic target.

Historically, cardiac arrhythmias have been interpreted as intrinsic ion channel disorders of the cardiomyocyte. However, the field is currently undergoing a fundamental paradigm shift, recognizing the brain–heart axis as the ultimate arbiter of electrical stability. Despite a wealth of preclinical evidence, the clinical translation of neuromodulatory interventions has reached a critical juncture, with many trials yielding conflicting or disappointing outcomes. This translational gap underscores a critical need to move beyond an oversimplified, efferent-centric view toward an integrated understanding of the neuro-cardiac hierarchy. This review redefines arrhythmogenesis as an emergent property of multi-level network instability, driven by 3 core mechanistic principles: spatial heterogeneity, temporal dynamics, and convergent remodeling. By synthesizing the anatomical architecture of the cardiac autonomic nervous system, integrating the often-overlooked afferent sensory limb and the intrinsic “little brain”, we illustrate how neural circuits translate systemic stressors into localized electrophysiological triggers. We examine the bidirectional neuroimmune crosstalk and neuropeptide dynamics that bridge inflammatory signaling with maladaptive remodeling. Furthermore, we explore how circadian rhythms impose temporal windows of vulnerability, transforming stable substrates into arrhythmogenic ones. Finally, we critically evaluate the therapeutic landscape, from established pharmacological blockade to the nascent frontiers of closed-loop bioelectronics and nanotechnology. By bridging molecular mechanisms with a hierarchical appraisal of clinical evidence, this review provides a roadmap for the next generation of precision neuromodulation designed to restore and sustain neuro-cardiac homeostasis.

Whole-body ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography (¹⁸F-FDG PET/CT) is central to lung cancer staging, yet report drafting remains time intensive and error sensitive, as a single mislocalized finding can alter TNM stage and treatment decisions. We cast PET/CT report drafting as TNM-accountable decision support and propose RIDE, a 2-stage dual-modality 3-dimensional framework that separates TNM-critical anchoring from narrative completion. Stage I generates TNM-oriented structured impressions from paired PET and CT volumes; stage II performs hierarchical organ-wise exemplar retrieval and prompts a large language model to synthesize complete Findings and Impression conditioned on these inspectable artifacts. We curate a multicenter whole-body FDG PET/CT cohort of 1,583 patients from 3 hospitals, all referred for suspected or confirmed lung cancer, and evaluate it on a held-out test set of 520 cases, including 276 external cases from 2 independent institutions. RIDE achieves the strongest overall drafting performance and cross-site generalization, improving a clinically grounded competency metric by +20.4 on the external set and maintaining high clinician ratings under shift (mean Likert 4.00 internal; 4.17 external) while also delivering the best TNM staging performance among evaluated baselines. These findings support workflow-decomposed, TNM-accountable PET/CT drafting as a promising decision-support approach for human verification, and prospective studies will be valuable for further characterizing its utility in real-world clinical workflows.

Bioplastics derived from hemicellulose exhibit marked potential to substitute petroleum-based plastics due to their sustainability and biodegradability. However, developing bioplastics that combine facile manufacturing processes, excellent mechanical properties, and a low carbon footprint remains challenging. Herein, we present a strategy for fabricating high-performance bioplastics (XAGP) by crosslinking xylan molecular chains via photo-induced free-radical polymerization. The XAGP exhibits high light transmittance (95%), exceptional mechanical toughness (26 MJ/m³) and mechanical strength (84 MPa), outstanding thermal stability, water-assisted processability, rapid biodegradability (10 days in nature soil), hypotoxicity in aquatic environments, and good biocompatibility (cell viability above 98%). Furthermore, cost and life cycle assessment results demonstrate that XAGP is a more sustainable alternative to commercial biodegradable plastics, offering greater cost-effectiveness and a reduced carbon dioxide emission. This work establishes a promising route for transforming pulp waste into degradable, high-performance bioplastics, providing an effective solution to both waste disposal and plastic pollution.

The understanding of type 2 inflammatory diseases is undergoing a paradigm shift from “immune imbalance” toward “immune–metabolic crosstalk”. Energy metabolism not only fuels immune responses but also fundamentally dictates the functional phenotypes of immune cells through metabolic reprogramming. By systematically integrating metabolic programming data of key immune cells across diverse tissues (skin, gut, nasal, and ocular mucosa), this review constructs a cross-disease “metabolism–signaling network” atlas. The synthesis highlights that glycolysis and mTORC1 signaling are predominantly coupled with the pro-inflammatory outputs of Th2 cells and ILC2s, whereas fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) sustain the homeostasis of Tregs and M2-like macrophages. Furthermore, this review characterizes how the tryptophan, glutamine, and arginine pathways fine-tune the immune tolerance boundary via the IDO–AhR–mTOR axis. We also elucidate a conserved inter-organ “hypoxia–HIF-1α–lactylation” axis, which, in conjunction with tissue-specific metabolic branches (e.g., the ceramide pathway in the skin, the SCFA circuit in the gut, and the lactate–GPR81 loop in the mucosa), collectively sculpts local microenvironments and remodeling trajectories. Ultimately, a novel diagnostic and therapeutic framework centered on metabolic phenotyping is proposed, providing prospective insights into targeting metabolic checkpoints for precision immunotherapy in type 2 inflammation.

The widespread occurrence of antimicrobial-resistance-associated contaminants in natural and engineered water systems poses a major threat to environmental and public health. Conventional contact-electro-catalysis (CEC) can generate interfacial H₂O₂ and reactive oxygen species, but its efficiency is often constrained by sluggish H₂O₂ activation and limited reactive oxygen species flux. Here, we report an additive-free contact-electro-catalysis/vacuum ultraviolet (CEC–VUV) system that uses low-cost polytetrafluoroethylene as a dielectric catalyst for rapid mitigation of antibiotics, pathogens, and antibiotic resistance genes in water. Mechanistic analyses reveal that VUV irradiation activates CEC-derived H₂O₂ and O₃ through charge–photon coupling, converting these otherwise underutilized intermediates into ^•OH. CEC continuously supplies interfacial charges and H₂O₂, while VUV promotes H₂O₂ photolysis and O₂-to-O₃ conversion. The generated O₃ is further activated at the charged polytetrafluoroethylene/water interface, establishing an interconnected H₂O₂/O₃-to-^•OH conversion network that amplifies ^•OH generation. This mechanism enables complete degradation of representative antibiotics within 10 min, complete inactivation of pathogenic bacteria within 5 min, effective antibiotic resistance gene removal in real water matrices, and stable bactericidal performance under continuous-flow operation.

With global space activities shifting from an exploration-oriented focus to large-scale development and utilization, low-cost, “airline-mode”, and high-capability space transportation capabilities have become the critical foundation for supporting the construction of space infrastructure and the flourishing of the space economy. This paper targets the “dual-hundredfold” goal, aiming for a hundredfold increase in both payload insertion mass and launch frequency compared to current levels. After analyzing the development trends and challenges of large-scale space transportation systems, key technologies—such as ultra-high-speed re-entry active thermal management, long life-cycle engines, efficient low-temperature propellant transfer control and precise sensing, aerodynamic-assisted orbital maneuvers, aerodynamic and control integration design for the payloads featuring high lift-to-drag ratios and high packing densities, and fully electric-driven pressurization and fluid transport control technologies—are discussed. Breakthroughs in these technologies are expected to revolutionize human access to space, give rise to new intercontinental travel paradigms, and reshape the global technological competition landscape and strategic balance.

Structural phase transitions driven by atomic rearrangements at the interaction interfaces of biological macromolecules, particularly proteins, are fundamental to regulating critical physiological processes, making their effective modulation key to developing targeted therapeutics. Existing induction strategies encounter substantial limitations: Chemical methods have difficulty accessing shallow binding pockets and can lead to invasive, irreversible modifications, while common visible and near-infrared modulation technologies are hindered by side effects induced by exogenous agents and restricted deep-tissue penetration. Here, using molecular dynamics simulations of the programmed cell death protein 1/programmed cell death 1 ligand 2 complex, we find terahertz light (40.2 THz) to be a reversible, nonthermal, and noninvasive physical induction modality to drive a directed structural phase transition. Energetic analyses reveal that the terahertz field markedly decreases the binding affinity by more than 3-fold and reduces the free energy barrier by nearly 3-fold. Fundamentally, our research demonstrates that this directed decoupling process originates from the coherent resonance of certain key interfacial residues. Collectively, our findings propose a universal physical strategy to modulate macromolecular interfaces, providing an essential computational framework to guide future experimental validations in noninvasive tumor immunotherapy.

Endothelial cells (ECs) sense hemodynamic forces and critically influence aortic aneurysm and dissection (AAD) development. However, the possible contribution of the mechanical sensor Piezo1 to AAD remains elusive. Single-cell mRNA sequencing identified Piezo1 as the most up-regulated mechanical sensor in ECs from AAD model mice. Immunofluorescence and immunoblotting confirmed markedly increased Piezo1 protein in human and mouse AAD samples. Disturbed flow induced by abdominal aortic constriction plus Angiotensin II up-regulated Piezo1 expression and AAD incidence, whereas Piezo1 inhibition attenuated both. Moreover, EC-specific Piezo1 deficiency was sufficient to suppress β-aminopropionitrile- and Ang II-induced AAD formation in mice. Mechanistically, we discovered the disturbed shear stress-induced opening of the endothelial barrier via Piezo1 and subsequent Ca²⁺/MLC/PYK2/SRC-mediated activation of downstream signaling. In addition, in an Ang II-induced endothelial barrier dysfunction model, Piezo1 deficiency in ECs ameliorated Ang II-induced barrier dysfunction. Further study revealed that Piezo1 activation in ECs promoted the up-regulation of CCL2 in a STAT3-dependent manner and strongly promoted the chemotactic recruitment of monocytes/macrophages to the aorta. Importantly, blocking CCR2 reduced monocyte/macrophage recruitment and subsequently attenuated Piezo1 up-regulation-aggravated AAD formation. Transcriptome analysis of human AAD samples revealed a positive correlation between Piezo1 and inflammation of the aorta. We demonstrate that Piezo1 directly links mechanical sensing under disturbed flow to a pathogenic cascade of endothelial barrier dysfunction and inflammatory cell recruitment. Consequently, interventions targeting Piezo1 or the downstream STAT3-CCL2/CCR2 signaling hold therapeutic promise for AAD.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease with limited mechanism-based therapies, and ferroptosis—an iron-dependent lipid peroxidation-driven cell death—has emerged as a critical pathogenic event. Using a machine learning model that combines molecular fingerprints and transfer learning representations to screen for ALOX15 inhibitors, we identified rosmarinic acid (RA) from natural product libraries. RA exhibited high-affinity binding to ALOX15 and maintained stable complex conformation in molecular dynamics simulations. In dextran sulfate sodium-induced colitis mice and lipopolysaccharide-treated intestinal epithelial cells (IEC-6 and mouse colonic epithelial cell), RA alleviated disease activity index, colon shortening, histological damage, and barrier protein loss (ZO-1, Occludin, and Claudin-1). Mechanistically, RA suppressed ferroptosis by restoring GPX4, SLC7A11, and FTH1; reducing ACSL4, COX-2, and lipid reactive oxygen species (ROS); and lowering intracellular Fe²⁺ and malondialdehyde. Crucially, RA disrupted the ALOX15–VDAC1 protein complex, preserved mitochondrial membrane potential, and reduced mitochondrial ROS, effects that were abrogated by ALOX15 knockdown or VDAC1 knockdown. Serum metabolomics further revealed that RA remodels lipid metabolism pathways (arachidonic acid and linoleic acid metabolism) linked to ferroptosis. Collectively, this artificial intelligence-driven discovery positions RA as a novel ferroptosis inhibitor that targets the ALOX15–VDAC1 axis, offering a promising therapeutic candidate for UC.

With the ongoing progress in coronary interventional therapy, the progression of atherosclerosis is no longer solely governed by its natural course. Postprocedural neointimal hyperplasia and plaque formation markedly increase the risk of cardiovascular events, where chronic, unresolved inflammation and the overproduction of reactive oxygen species (ROS) play a critical role in driving plaque development. Drawing inspiration from the reaction mechanisms of intracellular antioxidant defense systems, we report the de novo design of a ruthenium arene complex (RuC₆H₆) with pseudo-vacant coordination sites, which serves as efficient small-molecular antioxidant enzyme mimics for biocatalytic ROS elimination and the attenuation of vascular restenosis. Our findings reveal that the ligands in RuC₆H₆ undergo rapid hydrolysis during the reaction and chloride ligands are replaced by H₂O₂, thereby generating abundant reactive sites and conferring the complex with efficient, broad-spectrum, and stable ROS-scavenging properties. When encapsulated in liposomes (Lipid-Ru), the complex effectively reprogrammed macrophages from the M1 phenotype, diminished the secretion of inflammatory cytokines, and suppressed foam cell formation. Moreover, the Lipid-Ru administration led to a significant reduction in smooth muscle cell migration and neointimal area, ultimately alleviating vascular restenosis. This class of structurally tunable arene ruthenium complexes thus provides a promising strategy for designing biomimetic antioxidant reagents, holding considerable potential for the treatment of diverse inflammation-associated diseases.

Lightweight structural materials that combine high strength, machinability, and sustainability are essential for next-generation construction. Wood, a renewable and low-carbon resource, offers excellent mechanical performance but remains limited by fastener stability and reliance on metals and adhesives. Here, we report a superstrong engineered wood produced through synergistic cell-wall engineering across cellular and molecular scales, enabling metal-free and adhesive-free cross-laminated timber. Pressure-controlled densification induces near-complete closure of open cells in natural beech wood, generating a dense, smooth architecture with a 3-dimensional mechanical interlocking network analogous to micro-mortise-and-tenon joints. The resulting material preserves the intrinsic anisotropic architecture of wood while forming a 3-dimensional mechanical interlocking network resembling micro-mortise-and-tenon joints. Wooden structural material exhibits substantially improved dimensional stability and mechanical performance, including a density of 1.33 g cm⁻³, a flexural strength of 150.89 MPa, a compressive strength of 88.48 MPa, and an exceptional Janka hardness of 18.84 kN. Wood-derived nails fabricated from this material function comparably to steel fasteners, providing high strength-to-weight ratios while eliminating corrosion and adhesive contamination. This approach advances timber construction toward higher performance, reduced environmental impact, and improved sustainability, offering a scalable pathway for green building applications.

Milk is an essential nutritional source for human health, yet developing efficient and sustainable indoor dairy production systems to produce milk-associated components remains a major challenge. Here, we propose a biomimetic mammary gland-on-a-chip system that recapitulates both the structural features and lactation mechanism of the mammary gland for producing milk-associated bioactive components. The chip is designed with a medium channel providing circulation, an intermediate porous hydrogel layer for substance diffusion, and highly specialized microchambers for culturing mammary epithelial cells. The mammary gland-on-a-chip enables tight-junction formation and active secretion of milk bioactive components such as lactotransferrin and triglycerides. More importantly, by expanding the microchambers and parallelizing the chips, increased collection of partial milklike secretions containing selected bioactive components was achieved. Our work represents the successful development of a robust microphysiological system as a potential in vitro platform for mammary gland research and is promising in addressing future food and environmental crises.

Gastric cancer (GC) remains a lethal malignancy with limited therapeutic options and poor prognosis. In this study, we employed integrated RNA sequencing and ribosome nascent-chain complex sequencing analyses to identify a coding circular RNA (circRNA), circRAD23B, which is markedly up-regulated in GC tissues. Its expression correlates strongly with advanced tumor stage, lymph node metastasis, and reduced overall survival. We further demonstrate that the splicing factor U2AF65 facilitates circRAD23B biogenesis through direct binding to intron 1 of the RAD23B pre-mRNA. Functionally, circRAD23B encodes a novel 208-amino acid protein via an internal ribosome entry site-dependent mechanism. This protein promotes GC proliferation, invasion, and lung metastasis in vivo. Mechanistically, circRAD23B-208aa recruits the E2 ligase UBC9 to catalyze SUMOylation of PDIA5 at lysine 25, thereby attenuating its ubiquitination and enhancing protein stability. Stabilized PDIA5 facilitates ATF6 activation by promoting its proteolytic processing, nuclear translocation, and transcriptional induction of key unfolded protein response (UPR) effectors—TXNRD1 and HERPUD1—thereby alleviating endoplasmic reticulum stress and promoting tumor survival. Our findings reveal circRAD23B-208aa as the first circRNA-encoded activator of the UPR pathway via posttranslational regulation of PDIA5, highlighting the therapeutic potential of targeting the SUMOylation-dependent PDIA5/ATF6 axis in GC.

Natural biomaterials achieve exceptional mechanical performance through multi-level hierarchical architectures, yet replicating or surpassing such topological control and multiscale synergy in synthetic hydrogels remains challenging. A key obstacle is the often-overlooked macro–microscale competition mechanism, where macroscopic reinforcement can conflict with finer-scale energy-dissipation pathways. Here, we overcome this limitation by embedding a 3-dimensionally printed gradient-twisted plywood (GT) framework into a hierarchically anisotropic (HA) hydrogel matrix, creating a topologically controllable supra-biomimetic composite (GT-HA composite). A supra-biomimetic design strategy is employed to regulate the macro–microscale competition, wherein the GT framework is expressly designed to coordinate macroscale stress guidance and crack deflection with micrometer-, nanometer-, and molecular-scale dissipation pathways. This coordinated multiscale dissipation endows composites with superior impact resistance. The GT-HA composite attenuates up to 88% of impact force at a low velocity and achieves a compressive strength of 183.57 MPa at a large strain rate of around 4,000 s⁻¹ while maintaining long-term stability (<5% decay over 35 d). Notably, the fabrication process is compatible with integrated circuit/microelectromechanical system technologies, allowing wafer-level integration that effectively protects high-value devices such as processor dies and flexible circuits under high-speed impact. This work establishes a scalable strategy for designing ultra-impact-resistant materials by actively harnessing macro–micro competition, with promising applications in embodied intelligence, aerospace, and advanced electronics protection.

There is a lack of high-frequency electronics based on 2-dimensional p-type transitional metal dichalcogenides, which originates from channel defects during device fabrication and non-optimized metal–semiconductor–insulator interface. Direct metal deposition inevitably induces n-type dominant carrier transport, and high-k dielectric layers cause an elevated carrier concentration enhancing carrier–carrier scattering. Herein, taking tungsten diselenide (WSe₂) as an example, we employ a polyvinyl alcohol (PVA)-assisted transfer of electrodes to realize WSe₂ devices with a high carrier mobility and low hole concentration at the same time. This approach circumvents the interfacial defects and lattice distortions caused by atomic bombardment, cluster dynamics, and localized heating of the contact region during direct metal deposition. Compared to polymethyl methacrylate (PMMA) and other transfer media, the water-soluble PVA layer can be removed without organic solvents, leading to high-quality channel and ideal dielectric interface effectively, which suppress Coulomb impurity scattering and carrier–carrier scattering at low hole concentration (~3.5 × 10¹² cm⁻²). This enables a carrier mobility exceeding 140 cm² V⁻¹ s⁻¹ at room temperature, superior to other heavily doped counterparts. Radio-frequency switches fabricated by transferring a top electrode exhibit a cutoff frequency of 57.5 GHz with a low series resistance of 25 Ω. This realizes the path loss and signal integrity required by 6G communications, rendering WSe₂ a highly promising candidate for millimeter-wave applications.

The perithyroidal adipose tissue (PAT), given its direct anatomical proximity to the thyroid gland, has long been postulated as a modulator of the thyroid tumor microenvironment. However, its cellular composition, functional heterogeneity, and specific roles in thyroid cancer progression remain unknown. To address these knowledge gap, we performed single-nucleus RNA sequencing of PAT from patients with papillary thyroid carcinoma (PTC) and multinodular goiter (MNG), combined with machine learning, proteomics, immunofluorescence, ex vivo assays, and human serum analysis. We constructed the first high-resolution atlas of human PAT, revealing an immune-rich niche and previously unrecognized adipocyte heterogeneity, including thermogenic subpopulations (BL-Ad1, BL-Ad2, OXPHOS-Ad) from distinct progenitors. Functionally, the PAT secretome from PTC substantially enhanced thyroid cancer cell proliferation compared to MNG. Integrated analyses identified a pathogenic adipokine triad characterized by loss of ADIPOQ and gain of NAMPT and IGF1. Restoring ADIPOQ signaling or inhibiting NAMPT/IGF1 suppressed tumor growth in vitro and in vivo. Additionally, we identified CCL14, down-regulated in PTC-derived OXPHOS-Ad, as a key immune regulator. Reduced CCL14–CCR1 signaling impaired CD80 expression in M1-like macrophages, disrupting CD80–CD28 costimulation and consequently diminishing T cell proliferation and recruitment. Consistently, circulating CCL14 levels were reduced in PTC patients. In conclusion, PAT acts as a dynamic endocrine and immunomodulatory component of the tumor microenvironment that promotes thyroid tumor growth through adipokine-mediated and immune-dependent mechanisms.

Spinal cord injury triggers a profound, spatiotemporally dynamic remodeling of the local mechanical microenvironment. Acute tissue softening and extracellular matrix degradation give way progressively to chronic fibrotic stiffening and dense matrix cross-linking. This pathological transformation establishes a formidable physical barrier to axonal regeneration while simultaneously disrupting the biomechanical signals that normally guide cellular behavior and maintain tissue homeostasis. Within this evolving niche, diverse cell populations decode altered stiffness and matrix composition through an array of specialized mechanosensitive receptors. The resulting intracellular signaling cascades orchestrate lineage-specific transcriptional and cytoskeletal programs that ultimately govern the delicate equilibrium between endogenous repair and irreversible fibrotic scar consolidation. This review examines the temporal progression and spatial heterogeneity of postinjury mechanical alterations across the spinal parenchyma, delineates the principal mechanotransduction pathways engaged, and critically evaluates emerging therapeutic strategies designed to modulate this aberrant physical landscape and restore a permissive regenerative milieu. We highlight translational advances spanning surgical decompression, mechanically responsive biomaterials engineered for dynamic niche reprogramming, and mechanoprimed cellular therapies. By framing spinal cord injury as a disorder of aberrant mechanobiology, this work advances a conceptual foundation for precision interventions aimed at overcoming regenerative failure through active remodeling of the tissue microenvironment.

Paclitaxel resistance and poor tumor selectivity remain significant challenges in epithelial ovarian cancer therapy. To overcome these challenges, we engineered PSaA360, a structurally constrained aptamer–drug conjugate with a dual-functional molecular lock that simultaneously rigidifies the AS1411 aptamer and delivers potent telomerase inhibition. Unlike the conformational flexibility of conventional aptamer–drug conjugates, PSaA360 employs the G-quadruplex stabilizer 360A to simultaneously rigidify the AS1411 aptamer into a high-affinity conformation and deliver potent telomerase inhibition. This structure-constrained and therapy-integrated strategy improved nucleolin binding, enhanced cellular internalization, and counteracted paclitaxel chemoresistance. In vivo, PSaA360 exhibited marked tumor inhibition with minimal systemic toxicity. By transforming a therapeutic agent into a structural stabilizer, PSaA360 establishes a new paradigm for mechanism-guided aptamer engineering in chemotherapy-resistant malignancies.

G-quadruplex (G4) structures represent noncanonical secondary formations found in DNA and RNA. Recent research reveals that G4s are abnormally enriched in various cancers, with closely linked to malignancy, metastatic potential, and prognosis. These structures have emerged as promising biomarkers for cancer with notable clinical relevance. Concurrently, investigations into compounds that selectively recognize DNA or RNA G4s as potential anticancer agents offer new avenues for early cancer diagnosis and therapeutic strategies. This review systematically analyzes the chemical structural characteristics, structure–activity relationships, anticancer effects, and mechanisms of G4-targeting molecules in cancer treatment. Additionally, it summarizes novel nucleic acid-based drugs targeting G4 structures, providing valuable insights for the future development of more specific and effective G4-targeted therapeutic agents.

Calcium oxalate (CaOx) kidney stones are common and recur frequently, yet effective pharmacological prevention is limited. Randall’s plaques (RPs), calcium deposits on renal papillae, act as anchoring sites for CaOx crystal growth, but the cellular origin and immunoregulatory mechanism underlying early calcium deposition remain unclear. Here, we found that early calcium deposition was partially localized to the renal interstitium surrounding aquaporin 2 (AQP2)-labeled collecting duct cells with apoptotic phenotype, and inhibiting high calcium-induced apoptosis of AQP2⁺ cells markedly reduced cell layer calcium deposition. Given the regulatory role of macrophages in renal stone formation, we revealed that M2 macrophages protected AQP2⁺ cells by delivering TRAF2 via exosomes. Mechanistically, exosomal TRAF2 interacted with intracellular TRAF1 to form a stable complex, which mutually inhibited their ubiquitin-mediated degradation by excluding the shared E3 ubiquitin ligase CBLC. This complex activated downstream nuclear factor κB1 (NF-κB1) and NF-κB2 signaling. NF-κB1 enhanced TRAF1 transcription, whereas NF-κB2 increased BCL2 expression while suppressing BAX and cleaved-PARP1, thereby limiting apoptosis and subsequent calcium deposition. Based on these findings, we developed M2 exosome-loaded, AQP2⁺ cell membrane-coated poly (lactic-co-glycolic acid) nanoparticles (Exo@A-P) for renal-targeted delivery. Exo@A-P treatment reduced collecting duct apoptosis and calcium deposition in hypercalciuria and renal calcified mice (Umod^−/−) without detectable toxicity, potentially supporting a targeted nanotherapeutic strategy to prevent early RP formation by utilizing TRAF2-rich exosome from M2 macrophages.

Lignocellulosic structural boards are often regarded as sustainable materials, yet most still depend on fossil-derived thermoset resins that generate volatile emissions, form weak and irreversible bonded interfaces, and complicate circular end-of-life management. Here, we introduce deep eutectic solvent (DES) ignition-triggered interfacial fusion, a closed-loop strategy that replaces external adhesives through a 2-stage sequence. In the ignition stage, a minimal amount of recyclable DES selectively activates lignocellulosic cell walls and mobilizes native lignin/hemicellulose toward particle contact zones, creating an interface-ready state. In the subsequent fusion stage, hot pressing reconstructs and locks these redistributed components into a continuous, lignin-rich bonding interphase, yielding an adhesive-free BioFuse-Board. The resulting BioFuse-Board delivers an internal bond strength up to 2.53 MPa (vs. the 0.45 MPa commercial requirement) and a 24-h thickness swelling of 10.05%. Mechanistically, ignition promotes β–O–4 bond cleavage, lowers lignin molecular weight, and enriches phenolic and carboxyl sites, whereas fusion promotes condensation while depleting reactive sites, consistent with a locked interfacial network involving oxygen-bridged environments, lignin-rich C–C connectivity, and strengthened hydrogen bonding with cellulose. Beyond performance, the same ignition–fusion architecture embeds circularity via reagent reuse, stream valorization into wood adhesives, and mechanical remanufacturing of end-of-life boards. Technoeconomic and cradle-to-gate life-cycle analyses further demonstrate that DES ignition-triggered interfacial fusion is economically viable and substantially reduces environmental impacts. Collectively, this strategy provides a generalizable route to circular manufacturing of structural-grade, adhesive-free lignocellulosic structural materials.

Neuropathic pain, resulting from somatosensory nervous system damage or disease, is a debilitating condition marked by spontaneous pain, hypersensitivity, and sensory abnormalities. Neuropathic pain involves spinal neuronal hyperexcitability, yet its molecular basis remains poorly defined. We utilized a comprehensive multi-omics approach, incorporating proteomics, phosphoproteomics, concatenated tandem array of consensus transcription response elements, and both single-cell and spatial transcriptomics, to chart time-resolved adaptations in the L4 to L6 spinal cord of a chronic constriction injury rat model. Multi-omics revealed remodeling of glutamatergic synapse pathways and identified non-POU (Pit-Oct-Unc) domain-containing octamer binding (Nono) as a down-regulated transcription factor associated with reduced potassium voltage-gated channel subfamily Q member 2 (Kcnq2) expression. Nono and Kcnq2 were co-enriched in neurexin 3-positive and peripherin-positive spinal neurons. Restoring Nono expression up-regulated Kcnq2, enhanced K⁺ outward currents (an effect largely abolished by the Kcnq2/3 blocker XE991), and alleviated pain hypersensitivity. Mechanistically, Nono was enriched at a conserved Kcnq2 promoter region in vivo and enhanced Kcnq2 promoter activity in reporter assays. Together, these findings established a Nono–Kcnq2 transcriptional axis that constrained spinal excitability and suggested a therapeutic entry point for neuropathic pain.

Nanozymes are emerging as versatile antimicrobial agents to tackle drug-resistant infections and biofilm-associated persistence. In this review, we present an integrated framework that links natural enzyme-mediated host defense to the rational development of antimicrobial nanozymes, and summarize recent advances through a mechanism-materials-engineering-application pipeline. We first summarize representative bactericidal principles of natural enzymes to highlight bioinspired catalytic motifs relevant to nanozyme design. We then classify antibacterial nanozymes by catalytic reaction types, including oxidoreductase- and hydrolase-like activities, and by material platforms, highlighting structure–activity relationships that govern catalytic behavior and antimicrobial performance. Building on these mechanistic and structural insights, we summarize engineering-enhanced bactericidal modalities, including photothermal and photodynamic assistance, metal ion release, immune modulation, cascade catalysis, microenvironment-responsive regulation, and targeting, that help overcome constraints imposed by infectious microenvironments, such as hypoxia, limited hydrogen peroxide availability, elevated antioxidant levels, and biofilm barriers. Finally, we translate these principles into application-oriented guidance across interfaces ranging from abiotic surface protection, including antifouling and device coatings, to superficial and deep-seated infections, and we briefly discuss emerging nanozyme strategies for antifungal and antiviral interventions. Throughout, we emphasize translational considerations, such as activity benchmarking, biosafety evaluation, and scalable manufacturing, to support the development of clinically relevant antimicrobial nanozymes.

Precision surgery in soft tissues is currently hindered by the lack of real-time, depth-resolved visualization. Conventional navigation relies on preoperative images that fail to account for intraoperative deformation, while existing intraoperative tools often lack intuitive spatial correspondence. Here, we propose Surgical Anatomical Structure Transparentization (SAST), an emerging framework anchored by second near-infrared fluorescence imaging. Unlike augmented reality, which merely displays static preoperative models, SAST represents a sensing paradigm that utilizes direct photon scattering suppression to visualize deep anatomy in situ. We delineate the critical technological trajectory—from monocular 2-dimensional fluorescence to 3-dimensional volumetric perception via stereoscopic vision and computational imaging—required to bridge the dimensional gap. By transforming navigation from “referencing a map” to “seeing through tissue”, SAST promises to redefine surgical perception through continuous, real-time anatomical transparency.

Intrahepatic metastasis in multifocal hepatocellular carcinoma is associated with poor prognosis and therapeutic resistance, yet the immune mechanisms driving disease progression remain unclear. Here, we analyzed genetic and immune differences between primary tumors and intrahepatic metastatic lesions using sequencing approaches and spatial validation methods. We found that metastatic lesions shared key genomic features with primary tumors but exhibited a distinct immunosuppressive environment enriched in myeloid and T cell populations. In particular, a subset of macrophages expressing glycoprotein nonmetastatic melanoma protein B (GPNMB) was consistently enriched in metastatic niches across multiple independent cohorts. These macrophages were spatially colocalized with CD8⁺ T cells exhibiting features of terminal exhaustion. Mechanistically, integrated multiomics and functional analyses revealed that GPNMB overexpression triggers lipid metabolic rewiring via the phosphatidylinositol 3-kinase/AKT-cyclooxygenase-2 cascade, leading to elevated prostaglandin E2 secretion, which directly suppresses CD8⁺ T cell cytotoxicity. Specific silencing of this subset using a dual-targeted, lipid-polymer nanoparticle (APL_siGpnmb) effectively reversed T cell exhaustion, inhibited metastasis, and synergized with anti-programmed death 1 immunotherapy in mouse models without inducing systemic toxicity. These findings identify GPNMB-positive macrophages as key metabolic and immune regulatory hubs, suggesting that targeting the GPNMB–prostaglandin E2 axis provides a promising precision therapeutic strategy for intrahepatic metastasis in multifocal hepatocellular carcinoma.

Epidemiological and clinical evidence increasingly highlights a close association between metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular disease (CVD). The transition from nonalcoholic fatty liver disease (NAFLD) to MASLD represents a conceptual shift toward a metabolism-centered framework with important implications for cardiovascular risk assessment. As the global burden of both conditions continues to rise, clarifying their bidirectional relationship has become increasingly important. This review summarizes current epidemiological and clinical evidence linking MASLD to adverse cardiovascular outcomes and discusses the potential value of liver-specific markers, particularly fibrosis indices, in cardiovascular risk stratification beyond traditional risk factors. Mechanistically, we examine shared upstream metabolic mechanisms linking MASLD and CVD, as well as the bidirectional liver–heart axis involving liver-to-heart effects and cardiovascular feedback to the liver. We further summarize key molecular mediators involved in these processes and their potential relevance to both cardiovascular and hepatic injury. Finally, we discuss the clinical and therapeutic implications of this integrated framework, including the potential to achieve dual hepatic and cardiovascular benefit. A clearer understanding of the MASLD–CVD interplay may support earlier detection, more precise risk stratification, and multidisciplinary management.

Health research is shifting from isolated risk snapshots toward longitudinal, multimodal representations of disease. In type 2 diabetes, patients with comparable glycemic control may follow sharply divergent renal, cardiovascular, hepatic, and neurocognitive courses—heterogeneity that single-endpoint, single-window risk models cannot resolve. Here, we propose the Health Galaxy, a state-space framework that represents each individual by multi-organ position and direction of motion over time, integrating organ-aging clocks, cross-organ coupling, and trajectory-aware generative modeling. We operationalize this framework through 3 falsifiable structural units—clusters, channels, and hubs—that can be tested for reproducibility across cohorts and modalities. The framework reframes intervention as trajectory rerouting rather than marker reduction, with type 2 diabetes as a tractable first test case.

Cigarette butts are common yet overlooked pollutants in urban environments. How this anthropogenic niche shapes microbial life-history strategies and evolutionary mechanisms remains poorly understood, limiting assessments of microbial adaption and urban ecosystem health. However, systematic and multiscale evidence on the ecological effects of cigarette butts on microbial communities remains scarce. Here, we collected cigarette butts, litter, and soil samples from urban parks in 35 Chinese cities and integrated third-generation 16S ribosomal RNA sequencing, metagenomics, and transcriptomics to resolve microbial community composition, functional potential, and evolutionary patterns. The results revealed that microbial communities in cigarette butts were shaped by strong deterministic processes, showed low spatial heterogeneity, and were taxonomically distinct from those in natural niche (i.e., litter) and surrounding soil, with notable enrichment of Proteobacteria, particularly the family Pseudomonadaceae. Functional trait analysis showed that butt-associated communities favored environmental responsiveness and fast-growth strategies, contrasting with metabolism- and resource acquisition-oriented strategies in the litter. Population genomic analysis suggested stronger positive selection in cigarette butt-associated Pseudomonadaceae, while the pure culture experiment provided strain-level evidence that cigarette butt exposure induced the up-regulation of key functional genes in Pseudomonas aeruginosa PAO1. This study demonstrates that cigarette butts, as an emerging ecological niche, reshape microbial community assembly, life-history strategies, and adaptive evolution, offering new insights into microbe-driven evolution on artificial surfaces.