骨科领域文献阅读汇编

Deep learning-based automated analysis offers the potential to streamline workflows, improve reproducibility, and reduce clinician workload. We developed an artificial intelligence (AI) system based on convolutional neural networks to automatically measure spinal alignment and detect spinal implants (pedicle screws and hooks combined as a single category) from scoliosis radiographs. A total of 4585 radiographs from 1671 adolescent idiopathic scoliosis patients across 10 institutions in 2 countries were used to train, validate, and externally test the model. The AI measured coronal and sagittal parameters with mean absolute errors (MAEs) of 2.7° (r = 0.99) for the major curve and 3.7° (r = 0.91) for thoracic kyphosis, regardless of implant presence. Vertebral numbering was performed with an accuracy of 0.97 for recognizing transitional vertebrae. Implant detection achieved high accuracy, with an MAE of 0.18 implants per image (r = 0.99). This comprehensive, multi-institutional validation demonstrates the clinical and research utility of the model in enabling fully automated assessment of spinal deformity. While external validation for coronal preoperative measurements was conducted across four cohorts in four countries, sagittal and postoperative measurements were externally validated at two sites (the United States and Japan); broader multi-region validation of sagittal and postoperative measurements, therefore, remains an important direction for future work.

Distinguishing degenerative cervical myelopathy from natural aging-related functional decline remains a critical challenge in primary care. The standard 10-s grip-and-release test loses specificity in older adults due to aging-induced motor slowing, creating a diagnostic gray zone that confounds risk stratification. Here we present a smartphone-based computer vision framework designed to disentangle pathological motor deficits from physiological aging. In a multicenter study comprising 2340 participants, we identified eight demographically robust kinematic digital biomarkers, including maximum release velocities and inter-finger synchronization. These metrics serve as objective surrogates for corticospinal integrity and maintain biological stability despite muscle senescence. Our model achieved an area under the curve (AUC) of 0.896 (95% CI 0.882-0.909) in the development cohort (80.0% sensitivity, 83.5% specificity), significantly outperforming the conventional 20-cycle threshold (AUC 0.768; P < 0.001). Crucially, this discriminative accuracy remained robust within the diagnostic gray zone. In the external validation cohort, the model yielded an AUC of 0.856 (95% CI 0.818-0.895), achieving 83.1% sensitivity, 79.9% specificity, 64.1% positive predictive value (PPV), and 91.8% negative predictive value (NPV) at an observed 30% prevalence. By shifting the diagnostic paradigm from the quantity of movement to the quality of kinematic patterns, this tool provides a scalable and objective solution for DCM risk stratification in aging populations within primary care.

Intervertebral disc degeneration (IVDD), primarily driven by oxidative stress and inflammation, significantly impacts patient quality of life. Current therapies lack efficacy, highlighting the need for novel treatment strategies. This study investigates the protective effect of antioxidant hydrogel microspheres containing black phosphorus (BP) nanosheets and extracellular vesicles (EVs), fabricated using a microfluidic technology-based delivery system, designated as EVs@BPMS. In vitro analyses of EVs@BPMS revealed that BP nanosheets enhanced the antioxidant capacity of the hydrogel microspheres. The EVs@BPMS system functioned through the sustained release of extracellular vesicles. These vesicles collectively mitigated oxidative damage by scavenging reactive oxygen species (ROS), reducing oxidative stress, suppressing cellular senescence, and ultimately restoring extracellular matrix homeostasis in nucleus pulposus cells. Transcriptomic analysis further elucidated that the microspheres inhibited inflammatory responses via the IL-17-ferroptosis pathway, providing a theoretical basis for the development of targeted therapeutic interventions. In vivo studies confirmed the protective efficacy of EVs@BPMS in a rat model of IVDD, demonstrating substantial attenuation of disc degeneration. The findings underscored the innovative capacity of antioxidant hydrogel microspheres in regulating oxidative stress and maintaining cellular homeostasis. Moreover, they highlighted the potential of these microspheres for clinical application in degenerative disc disease.

Spinal cord injury (SCI) has traditionally been viewed as a focal trauma to the central nervous system, with research focusing primarily on the disruption of motor and sensory pathways. However, emerging evidence reveals that SCI rapidly induces systemic changes that extend far beyond the spinal cord. This review synthesizes current evidence to conceptualize SCI as a comprehensive systemic disorder, utilizing the "neuro-immune-metabolic network" as a central explanatory framework. Following the initial injury, the disruption of descending autonomic pathways contributes to widespread physiological dysregulation, driving peripheral organ dysfunction such as cardiovascular aberrations and splenic atrophy. Concurrently, systemic inflammation and metabolic disturbances, characterized by the release of pro-inflammatory cytokines, hepatic steatosis, and gut microbiota dysbiosis, generate circulating mediators that subsequently exacerbate central neuroinflammation. This bidirectional crosstalk establishes a self-perpetuating pathogenic cycle in which peripheral deterioration may further impede intrinsic neural repair. By mapping these multi-organ pathological interactions, this review underscores the limitations of isolated spinal interventions. Ultimately, future therapeutics should extend beyond localized spinal repair to target the restoration of systemic physiological networks, thereby advancing clinical management toward comprehensive, multi-targeted interventions.

As the rapid growth of aging population, intervertebral disc degeneration (IVDD) becomes a prevalent degenerative disorder in clinical practice. Ferroptosis-induced senescence in nucleus pulposus cells (NPCs) represents a primary pathological mechanism underlying IVDD. Strategies for reducing ferroptosis to delay NPC senescence hold prospects for therapeutic advances. According to previously reported proteomic profiles of apoptotic extracellular vesicles (ApoEVs), we noticed that most key ferroptosis-regulating proteins were identified in the ApoEVs proteome, including upregulation of Glutathione Peroxidase 4 (GPX4). In this study, we developed injectable hydrogel microspheres (HMs) integrating with senescent NPC-targeting ApoEVs as GPX4 delivery vehicle and anti-inflammatory diclofenac sodium (DFS) for IVDD treatment. The effect of ApoEVs on reducing NPC ferroptosis and reversing NPC senescence-related metabolic dysfunction and damage was reinforced through modification of reactive oxygen species (ROS) responsive and senescent NPC-targeting peptide. In vivo experiments and single cell RNA sequencing analysis elucidated that the senescence-targeted system significantly attenuated ferroptosis and inflammatory pathways, and prevented the transformation of inflammatory NPC phenotypes, thereby offering opportunities for reducing senescent NPCs from ferroptosis and mitigating IVDD progression.

Spine degeneration is associated with low back pain (LBP), a major cause of disability and functional decline. However, effective therapies for non-specific LBP remain limited because its underlying mechanisms are poorly understood. Here, we show that spine degeneration induces netrin-1 secretion in porous endplates to activate DCC signaling in dorsal root ganglion (DRG) neurons in both LBP and naturally aged male mice. Conditional loss of netrin-1 in Trap+ osteoclasts, or Dcc in Avil+ DRG neurons reduced spinal hypersensitivity. Importantly, DCC activation induces Src phosphorylation and SNARE complex docking, leading to presynaptic glutamate release in the dorsal horn (DH). Consequently, presynaptic glutamate release induces expression of both netrin-1 and DCC in DH neurons as a form of postsynaptic plasticity that initiates a positive feedback loop to amplify spinal hypersensitivity. Moreover, netrin-1/DCC expression is also amplified in the parabrachial nucleus (PBN) in the brain in both LBP and aged male mice. Thus, osteoclast-derived netrin-1 in porous endplates activates DCC-mediated hypersensitivity in DRG neurons to be further amplified in the DH neurons. These results promote the concept of non-specific LBP as a form of nociplastic pain.

Anisotropic biomaterials are broadly studied in regenerative medicine as they aim to mimic the hierarchical structures of native tissue. The Anisogel, an anisotropic microgel-in-hydrogel system, involves two key factors for tissue engineering: guidance cues-magnetically aligned rod-shape structures-and a surrounding matrix-polyethylene glycol-vinylsulfone (PEG-VS) with a degradable peptide crosslinker. This research shows the potential of using a PEG-VS- based Anisogel to allow for guided ingrowth and chondrogenic differentiation of human mesenchymal stromal cells (hMSCs) modulated by the alignment and size of anisometric microgels. The properties of the surrounding matrix are optimized for the availability of anchoring peptides (RGD concentration) and matrix density (hydrogel precursor concentration). The microgels of highest tested dimensions (10 × 10 × 100 µm3) lead to a donor-independent significant upregulation of chondrogenic markers (SOX 9, ACAN and COL2A1) and a decrease of hypertrophic chondrogenic markers (RUNX 2, COL10A1), compared to unaligned and smaller microgel sizes. As a proof of concept, the Anisogel is tested in a semi-orthotopic mouse model where the effect of microgel alignment on cell infiltration and osteochondral tissue formation is evaluated.

The phosphorylation of Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in regulating inflammatory factors secretion and chondrocyte degeneration, yet the mechanism maintaining its homeostasis remains unclear. To Identify UFMylation system mediated by DDRGK domain-containing protein 1 (DDRGK1) as a critical regulator of STAT3 phosphorylation to prevent cartilage degeneration. After screening differentially expressed genes and performing immunofluorescence on human cartilage, we generated cartilage-specific Ddrgk1 conditional knockout (cKo) mice and a K268R mutation at DDRGK1's key UFMylation site. Cartilage histology, RNA-seq, proteomics, phosphorylated protein microarray, western blot (WB), PCR and luciferase assays confirmed upregulated STAT3 phosphorylation. Co-IP, purified protein binding, cross-linking with mass spectrometry, and immunofluorescence explored the regulatory mechanism of STAT3 phosphorylation. A specific inhibitor was then selected for interventional treatment. DDRGK1 expression decreased significantly in human degenerated cartilage, especially in the deep zone. Conditional knockout of Ddrgk1 in murine chondrocytes or K268 mutation exacerbated cartilage degeneration in the destabilization of medial meniscus (DMM) model. Multi-omics analysis revealed dysregulation of the STAT signaling pathway in both Ddrgk1 knockout and K268R mutant chondrocytes, with Il-6 and Stat3 as the core genes. Crosslinking MS data demonstrated direct DDRGK1-STAT3 interaction mediated by DDRGK1-K267 and STAT3-K531. Mutations in these regions disrupted their interaction. DDRGK1-K267 mediated UFMylation of STAT3 and phosphorylated STAT3, leading to impaired phosphorylation and subsequent nuclear translocation. Importantly, in human degenerated cartilage, decreased DDRGK1 expression was associated with increased phosphorylation and nuclear translocation of STAT3. This finding was recapitulated in murine models, where cKo of Ddrgk1 or K268R mutation of Ddrgk1 in chondrocytes similarly enhanced STAT3 phosphorylation and nuclear translocation. Strikingly, the specific inhibitor of STAT3 phosphorylation, SH-4-54, effectively rescued cartilage degeneration in Ddrgk1 cKo mice. These findings unveil a novel, UFMylation-dependent role of DDRGK1 in regulating STAT3 activity and maintaining cartilage homeostasis.

Beyond their canonical role in bioenergetics, mitochondria are now recognized as critical signaling platforms that orchestrate innate immune responses. Central to this function is mitochondrial dynamics-the controlled equilibrium between fission and fusion-which serves as a critical structural and thermodynamic checkpoint for cellular fate and immunological status. A substantial body of evidence indicates that pathological mitochondrial fission, frequently driven by Dynamin-related protein 1 (Drp1), is a hallmark of numerous inflammatory conditions. Mechanistically, fragmented mitochondria release damage-associated molecular patterns (DAMPs) and induce acute ATP suppression, metabolically "licensing" NLRP3 activation by collapsing the ATP hydrolysis potential (ΔGATP). Recent breakthroughs have redefined this axis, distinguishing between physical damage and metabolic triggers, such as pyrimidine imbalance via the YME1L-SLC25A33 axis. Furthermore, the immunogenicity of DAMPs is strictly context-dependent; oxidized or "fragile" mtDNA containing ribonucleotides act as hyper-immunogenic ligands for cytosolic sensors like cGAS-STING. Emerging evidence further highlights that endosomal-mitochondrial crosstalk, intercellular mitochondrial transfer, and lipid-driven metabolic rewiring profoundly govern macrophage polarization and tissue homeostasis. Conversely, promoting mitochondrial fusion and robust quality control preserves organellar integrity and attenuates inflammatory cascades. This review critically synthesizes current literature, deconstructing the molecular linkages between organelle structure and metabolic signaling. By exploring the consequences in sepsis, neuroinflammation, osteoarthritis, and cancer, this treatise evaluates the pharmacological potential of modulating mitochondrial dynamics-ranging from direct Drp1 inhibitors and unfractionated heparin to metabolic stabilizers (e.g., GLP-1 receptor agonists), multi-pronged disruptors (e.g., Antimycin A), targeted nanomedicine, and communication-driven mitochondrial transplantation-positioning this axis as a promising frontier for precision pharmacology.

Osteoarthritis (OA) is driven by intertwined pathological processes, including chronic inflammation, oxidative stress, immune imbalance, hypoxia, and aberrant angiogenesis, while current noninvasive therapies remain limited by insufficient deep-joint delivery and poor multidimensional regulation. Here, an extracellular vesicle (EV)-centered, near-infrared (NIR)-responsive transdermal platform is developed to address these challenges. Apple-derived extracellular vesicles (AEVs) are used as intrinsically bioactive nanocarriers to co-deliver berberine (BBR) and piperine (PIP), and are integrated into a biocompatible dextran/alginate hydrogel containing graphene oxide (GO). Under NIR stimulation, GO provides on-demand energy conversion that supports mild hyperthermia-assisted barrier loosening together with potential photo-redox-associated microenvironment modulation, thereby enhancing local therapeutic availability while maintaining a safe thermal window. In vivo assessment of TRPV1 expression and tight-junction-related responses provides supportive indication for transport-associated modulation, whereas ex vivo diffusion findings are interpreted as barrier-level permeation evidence rather than direct confirmation of in vivo mechanisms. In an OA rat model, the NIR-activated platform is associated with reduced joint inflammation and edema, attenuated oxidative stress, improved macrophage polarization toward an anti-inflammatory phenotype, enhanced gait-related joint function, and preservation of cartilage structure. This study establishes a noninvasive, stimulus-responsive transdermal strategy for localized and multifaceted OA microenvironment modulation.

Osteoarthritis (OA) is a leading cause of disability among the elderly, characterized by aberrant subchondral bone remodeling that precedes cartilage degeneration. We identify parvalbumin (Pvalb) in osteocytes as a critical mechanosensory regulator of this pathological process. Pvalb expression is significantly reduced in osteocytes from both OA patients and male murine models of the disease. Conditional deletion of Pvalb in osteocytes accelerates OA progression, whereas bone-targeted restoration of Pvalb expression mitigates disease manifestations. Mechanistically, Pvalb maintains calcium homeostasis by competing with CaMKIV for calmodulin binding. Under excessive mechanical loading, Pvalb expression is suppressed, leading to activation of the Ca²+-CaMKIV-CREB signaling pathway, increased RANKL production, and subsequent osteoclast activation and pathological bone remodeling. These findings identifies an osteocyte-mediated mechanotransduction pathway in OA pathogenesis and underscore Pvalb as a promising therapeutic target.

Growth differentiation factor-15 (GDF-15), a stress-induced cytokine, has been implicated in pathways related to muscle degeneration, although findings regarding its association with sarcopenia remain heterogeneous. This study investigated the association between serum levels of GDF-15 and sarcopenia progression in community-dwelling older adults. 2347 individuals (mean age 72.3 years [SD 10.4]; 61.6% women), participating in the Swedish National Study on Aging and Care in Kungsholmen, were included in the study. Sarcopenia status (no, probable, and confirmed sarcopenia) were defined according to modified European Working Group on Sarcopenia in Older People 2 criteria. Twelve-year longitudinal sarcopenia trajectories were identified through latent class analysis. GDF-15 was measured in serum samples collected at baseline. Logistic regression was employed to assess the associations between GDF-15 and sarcopenia progression. Two trajectories of sarcopenia were identified: an early-progression pattern around the age of 70 and a later-progression pattern around the age of 80. Baseline sarcopenia prevalence differed between trajectories (p < 0.001), and GDF-15 levels were higher in the early trajectory (1.00 ng/mL vs. 0.86 ng/mL, p < 0.001). In adjusted multinomial logistic models, higher GDF-15 was associated with greater odds of probable (aOR = 1.6; 95% CI: 1.2-2.0) and confirmed sarcopenia (aOR = 1.9; 95% CI: 1.3-2.6). GDF-15 levels were also linked to increased odds of belonging to the early progression trajectory (aOR = 1.5; 95% CI: 1.2-1.9), with the association driven by the highest quintiles. GDF-15 reflects biological processes linked to muscle degeneration and may provide complementary information alongside established measures of sarcopenia in community-dwelling older adults. The Swedish Research Council, the Swedish Ministry of Health and Social Affairs, and the County Councils and Municipalities.

Postmenopausal women experience ongoing loss of bone mass, with resulting increases in the risk of fracture. This review describes the nature of postmenopausal bone loss, the definition of osteoporosis, and the current status of fracture risk estimation, which is pivotal in osteoporosis management. Important lifestyle measures include taking a balanced diet to maintain a healthy weight throughout life, safe physical activity, not smoking, and moderating alcohol intake. Severe vitamin D deficiency accelerates bone loss so should be avoided. Falls prevention becomes increasingly important with age, since falls cause most fractures. Pharmaceuticals to increase bone mass and prevent fractures either act by inhibiting bone resorption or by stimulating bone formation. Bisphosphonates are the most widely used antiresorptives, often taken as weekly oral doses. The intravenous bisphosphonate, zoledronate, has a long duration of action with effects on bone turnover, density, and fractures over a decade after a single dose. It is increasingly used in both prevention and treatment of osteoporosis. Denosumab is effective in preventing fractures but has a rapid offset of effect after its cessation. Some anabolic agents act via the PTH1 receptor, producing substantial increases in spine bone density but are not yet proven to prevent hip fractures. Romosozumab is a monoclonal antibody directed at sclerostin. It has both anabolic and antiresorptive effects and shows broad antifracture efficacy. Anabolics are used for 1 to 2 years in those with high fracture risk, before transition to long-term antiresorptive therapy. Treatment sequence options are discussed but more research is needed to establish which provide optimal fracture reduction.

Senile osteoporosis (SOP) is a chronic age-related skeletal disorder characterized by progressive bone loss and high fracture risk, with pathogenesis linked to excessive reactive oxygen species (ROS), osteoprogenitor cell senescence, and macrophage inflammation. Prussian Blue (PB) nanozymes show antioxidative potential for SOP but are limited by poor targeting, short circulation time, and unclear mechanisms, restricting clinical translation. Herein, we fabricated macrophage membrane-camouflaged citrate-modified PB (M@CPB) nanozymes for targeted SOP therapy and elucidated the underlying mechanism. Macrophage membrane coating prolonged the blood half-life of M@CPB by 1.47-fold and enhanced its bone tissue accumulation by 3.09-fold relative to CPB. In vitro, M@CPB inhibited O₂⁻ by 42.17% and scavenged H2O2 by 22.38%, reduced osteoprogenitor cell senescence, promoted M1-to-M2 macrophage polarization, and decreased the secretion of receptor activator of nuclear factor-κB ligand (RANKL) and tumor necrosis factor-α (TNF-α) to 47.41% and 53.10% of the model group, respectively. In vivo, M@CPB increased bone volume/tissue volume ratio by 3.83-fold relative to SOP mice, effectively ameliorating bone loss, motor dysfunction, and depressive-like behaviors. Collectively, M@CPB mitigated SOP by intervening in the ROS-senescence-inflammation axis and balancing bone remodeling, providing an innovative therapeutic strategy for SOP and potentially other age-related disorders.

Bisphosphonates (BPs) have been used effectively to treat excessive bone loss for over 50 years. Recent clinical evidence suggests extra-skeletal benefits but how this occurs remains unknown. Here we use a panel of human, murine and cellular assessments to chart BP-induced ageing-related changes both systemically and at local organ sites. In vivo spatial transcriptomics in aged mice treated with zoledronate showed a shift in cellular composition towards that of young animals specifically in heart, liver and intestine, with upregulation of genes governing detoxification, mitochondrial stability, energy metabolism, and antioxidation. A 5000-plex randomized trial based human proteomic analysis showed significant alterations in ~400 proteins after zoledronate treatment, with downregulation of proteins linked to genomic instability, proteostasis loss, mitochondrial dysfunction, stem cell exhaustion, and SASPs. Fluorescent labeling and tracing confirmed uptake of bisphosphonates by non-skeletal cells. In addition, low doses of several common, clinically utilized BPs stimulated growth and protected against DNA damage-induced senescence in multiple human cell types, with strongest effects in cardiomyocytes. Finally, proteome-wide target deconvolution with AlphaFold identified previously unrecognized binding partners, including PHB2 and ASAH1, and downstream upregulation of MEF2A was validated to be a key mediator of zoledronate triggered benefits in cardiomyocytes. Collectively, these results identify potential geroprotective mechanisms for BP action in multiple non-skeletal tissues.

To describe the evidence- and practice-based processes that led to the International Olympic Committee Sport Mental Health Assessment Tool 2 (IOC SMHAT2). Seven stages were conducted including: (1) reviewing the scientific literature related to the use (eg, uptake by physicians) of the IOC SMHAT-1; (2) gathering the view (eg, experience with the tool, advice for improvements) of IOC SMHAT-1 users; (3) exploring the misclassification and measurement properties of the IOC SMHAT-1; (4) performing misclassification analysis of available IOC SMHAT-1 data; (5) designing the initial IOC SMHAT2; (6) evaluating the content validity and feasibility of the initial IOC SMHAT2; and (7) finalising the IOC SMHAT2. The IOC SMHAT2 was developed for sports medicine physicians and other licensed/registered health professionals with the objective of identifying elite athletes (defined as professional, Olympic, Paralympic or collegiate level; 16 years of age and older) potentially experiencing mental health symptoms and disorders. The IOC SMHAT2 is comprised of a three-step approach: (1) universal screening as step 1, including five disorder-specific screening questionnaires and two single questions; (2) conditional screening as step 2, including two disorder-specific screening questionnaires; and (3) an aid to clinical assessment and treatment as step 3 that should be conducted by sports medicine physicians or licensed/registered mental health professionals. Based on scientific and anecdotal reflections on its first version, we developed the IOC SMHAT2 as a second updated version of the tool to identify elite athletes potentially experiencing mental health symptoms and disorders.

The velocity revolution in modern baseball has dramatically increased mechanical and metabolic demands on pitchers, elevating injury risk through cumulative upper extremity loading and impaired recovery. Traditional fatigue markers fail to capture real-time metabolic stress during pitching. Here, we report the first-in-human demonstration and validation of a minimally invasive wearable microneedle-based electrochemical biosensor for continuous interstitial fluid (ISF) lactate monitoring in Division I collegiate pitchers (n = 11), toward real-time performance tracking in real-world athletic settings. The wearable device integrates lactate oxidase-modified platinum microneedles with wireless telemetry and was applied to the non-dominant arm and calibrated against capillary point-of-care (POC) blood lactate. Pitchers underwent a standardized 2-h protocol including baseline rest, performance testing, warm-up, simulated acute pitching, and post-pitch grip strength assessment, with synchronous heart rate data acquisition. ISF lactate profiles revealed dynamic elevations during pitching (peak Δ ∼4.1 mmol/L from baseline 3.1 ± 1.1 mmol/L) that resolved within 20-30 min post-activity, correlating strongly with blood lactate levels and heart rate (HR) excursions. Unlike discrete blood sampling, continuous ISF monitoring captured transient lactate spikes associated with pitch intensity, speed, and inning transitions, revealing early signs of metabolic strain. Such ability to continuously monitor lactate in athletics holds considerable promise for physiological monitoring across professional sports towards performance enhancement and personalized athlete care.

Repair of the tendon-to-bone interface remains a major clinical challenge owing to its complex hierarchical architecture and limited intrinsic regenerative capacity. Decellularized biomaterials have emerged as promising scaffolds for tendon and ligament repair due to their native extracellular matrix composition, structural similarity, and biological activity. This review summarizes recent advances in the application of decellularized biomaterials for tendon-to-bone interface healing, covering both preclinical investigations and clinical trials of scaffolds derived from diverse sources, including porcine small intestinal submucosa, dermal matrix, tendon, amniotic membrane, pericardium, and Wharton's jelly. Particular emphasis is placed on current design strategies aimed at improving regenerative performance, including biomimetic architectural design, three-dimensional bioprinting for gradient interface engineering, regulation of the immune microenvironment, integration of stem cells or their derivatives, and sequential delivery of bioactive components. Despite encouraging preclinical outcomes, clinical translation remains limited and inconsistent. Major barriers include residual immunogenicity, batch-to-batch variations in bioactivity, an incomplete understanding of the mechanisms governing interface regeneration, and the scarcity of high-quality clinical evidence. Future research should therefore focus on optimizing decellularization protocols, refining scaffold architecture and functional modification strategies, integrating stem cells or stem cell-derived therapeutics, and conducting rigorous translational and clinical studies to bridge the gap between experimental success and clinical application. STATEMENT OF SIGNIFICANCE: Tendon-to-bone interface (TBI) healing remains a major challenge in regenerative medicine because the native enthesis has a complex graded architecture that is difficult to restore after injury. Decellularized biomaterials are promising for TBI repair because they retain native extracellular matrix components, structural biomimicry, and intrinsic bioactivity. This review provides a critical synthesis of recent advances in decellularized biomaterials for TBI healing, covering tissue sources and preclinical and clinical evidence. It also highlights emerging functionalization strategies, including biomimetic design, three-dimensional bioprinting, immune modulation, stem cell integration, and spatiotemporally controlled bioactive delivery. By addressing both regenerative potential and translational barriers, this review offers a timely framework for designing decellularized scaffolds for clinically effective tendon-to-bone regeneration.

The composites inspired by nacre, bone and teeth etc, often display anisotropic mechanical properties due to the high aspect ratio of their structural units, resulting in sudden failures under specific loading conditions. It still remains great challenge for fabricating the nanocomposites with weakly anisotropic mechanical properties. Herein, we discover the unique structure of the Raphia hookeri seed with a weakly anisotropic crack resistance in multiple directions. The remarkable mechanical properties stem from its tightly bonded, isodiametric cells and interlocking pits. Drawing inspiration from Raphia hookeri seed, we demonstrate an artificial Raphia hookeri seed nanocomposites by assembling layered polymethyl methacrylate-graphene microspheres with pits, which were then interwoven with polymethyl methacrylate to mimic the essential hierarchical structure. The artificial Raphia hookeri seed exhibits effective toughening performance across all crack orientations, and achieves a fracture toughness of up to 4.84 MPa m1/2 and specific toughness of 4.28 MPa m1/2/(Mg m-3), which are higher than both natural Raphia hookeri seed and previously fabricated weakly anisotropic polymer nanocomposites. The optimal distribution of pits and enhanced interfacial interactions between microspheres effectively inhibit crack propagation, contributing to the artificial Raphia hookeri seed's superior toughness in all directions. This pit-enabled granular microsphere architecture provides an avenue for fabrication high-performance weakly anisotropic nanocomposites.

Wound healing is a complex process that involves the interplay of infection, inflammation, and tissue regeneration. Nevertheless, the conventional therapies tend to treat these processes individually. Silver nanomaterials have been found to serve as platforms for surface chemistry and controlled ion-release kinetics, conferring a wide array of biological activities beyond their traditional antimicrobial applications and making them promising therapeutic platforms with broad-spectrum antimicrobial, immunomodulatory, and regenerative properties. Their versatile physicochemical properties, such as size and morphology. This review provides a critical, detailed examination of the biological processes that determine the therapeutic effects of silver nanomaterials, as well as their design principles and physicochemical properties. We discuss their multi-target antimicrobial effects against bacterial, fungal, and viral infections, as well as their role in regulating innate and adaptive immunity during wound healing, including in biofilm infections. These materials, along with soft-tissue and internal-organ repair, are discussed in both cutaneous and non-cutaneous applications, as well as in orthopedic and dental applications. Moreover, the most significant translational considerations, such as safety, dose-dependent toxicity, biodistribution, the long-term fate, and regulatory factors, are critically examined. The review highlights the importance of drawing on insights from materials science, microbiology, immunology, and regenerative medicine to demonstrate how rationally designed silver nanomaterials can address unmet clinical needs and identify opportunities for their safe and effective clinical use.

The treatment of post-traumatic osteomyelitis (PTO) is impeded by bacterial biofilms and disruption of drug delivery systems in acidic lesions. Here, we develop an acid-resistant amine-linked heteroporous covalent organic framework (ARCOF) using a reductive amination strategy. This approach overcomes the insufficient chemical stability and drug delivery capacity of conventional COFs arising from the trade-off between high bond strength and crystalline reversibility. The pre-designed hetero-environmental channels of ARCOF enable synergistic loading of vancomycin and the anti-biofilm agent felodipine. When combined with calcium phosphate cement, both drugs exhibit sustained release over 240 h under inflammatory conditions. The therapeutic efficacy is evaluated in a rat PTO model, where the co-delivery system significantly enhances antibacterial efficacy by disrupting biofilm integrity and concurrently modulates the local inflammatory microenvironment to support bone tissue recovery. This strategy provides an integrated local delivery approach to overcome pharmacokinetic barriers and biofilm resistance in osteomyelitis treatment.

Microbiome and transcriptome analyses revealed that Fusobacterium nucleatum (F.n) in clinical samples is associated with immune suppression and poor prognosis in triple-negative breast cancer spinal metastasis. However, its preferential localization in hypoxic tumor regions limits the efficacy of conventional antimicrobial therapies, which poorly penetrate solid tumors and function suboptimally under anaerobic conditions. Developing strategies that enable deep tumor penetration, eliminate anaerobic bacteria, and induce immunogenic cell death remains a major challenge. In this study, a novel charge-enrichment and light-activated biomimetic nanosystem, designated as polyion liquid-bridged eosin Y (PIL-BEY), was developed. On one hand, interionic hydrogen bonding and dynamic electrostatic interactions within polyionic liquids reduce the surface energy of the nanoprobe and synergistically remodel the dense tumor stromal microenvironment via photodynamic therapy, thereby facilitating the deep intratumoral penetration and accumulation of PIL-BEY. On the other hand, the novel photosensitizer BEY generates reactive oxygen species via electron transfer under hypoxic conditions, thereby effectively eradicating bacteria within hypoxic tumor regions. The resulting pathogen-associated molecular patterns, together with damage-associated molecular patterns, activate dendritic cells, promote cytotoxic T lymphocyte infiltration, trigger immunogenic cell death, and induce systemic antitumor immune responses with durable immune memory. This oxygen-independent, dual-functional nanoplatform offers a promising strategy for treating invasive metastatic tumors.

We evaluated whether combined general and regional anaesthesia (GA+RA) was associated with improvements in activities of daily living compared with GA alone in adult patients having major orthopaedic surgery. This target trial emulation used data from the Japanese Diagnosis Procedure Combination system (April 1, 2016-December 31, 2023) for patients undergoing major orthopaedic surgery. The primary outcome was discharge-anchored functional change, defined as the difference in the Barthel Index scores between admission and discharge, among admissions with observed and comparable discharge Barthel Index scores. We conducted stabilised inverse probability of treatment weighting using preoperative covariates, and weighted linear regression models were fitted. Secondary outcomes included in-hospital mortality and postoperative length of stay. Missing data were handled using multiple imputations, and sensitivity analyses (inverse probability of censoring weighting, subgroup analyses, and complete case analysis) were performed. A total of 244 212 patients received GA+RA (peripheral nerve block: 183 564; epidural anaesthesia: 60 648) and 435 462 patients received GA alone. After propensity score weighting, GA+RA yielded a higher change in Barthel Index scores (mean difference 0.73, 95% confidence interval [CI] 0.57-0.88, P<0.001), shorter postoperative length of stay (-1.40 days, 95% CI -1.45 to -1.35, P<0.001) and lower in-hospital mortality (hazard ratio 0.85, 95% CI 0.76-0.96, P=0.006). Sensitivity analyses yielded directionally consistent findings. Combined general and regional anaesthesia was associated clinically with modest improvements in discharge-anchored functional change, postoperative stay and in-hospital mortality. Residual confounding and heterogeneity of regional anaesthesia techniques warrant cautious interpretation and prospective confirmation.

Ethnicity data are essential in understanding how different groups are impacted by different treatments/healthcare interventions, but more work is needed in how these data should be collected, handled and reported in trials to address distrust among marginalised ethnic groups towards healthcare research. To do this, researchers need effective training and opportunities to engage with communities from a diverse range of ethnicities. Developing guidance on how to meaningfully involve diverse ethnic groups in all stages of a trial including planning the collection of ethnicity data is one way to improve the impact of clinical trial results and ensure these groups can access equitable healthcare.Our collaborative work between health researchers and diverse ethnic communities produced 13 initial recommendations aimed at academic health researchers to change their practice involving diverse ethnic communities in areas from trial design through to reporting. The first four recommendations are concerned with the planning stage of the trial, the fifth with how researchers interact with funding bodies. Recommendations 6, 7 and 8 are relevant to data collection during trial set up, and recommendations 9, 10 and 11 focus on training and responsibility during the trial set up and the trial conduct stage. Recommendations 12 and 13 cover reporting.The recommendations will benefit from piloting but have the potential to help trial teams make their research more inclusive with regard to ethnicity, which in turn will support more representative, equitable and impactful research.

Cardiovascular disease is a leading cause of mortality, with significant investments in research to improve treatment and prevention. Data sharing enhances transparency, reproducibility, and collaboration, yet data sharing statement (DSS) inclusion remains inconsistent. This study evaluates DSS prevalence, content, and influencing factors in high-impact cardiology journals, examines journal policy influence, and assesses data sharing feasibility by contacting authors who indicated data availability. A cross-sectional analysis was conducted to assess DSS inclusion in top cardiology, selected general medicine, emergency medicine, and orthopaedic surgery journals. A systematic PubMed search identified clinical studies published from 2020 to 2023. Logistic regression models assessed factors associated with DSS inclusion, while thematic analysis categorized DSS content. Corresponding authors who indicated data availability upon request were contacted to evaluate follow-through. Among 2941 articles, 1004 (34.14%) included a DSS. Data sharing statement prevalence varied by discipline: cardiology (52%), general medicine (96%), emergency medicine (12%), and orthopedic surgery (14%). Policy enforcement drove DSS inclusion, with post-policy articles significantly more likely to contain a DSS. Funding status, study design, article access, and impact factor also influenced DSS presence. Thematic analysis identified conditional availability and gatekeeping as dominant DSS themes. Of authors who stated data were available upon request, only 31% ultimately provided access. Data sharing statement inclusion in cardiology research remains inconsistent, with journal policies playing a key role in increasing prevalence. However, real-world data-sharing practices often fall short of stated commitments. Addressing logistical and financial barriers will be essential to improving data availability in cardiology research.

Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events. Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing. A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro. This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies.

Dentinogenesis Imperfecta (DI) is a rare genetic disorder that disrupts the structure and mechanical integrity of dentin, often through alterations to the collagen matrix. In cases associated with Osteogenesis Imperfecta, DI arises from COL1A1 or COL1A2 variants (DI type I). The multiscale mechanisms linking alterations of the collagenic scaffold to dentin microstructural defects remain poorly understood. In this proof-of-concept study, we employed a multimodal 3D characterization framework combining biochemical assays and advanced imaging techniques to investigate the relationship between collagen integrity, mineral organization, and microstructural defects in four (n=4) primary teeth from a DI patient carrying a COL1A2 variant (c.982G>A (p.Gly328Ser)) and eight (n=8) primary teeth from healthy donors. A threefold increase in molecular-level collagen uncoiling (i.e., denaturation) was found in DI dentin compared to healthy dentin using trypsin-hydroxyproline assays. A reduction in the second harmonic generation signal combined with increased spatial variability were observed, indicating pronounced heterogeneities in the collagen scaffold. These heterogeneities were spatially associated with disorganization of the mineral phase, the emergence of hypermineralized regions, and a 30% higher mean mineral density, as measured by high-resolution micro-computed tomography. Severe disruption and partial occlusion of the tubular network were further identified using confocal microscopy, resulting in reduced porosity. These results support a multiscale association between collagen alterations, mineral heterogeneity, and pore network disruption, consistent with a model in which compromised collagen integrity alters the mineral organization and the tubular network of dentin. Although requiring confirmation on larger cohorts, these findings provide a preliminary mechanistic framework for understanding how disruptions of the hierarchical structure of DI dentin, impairing its toughness, may originate from molecular collagen denaturation. Statement of significance: Dentinogenesis Imperfecta (DI) is a rare genetic disorder that weakens teeth, leading to fractures and enamel loss. However, how molecular defects translate into fragile dental tissue remains poorly understood. In this proof-of-concept study, we show that a COL1A2 mutation induces collagen denaturation at the molecular scale, which is associated with major disruptions in dentin structure and mineralization at larger scales. Such structural changes are known to reduce tissue toughness. Our findings provide early but compelling evidence for a direct link between molecular-scale collagen defects and macroscopic fragility in dentin. This work introduces a multiscale framework contributing to the understanding of structure-property relationships in mineralized biological tissues.

Bone regeneration in orthopedics is a great challenge, as efficient recovery affects patient's quality of life. Common methods encounter different limitations regarding diagnosis, implantation, and bone health monitoring. Recent advances in artificial intelligence (AI), specifically machine learning (ML) algorithms, have presented opportunities to enhance these aspects by accurately analyzing imaging data. This provides detailed evaluations that help to determine bone condition and guide treatment strategies. ML models can facilitate a patient-specific approach to select and design intelligent implants by examining extensive biomaterial datasets to identify the best match for each patient's biomechanical and biological needs. Furthermore, ML models can analyze data to accurately predict bone-healing timelines, allowing clinicians to track recovery trends, and make timely interventions in potential complications. In clinical settings, ML tools assist with preoperative planning, postoperative follow-up, and the design of intelligent implants, offering more effective, data-driven decision-making and favorable outcomes in bone regeneration. Looking ahead, while ML advancements show promise for effective orthopedic therapies, challenges persist. ML could revolutionize bone regeneration in various ways and offer predictive insights that promote patient-centered orthopedic care. Altogether, considering the continued evolution of ML, its integration into clinical applications will be crucial for developing truly intelligent bone regeneration therapies.

Peripheral nerve injury (PNI) affects over one million people annually, causing profound functional deficits and substantial socioeconomic burden. The intense oxidative stress following PNI disrupts mitochondrial energy metabolism, drives excessive reactive oxygen species production, and triggers Schwann cell ferroptosis, collectively forming a major barrier to nerve regeneration. This study aims to develop a biomimetic chiral nanozyme system that targets the oxidative stress-mitochondrial dysfunction-ferroptosis axis to enhance nerve regeneration following PNI. We engineered three types of chiral MoS2 nanozymes (D, L, and RCMS) and evaluated their antioxidant activities. The L-enantiomer CMS, exhibiting superior superoxide dismutase and catalase-like activities, was embedded into polycaprolactone (PCL) and loaded with indole-3-propionic acid (IPA) to form a controlled-release system (PCL@LCMS + IPA). Multi-omics analyses were performed to elucidate the therapeutic mechanisms. In vitro effects on Schwann cell mitochondrial function and ferroptosis were assessed, while in vivo efficacy was evaluated in PNI models. PCL@LCMS + IPA selectively modulated the mitochondrial tricarboxylic acid cycle while suppressing lipid peroxidation and ferroptosis-related signaling pathways. In vitro, the system enhanced mitochondrial respiratory chain function, elevated ATP and NADPH production, restored iron homeostasis, and strengthened the glutathione peroxidase system, thereby inhibiting ferroptotic death and supporting Schwann cell-mediated repair. In vivo, PCL@LCMS + IPA maintained mitochondrial metabolic stability under oxidative stress, leading to improved axonal regeneration, angiogenesis, remyelination, and motor function recovery. The controlled-release chiral nanozyme system effectively targets the oxidative stress-ferroptosis axis, restoring mitochondrial energy metabolism and preventing Schwann cell ferroptosis, thereby promoting functional nerve regeneration.

The integrity of the urethral epithelium is critical for functional urethral reconstruction. Once disrupted, persistent exposure of the injured wound to the harsh urinary microenvironment triggers inflammatory responses, hampers re-epithelialization, and leads to fibrosis and urethral dysfunction. In this study, we developed a biomimetic urethral scaffold with a spatiotemporally coordinated design that enables early-stage barrier protection and late-stage scar-free urethral reconstruction (termed PTAA scaffold). The luminal layer of the scaffold is constructed by covalent crosslinking of thioctic acid and allicin to mimic the barrier function of the urethral epithelium to effectively resist urine erosion and bacterial infection during the early stage of repair. The regenerative layer is a protocatechualdehyde-modified SIS multifunctional scaffold that mimics the porous structure of the urethral submucosa and provides an extracellular matrix-like regenerative microenvironment. In vivo investigations confirm that the scaffold effectively accelerates urethral re-epithelialization, preserves urethral patency, and markedly reduces fibrotic deposition, achieving functional restoration. Further transcriptome analysis revealed that the scaffold attenuates urine-triggered inflammatory response and while activating epithelial regenerative programs by remodeling regenerative microenvironment, thereby providing favorable conditions for scar-free urethral healing. This spatiotemporal design enables in situ, orderly, and scar-free urethral reconstruction, providing a proof of concept for stage-specific urethral repair.

Gastric cancer primarily originates from gastric stem/progenitor cells and is driven by somatic mutations. Although Helicobacter pylori is the main risk factor, how it drives malignancy is still not well understood. Analysis of single-cell RNA sequencing data reveals that human gastric cancer correlates with suppressed BMP signalling, a crucial niche signal for gastric stem cells, in stromal cells rather than epithelial cells. Genetic disruption of BMP signalling in Col1a2+ stromal cells or Acta2+ myocytes/pericytes alone, but not in gastric stem cells themselves, triggers mutations in gastric stem cells and initiates cancer development. Mechanistically, loss of BMP signalling increases stromal production of Wnt ligands, which dose-dependently drive transcription-replication collisions, R-loops, and DNA damage in gastric stem cells. The resulting DNA damage and carcinogenesis can be prevented by small-molecule inhibitors targeting Wnt pathway. Importantly, we identify inflammation as a key disruptor of stromal BMP signalling, as seen in patient samples with chronic atrophic gastritis and H. pylori-infected mouse gastric samples, which is associated with DNA damage. Together, these findings show how chronic inflammation derails niche signalling to drive stem cell mutations and gastric cancer and highlight promising avenues for early prevention.

Abnormal mechanical stimulation drives fibrotic scar formation in active wounds by sustaining mechanotransduction, promoting apoptotic cell accumulation and pro-fibrotic amplification that constrain functional regeneration. To address this challenge, we developed a mechanically adaptive hydrogel patch (Gel/VP) through the integration of an interpenetrating polymer network and CNC@PDA@ZIF8 dynamic nanofillers, in which the interpenetrating network provides structural load-bearing and adaptive deformation, while the nanofillers form a force-induced, reconfigurable dissipative network via hydrogen bonding and π-π interactions, collectively dissipating tensile energy upon pre-stretched application, establishing a reverse mechanical buffer at the wound interface, suppressing sustained Piezo1-YAP activation, restoring macrophage efferocytosis-mediated apoptotic cell clearance, and ultimately limiting fibrotic scar formation. The interpenetrating architecture endows the patch with a tunable elastic window matched to the mechanical environment of skin (elastic modulus of 7-15 kPa with twofold extensibility). Under reverse mechanical buffering, the macrophage phagocytic rate increases from 22.50% to 64.50%, significantly enhancing apoptotic cell clearance. In vivo, the patch achieves near-complete wound closure (>95%) within two weeks, markedly reduces α-SMA+ myofibroblast accumulation, promotes ordered collagen remodeling, and substantially decreases scar formation. Overall, by leveraging material-mediated reverse stress buffering to restore macrophage efferocytosis, this study targets apoptotic cell clearance at an early stage of fibrosis and provides a robust antifibrotic material strategy for the functional regeneration of active wounds. STATEMENT OF SIGNIFICANCE: Abnormal mechanical stretching during wound healing is a key yet underrecognized driver of fibrotic scar formation, and current therapies rarely address this physical cue. Here, we develop a stress-adapted hydrogel patch that forms a "reverse mechanical buffer" under pre-stretch, actively redistributing tensile forces at the wound interface. This buffering suppresses mechanotransduction (Piezo1-YAP signaling) while restoring macrophage-mediated clearance of apoptotic cells. By integrating an interpenetrating polymer network with dynamic nanofillers, the material achieves adaptive energy dissipation and mechanical compatibility with skin. This work establishes a mechanically guided, immunomodulatory approach to limit fibrosis, offering a promising biomaterials strategy for scarless healing and functional tissue regeneration.

Occipital neuralgia (ON) is a refractory chronic headache disorder characterized by paroxysmal shooting or stabbing pain in the posterior scalp, innervated by occipital nerves that originate from C2 and C3 dorsal root ganglion (DRG) neurons. Limited access to human DRG samples has impeded the understanding of the cellular and molecular mechanisms and the development of effective treatments for ON. We innovatively employed percutaneous full-endoscopic C2 ganglionectomy and subsequently performed single-nucleus RNA-sequencing (snRNA-seq) on C2 DRG from both ON patients and healthy controls. Somatostatin-expressing (SST+) neurons were selectively downregulated in patients with ON. Behavioral studies demonstrated that ablation of SST+ neurons induced pain, while optogenetic or chemogenetic activation of these neurons alleviated acute and chronic pain in mice. Altogether, this study provides new insights into the mechanisms underlying ON, revealing potential therapeutic targets for pain management.

The design of fracture-resistant materials has long been hindered by the complexity of toughening mechanisms across multiple length scales1,2. Mechanical metamaterials offer a promising platform to address this challenge, yet existing research has largely focused on passively characterizing fracture in conventional lattice architectures3-8. Recent studies have demonstrated the potential of elastic instabilities to enhance functionalities in architected materials9-18; however, their connection to fracture resistance remains unexplored. Here we demonstrate that fracture behaviours in mechanical metamaterials can be actively programmed by exploiting elastic instabilities, thereby bridging the two traditionally disconnected failure modes. Through a combination of experiments and simulations, we show that controlled manipulation of the inelastic zone size in pseudoplastic metamaterials enables a transition from intrinsic to extrinsic fracture behaviour, accompanied by up to a one-order-of-magnitude increase in fracture energy. This work represents a shift from passive observation to active control of fracture mechanics, establishing a new framework for designing metamaterials with tailored fracture resistance. Our findings not only advance the fundamental understanding of instability-fracture interactions in metamaterials but also suggest a broadly applicable route for programming fracture behaviours through instability design.

Mechanoluminescence (ML) is a phenomenon of force-response self-luminescence, which was observed long ago. However, the underlying mechanism of ML remains ambiguous due to the complexity of light-emitting processes. Atomically precise metal nanoclusters are expected to serve as ideal model systems for unraveling ML mechanisms in specific nano-systems. Herein, we report the observation of mechanoluminescent crystals of metal nanoclusters. Cu7 clusters, which crystallize in a non-centrosymmetric trigonal space group, exhibit bright green ML when subjected to mechanical stress. Through piezoelectric experiments and theoretical calculations, we demonstrate that piezoelectricity arising from mechanical deformation of the crystal leads to an asymmetric distribution of internal dipoles within the crystal. Furthermore, crystal fracture under external force induces charge separation. Such alterations modulate the transition dipole moments and induce localized electronic transitions through strain-induced charge asymmetry, thus triggering stress-dependent luminescence. The findings provide insights into the mechanism of ML in a nanocluster system at the atomic level.

Resistance to cyclin-dependent kinase (CDK) 4/6 inhibitors, such as ribociclib (RB), limits breast cancer therapy. Although PEG10 siRNA (siPEG10) can counteract this resistance, achieving targeted, synchronized co-delivery to reshape the immunosuppressive tumor microenvironment (TME) remains a formidable challenge. By loading RB and siPEG10 into PEG-β-CD-modified mesoporous silica nanoparticles (PMSNs) and coating them with breast cancer cell membranes (CM), the nanocomposite RB/siPEG10@PMSNs-CM was synthesized. The nanomaterials were characterized for their size, charge, drug loading, and pH-responsive release. Therapeutic efficacy, immunotherapy-related potentials, and underlying mechanisms were evaluated using in vitro functional assays, an anoikis resistance model, and in vivo breast cancer models. Toxicity was assessed in liver and kidney tissue. The nanodrug RB/siPEG10@PMSNs-CM (<200 nm) exhibited enhanced cellular uptake and pH-dependent drug release. The zeta potential of the RB/siPEG10@PMSNs-CM was negative. The nanodrug significantly inhibited tumor cell growth, migration, invasion, and metastasis, while inducing apoptosis. Crucially, the nanodrug overcame anoikis resistance, upregulated cleaved caspase-3 and cleaved PARP, reversed epithelial-mesenchymal transition (EMT) markers (increased E-cadherin and decreased Vimentin), and inhibited p-STAT3 and p-ERK signaling. Furthermore, the nanodrug exhibited lower toxicity to liver and kidney than RB. In Conclusion, the developed biomimetic nano-delivery system RB/siPEG10@PMSNs-CM successfully co-delivers RB and siPEG10 and exhibits a favorable safety profile. This platform exhibits anti-primary tumor and anti-metastatic efficacy and effectively overcomes anoikis resistance in breast cancer, which correlated with the suppression of the MEK/ERK and STAT3 signaling pathways, offering a promising combination strategy for advanced breast cancer immunotherapy and targeted treatment.

Safety assessment of a deep geological repository is essential to ensure the long-term isolation of spent nuclear fuel and protection of the environment. Uranium migration in groundwater is a key factor in evaluating the safety of the spent nuclear fuel disposal, and uranium mobility is significantly influenced by redox conditions. However, quantifying the effects of redox changes at the field-scale remains challenging. This study investigates uranium migration under changing redox conditions using a tracer test and reactive transport modeling. The study site consists of uranium-bearing black slate and has weakly oxidizing groundwater conditions (1.62 mg/L DO). Strongly oxidizing conditions were induced by injecting DO-saturated groundwater (10.16 mg/L DO) during the tracer test. Uranium migration during the tracer test was quantified using a reactive transport model (RTM) that couples a discrete fracture-matrix (DFM) model implemented in COMSOL Multiphysics with the geochemical code PhreeqcRM. The tracer test showed that uranium mobility increased under shifting redox conditions, with the maximum uranium concentration rising by 85.2% and the cumulative mass increasing by 66.0%. The RTM results indicate that desorption primarily contributes to the enhancement of uranium mobility, and that the oxidative dissolution rate of UO2 varies by up to six-fold depending on redox conditions. These findings highlight that redox changes can increase uranium mobility and the need to consider redox evolutions in the safety assessment of spent nuclear fuel disposal.

Per- and polyfluoroalkyl substances (PFAS) are persistent environmental pollutants linked to diabetes, yet their role in diabetic complications is poorly understood. This study demonstrates that exposure to multiple PFAS subtypes significantly delays wound healing in diabetic rats. Through integrated transcriptomic and network toxicology approaches, we identified heat shock protein 90 beta family member 1 (HSP90B1/GRP94) as a key mediator of this toxicity. A natural product screen suggested ligustilide as a potential protective agent. Computational docking revealed that both ligustilide and the representative PFAS compound OBS target the Asn107 site on GRP94. Subsequent site-directed mutagenesis and knockdown-rescue experiments confirmed that OBS binding at Asn107 induces N-glycosylation of GRP94. Ligustilide competitively occupies this site, thereby blocking OBS-induced glycosylation, restoring GRP94's chaperone function, and alleviating endoplasmic reticulum stress and apoptosis. In PFAS-exposed diabetic rats, ligustilide treatment effectively rescued impaired wound healing, as evidenced by accelerated wound closure, improved tissue perfusion and vascular maturation, and enhanced collagen deposition. Our findings elucidate a novel mechanism through which PFAS disrupt tissue repair via precise glycosylation of GRP94 and highlight ligustilide as a promising therapeutic candidate against PFAS-aggravated diabetic complications.

Designing a temporal regulation system for responsive stem cell delivery that simultaneously addresses micro-environmental improvement in the infarcted area and electromechanical coupling compensation through synergistic stem cell therapy continues to pose substantial research challenges. We present a micro-environmentally induced smart temporal regulation composite conductive hydrogel for myocardial infarction therapy. Adipose derived stem cells (ADSC) were seeded on alginate (Alg)/gelatin (GT) composite microspheres (Alg/GT), which were encapsulated into reactive oxygen species (ROS) responsive conductive hydrogels (HGB) based on hyaluronic acid functionalized with phenylboronic acid (HA-PBA), dopamine-modified GT (GT-DA), and borate-functionalized polyaniline (BPA). Alg/GT microspheres exhibit excellent carrying capacity for ADSC and promoting ADSC paracrine effects. Besides the smart controlled release properties, the optimised hydrogel (HGB3) possesses a variety of functional properties including injectability, appropriate mechanical strength and electrical conductivity, anti-inflammatory and antioxidant properties. Together, these properties contribute to micro-environmental enhancement and electromechanical coupling restoration in the infarcted myocardial region. When the composite system was injected into the infarcted myocardifm, it achieved benign remodeling of the infarcted myocardium through regulation of inflammation, inhibition of fibrosis and promotion of vascular regeneration. This micro-environmentally induced smart temporal regulation composite conductive hydrogel system offers a novel therapeutic strategy for the management of acute myocardial infarction.

Vanillin, a widely used flavouring agent in food, pharmaceutical, and cosmetic industries, requires precise monitoring due to potential health risks at excessive consumption. This study reports a highly sensitive electrochemical sensor based on defect-engineered Co-Fe₃N/rGO synthesized via urea-assisted nitridation. This process creates nitrogen vacancies in Co-Fe₃N, while rGO ensures uniform nanoparticle dispersion and enhanced electron transfer. Characterization confirmed 20-50 nm Co-Fe₃N nanospheres anchored on rGO with intimate interfacial contact. The modified electrode exhibited outstanding electrocatalytic activity toward vanillin oxidation, delivering a detection limit of 0.249 nM, a linear range of 0.01-1322 μM, and excellent selectivity. Practical applicability was validated through vanillin quantification in six commercial food products, achieving recoveries of 98.99-101.57% with good agreement to HPLC. The exceptional performance arises from synergistic effects between nitrogen-vacancy active sites and the conductive rGO network. This work presents a robust, cost-effective platform for food quality monitoring with potential for field-deployable applications.

Spatial transcriptomics is powerful but costly; hematoxylin and eosin (H&E) images are routine. We present Coladan-human3K, the largest human spatial transcriptomics resource (~ 3,000 profiles), and Coladan, a trimodal (image, language, spatial-gene) whole-slide framework predicting genome-wide genes per spot with calibrated uncertainty while preserving foundation-model representations. Across 32 Visium datasets, Coladan improves Pearson correlation from 0.230 to 0.431 (~ 1.9 ×), shows pathway-level enrichment consistency, and transfers zero-shot to VisiumHD and spot-level Xenium. Classification token (CLS) embedding-only perturbation performs on par with expression-based baselines, enabling image-only virtual perturbation without measured expression, illustrated on normal and cancer prostate sections for in-situ hypothesis generation.