Atherosclerosis and its complications are highly prevalent worldwide, and managing oxidative stress in endothelial cells to alleviate abnormal inflammatory damage is a critical therapeutic approach. Nanomedicine delivery systems offer promising solutions by overcoming the limitations of surgical interventions and the off-target effects of oral drugs. In this study, we developed a modified mesenchymal stem cell membrane (MSCM)-encapsulated nanoparticle drug delivery system that effectively delivers kaempferol to atherosclerotic sites. These biomimetic nanoparticles were able to specifically target endothelial cells in an inflammatory environment while evading macrophage-mediated endocytosis. Moreover, the modified MSCM-encapsulated kaempferol nanoparticles (KPM) had a protective effect on oxidatively damaged endothelial cells. In vivo, the modified nanoparticles successfully migrated toward atherosclerotic lesions, as demonstrated in a mouse model of susceptible atherosclerotic plaques. Intravenous injection of KPM significantly reduced the lipid plaque load and improved plaque structure. Furthermore, the biosafety of KPM was comprehensively assessed both in vitro and in vivo, with no significant effects on blood count, lipid balance, cellular activity, body weight, or liver or kidney function. This is the first report of the use of MSCM to encapsulate kaempferol nanodrugs to treat atherosclerosis. This strategy presents a novel and effective therapeutic system for targeted delivery of antioxidant therapy to atherosclerotic sites, offering potential for the treatment of atherosclerosis in cardio-cerebrovascular diseases.

Every year, millions of ureteroscopy patients must return for a second procedure to remove the ureteral stent, doubling both costs and infection risk. Biodegradable stents offer a promising solution by eliminating this second procedure, but achieving an optimal balance between robust mechanical performance, precise degradation kinetics, and excellent biocompatibility remains a major challenge. A novel tailorable biodegradable hydrogel ureteral stent (GAS) designed from Gelatin Methacryloyl (GelMA) and Alginate Methacryloyl (AlgMA), utilizing double network crosslinking and Hofmeister stretching treatment for programmed degradation. This design not only significantly enhances the stent's mechanical performance but also proposes a dynamic hydrogen bonds reconfiguration and crosslinking density tailorable degradation strategy to optimize degradation kinetics. By adjusting dynamic hydrogen bonds and optimizing GelMA concentration, GAS achieves adjustable degradation times ranging from 2 to 4 weeks. Furthermore, in animal models, not only can the degradation time be controlled within a range of 2-4 weeks, but the stents also exhibit lower signs of inflammation or fibrosis compared to clinically commonly used stents. In essence, GAS represents a simple yet powerful strategy for customizing the degradation kinetics of biomedical implants, and this stent is poised to significantly improve postoperative care and outcomes for ureteroscopy patients.

Ischemic stroke, a leading cause of global mortality and disability, is exacerbated by cerebral ischemiareperfusion injury (CIRI), wherein ferroptosis drives irreversible neuronal loss. Curcumin, a potent natural polyphenol, holds promise for combating CIRI but is thwarted by poor solubility and low bioavailability. To overcome this, we have created a biomimetic macrophage-vectored nanoinducer (Cur-P @ MM) that can actively target the ischemic brain. By keeping the original membrane proteins such as CD47 and integrin alpha 4 beta 1, Cur-P @ MM can achieve effective immune evasion and inflammation-tropic delivery, which helps with crossing the blood-brain barrier and achieving site-specific drug release. In the cellular model, Cur-P @ MM improved neuronal survival under oxidative stress, scavenge ROS, and preserve mitochondrial integrity. In a rat stroke model, it mainly concentrated in the ischemic side, greatly reduced the infarction area, and restored the neurological and cognitive function. Mechanistically, Cur-P @ MM suppresses ferroptosis by alleviating lipid peroxidation, reducing iron overload, and enhancing the Nrf2-associated antioxidant defense program. This leads to the coordinated upregulation of the solute carrier family 7 member 11 / glutathione peroxidase 4 (SLC7A11/ GPX4) axis and downregulation of transferrin receptor 1. Our work unveils a targeted nanotherapeutic strategy that harnesses the body's own antioxidant machinery to combat ferroptosis, offering a transformative avenue for ischemic stroke treatment.

Intestinal mucosal secretion is central to coordinating the gut microenvironment with mechanical signals. Yet, in situ monitoring of small-molecule in the intestine remains challenges because of the distinctive mechanical deformation and highly biofouling environment. Here, we introduce a sensing interface inspired by the host-guest molecular recognition. A stretchable electrode was constructed by co-electrodepositing 2-hydroxypropyl-β-cyclodextrin (HC) and poly(3,4-ethylenedioxythiophene) (PEDOT, P) onto the conductive gold nanotubes (Au NTs) framework. This approach couples the deformation-tolerant electrochemical performance of Au NTs with HC-enabled selective recognition of serotonin (5-HT), while effectively mitigating biofouling in complex biological environment. The resulting Au@HCP NTs sensor enables dynamic capture of mechanically evoked 5-HT release from enterochromaffin cells (ECs) under biomimetic stimulation, spanning both cellular and tissue-level readouts. Beyond monitoring, we further conceptualize ECs mechanosensory plasticity as an immunomodulatory node. Diverse microbial mimetics elevate ECs-derived 5-HT, and the platform reveals 5-HT signaling as a core mechanism that integrates immune information with mechanosensation in ECs. Collectively, this work establishes a host-guest recognition-based strategy for real-time small-molecule monitoring in complex, mechanically dynamic environments, offering a generalizable route toward in situ sensing under unique mechanical demand.

Background: Microvascular invasion (MVI) is a major determinant of recurrence and poor prognosis in hepatocellular carcinoma (HCC), yet accurate preoperative assessment remains challenging. We investigated the incremental value of multi-regional spatial interaction (MSI) features derived from supervoxel-based habitat analysis on Gd-EOB-DTPA-enhanced MRI for preoperative MVI prediction. Methods: In this retrospective dual-centre study, patients with HCC from two institutions who underwent preoperative Gd-EOB-DTPA-enhanced MRI were included. Tumour habitats were generated from T1-weighted, arterial phase, portal venous phase, and hepatobiliary phase images. Habitat radiomic and MSI features were extracted to build single-sequence models and a four-sequence fusion model. Centre 1 served as the development cohort and Centre 2 as the external validation cohort. Parallel subgroup analyses were performed for tumours smaller than 5 cm, 3 cm, and 2 cm. Findings: Four habitat subregions were consistently identified across sequences and showed differences in relative proportion, entropy, and radiomic feature distribution. Among single-sequence models, the hepatobiliary phase model performed best and retained the most MSI features. The MSI-inclusive fusion model achieved AUCs of 0.85 in the internal test cohort and 0.89 in the external validation cohort, with favourable performance maintained across all small-tumour subgroups. Interpretation: MSI features provide complementary information beyond conventional habitat radiomics for characterising spatial heterogeneity in HCC. Multi-sequence integration of MSI features improves preoperative MVI prediction and may support risk stratification.

Macrophage foaming, characterized by uncontrolled uptake of oxidized LDL (ox-LDL) by macrophages, critically drives atherosclerosis (AS) progression. Although NK cells are found to be atherogenic, their direct impact on macrophage foaming remains unknown. Here we examined the role of NK cells in macrophage foaming and found that NK cells exacerbated macrophage cholesterol accumulation both in the presence/absence of ox-LDL. Under ox-LDL exposure, NK cells promoted cholesterol accumulation via increasing cholesterol influx related gene CD36, and significantly reducing the expressions of cholesterol efflux associated receptors ABCA1 and ABCG1 in the macrophages. When without ox-LDL, NK cells accelerated cholesterol synthesis via the SREBP-2-LDLR/HMGCR pathway, and inhibited cholesterol efflux via the LXR-α-ABCA1/ABCG1 pathway of macrophages. These factors eventually led to the accumulation of cholesterol in macrophages, resulting in the formation of macrophage foam cells. Further, for the first time, we revealed the TIGIT/CD155 signaling pathway as a critical regulatory mechanism for macrophage foam cell formation. Specifically, the downregulation of TIGIT in highly active NK cells altered its interaction with CD155, which influenced macrophage cholesterol metabolism via CD155 and ultimately promoted foam cell formation. Furthermore, direct blockade of CD155 on macrophages exacerbated cholesterol accumulation, thereby establishing CD155 as an important regulator in macrophage-derived foam cell formation. These findings not only confirm NK cells as important drivers of macrophage foam cell formation but also highlight CD155 as a potential therapeutic target for atherosclerosis.

The integrity of blood-brain barrier (BBB) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by regulating Aβ clearance and neurotoxic compound exclusion. Hyperlipidemia exacerbates AD by impairing the BBB function. Inclisiran, a PCSK9-targeting siRNA, reduces cholesterol levels; however, its neuroprotective effects remain unclear. Here, we report the novel discovery that Inclisiran attenuates AD-like changes through the PCSK9-ferroptosis axis in brain microvascular endothelial cells (BMECs). First, integrated bioinformatics analysis and experimental validation of cortical tissues from patients with AD and healthy controls revealed a coordinated upregulation of PCSK9 and β-amyloid (Aβ), accompanied by increased iron deposition and significant activation of the ferroptosis pathway. Interestingly, these changes are located in the BMECs of the blood-brain barrier rather than in the brain parenchyma. Second, in hyperlipidemic ApoE-/- mouse models, integrated application of cerebral microvessel isolation, molecular biology techniques, immunofluorescence co-localization analysis, and behavioral tests demonstrated that Inclisiran significantly reduced AD-like changes by attenuating BBB dysfunction based on the suppression of PCSK9-mediated ferroptosis in BMECs. Third, in vitro studies employing the HCMEC/D3 BBB model with integrated assessments of lipid peroxidation, mitochondrial function, and transwell-based barrier integrity demonstrated that Inclisiran significantly reduced ferroptosis and restored BBB integrity via PCSK9 suppression. Our findings not only establish a novel PCSK9-ferroptosis-BBB regulatory axis in AD pathogenesis but also posit the clinically approved lipid-lowering drug, Inclisiran, as a promising therapeutic candidate for AD, providing new targets and mechanisms for the prevention and treatment of AD.

Recurrent drought stress seriously threatens plant growth and crop production, but plant drought adaptation often comes at a yield penalty, known as the growth-defense trade-off. Therefore, deciphering the mechanisms of trade-off between plant growth and drought tolerance is of great importance for plant survival and crop yield in fluctuating environments. Our recent studies have shown that U-box E3 ubiquitin ligase OsPUB33 reduces rice (Oryza sativa L.) grain yield via ubiquitination and degradation of the transcription factor OsNAC120, a positive regulator of grain size, whereas OsNAC120 compromises rice drought tolerance through transcriptionally repressing drought-responsive genes. In the present study, we found that the OsPUB33-OsNAC120 module acts as a molecular switch between drought response and growth recovery in rice. OsPUB33 enhanced ABA-induced drought tolerance, and its protein abundance rapidly increased at the early stage of drought stress and returned to normal at the rehydration stage, whereas OsNAC120 acted oppositely. Genetic evidence showed that OsPUB33 and OsNAC120 regulate rice drought response through a common pathway. Notably, OsNAC120 phosphorylation mediated by OsSAPK9, a key SnRK2 kinase in ABA signaling, enhanced its interaction with OsPUB33, thus promoting OsNAC120 ubiquitination for degradation under drought stress and increasing rice drought tolerance. When drought stress was relieved, OsPUB33 abundance declined, while OsNAC120 levels increased, consequently achieving growth recovery. These findings indicate that the OsPUB33-OsNAC120 module, which is controlled by OsSAPK9, is a molecular switch between the drought response and growth recovery, revealing a key mechanism of plant growth regulation under drought stress in rice.

Abstract The geometric configuration of prosthetic aortic valve is a key determinant of its mechanical response and associated hemodynamics during the cardiac cycle. In this work, high-fidelity fluid–structure interaction (FSI) analysis is conducted to provide physical insight into the effects of geometry on valve design. We integrate the data from the Doppler experiments and the Windkessel model for the inlet velocity and outlet pressure conditions, respectively. The arbitrary Lagrangian–Eulerian (ALE) method is employed to address the two-way interaction between hyperelastic leaflets undergoing periodic large deformation and the surrounding blood flow. The effects of leaflet aspect ratio (AR) and blood non-Newtonian properties on mechanical performance are systematically investigated. The FSI analysis shows that increasing AR elevates von Mises stress, wall shear stress (WSS), blood velocity magnitude, transvalvular pressure gradient (TPG), and regurgitation fraction (RF), while reducing geometric orifice area (GOA). These trends are opposite to the results from pure structural mechanical analysis. As AR increases from 0.86 to 1.26, the maximum von Mises stress increases by 58.66%, whereas GOA decreases by 71.54%. For the AR = 1.26 valve, the jet deviates from the centerline toward the lower vessel wall during peak systole and the subsequent deceleration phase, resulting in asymmetric deformation.

Nanoparticles (NPs) are promising for atherosclerosis (AS) drug delivery, which involves exposure to low magnitude shear stress, including low shear stress and oscillatory shear stress. While NPs surface charge affects biodistribution and cellular uptake, its role in AS-targeted accumulation remains unclear. In this study, positively charged NPs (pNPs), near-electrically neutrally charged NPs (eNPs), and negatively charged NPs (nNPs) were employed to investigate their distribution and uptake in mice and endothelial cells (ECs). Here, we found that nNPs exhibited significantly greater accumulation and uptake by ECs at both atherosclerotic sites and regions subjected to low magnitude shear stress compared to pNPs and eNPs. Proteomic analysis revealed that the surface charge of the NPs profoundly influenced the composition of the protein corona. Specifically, nNPs adsorbed several orders of magnitude more apolipoprotein H (APOH) from serum than pNPs. Furthermore, low magnitude shear stress increased the levels of surface phospholipids, which are specific receptors for APOH, on ECs, thereby promoting the uptake of nNPs by ECs. In conclusion, our study uncovers a mechanism by which nNPs preferentially accumulate within atherosclerotic areas and uptake by ECs exposure to low magnitude shear stress, and provides insights for designing charge-optimized NPs for cardiovascular drug delivery.

Cardiovascular diseases (CVDs) continue to be the primary cause of mortality globally. Abnormal liver function has been widely recognized as an independent risk factor for atherosclerotic CVDs. However, how alterations in liver function affect distal vascular function remains largely unknown. CREBZF, a bZIP transcription factor of the CREB/ATF family, has been identified as a driver of hepatic steatosis and fibrosis. Here, we provide the first demonstration that hepatic CREBZF acts as a critical regulator driving atherosclerotic progression. In vivo, hepatic-specific deletion of CREBZF attenuates endothelial inflammation and reduces macrophage infiltration, thereby ameliorating plaque formation in both high-fat diet-fed and spontaneous atherosclerotic mouse models. In vitro, overexpression or knockdown of CREBZF in hepatocytes correspondingly promotes or attenuates endothelial inflammation. Mechanistically, hepatocyte CREBZF regulates endothelial inflammation via exosomes, an effect independent of cholesterol metabolism or soluble cytokines. Furthermore, CREBZF dynamically modulates the expression of exosomal miR-210-3p and its subsequent levels in recipient endothelial cells. miR-210-3p, in turn, suppresses endothelial inflammation by targeting C-Rel, a component of the NF-κB transcription factor family. Importantly, the pro-inflammatory effect of exosomes derived from CREBZF-overexpressing hepatocytes on endothelial cells is abrogated by a miR-210-3p mimic. Collectively, these findings unveil a novel mechanism by which hepatic CREBZF regulates atherosclerosis through liver-vascular crosstalk mediated by the exosomal miR-210-3p/C-Rel signaling axis, suggesting a potential therapeutic strategy for atherosclerotic CVDs.

Atherosclerosis (AS) remains a leading cause of cardiovascular morbidity and mortality worldwide, with current treatments focused primarily on reducing low-density lipoprotein levels while failing to repair damaged endothelial cells, thus highlighting the urgent need for novel therapeutic drugs. To address this challenge, we analyzed human AS patient single-cell RNA sequencing datasets to identify disease-driving genes and then employed connectivity map analysis to screen for potential therapeutic compounds. Using network pharmacology and machine learning to predict core drug targets, the study validated drug-target interactions through molecular docking, molecular dynamics simulations, and surface plasmon resonance analysis, with experimental validation conducted using endothelial cell damage models and ApoE-/- atherosclerotic mice. The integrative approach successfully identified narciclasine as a promising therapeutic compound that targets vascular cell adhesion molecule 1 and intercellular adhesion molecule-1 (VCAM-1/ICAM-1) for AS treatment, with molecular studies confirming strong binding affinity and experimental validation demonstrating significant alleviation of endothelial dysfunction through downregulation of VCAM-1/ICAM-1 expression and reduction of aortic plaque burden in mouse models. This multiplatform methodology combining single-cell sequencing, network pharmacology, machine learning, computational simulation, and experimental validation provides a robust framework for drug discovery while positioning narciclasine as a promising therapeutic candidate warranting clinical investigation for AS treatment.

High-strength and high-toughness hydrogels have demonstrated exciting application prospects in soft robotics, artificial skin, and tissue engineering, but the development of such high-performance soft materials remains a challenging task. Here, inspired by the multiscale oriented hierarchical assembly structure of wood, this study innovatively reproduces the multilevel oriented compositional units of wood by incorporating millimeter-scale pulp fibers, nano-scale bacterial cellulose, and molecular-scale sodium lignosulfonate into pre-stretched polyvinyl alcohol hydrogels. The strong interfacial electrostatic interactions and hydrogen bonds formed between the functional groups of these components effectively stabilize and firmly bundle the hierarchical anisotropic structure. The resulting hierarchically oriented hydrogel exhibits remarkable mechanical properties, including an exceptional fracture strength exceeding 15.5 MPa, an ultimate strain of 130

Correction for ‘A multiplexed tension sensor reveals the distinct levels of integrin-mediated forces in adherent cells’ by Xiaojun Liu et al., Mater. Adv. , 2024, 5 , 9220–9230, https://doi.org/10.1039/D4MA00600C.

[This corrects the article DOI: 10.7150/thno.108875.].

Brain organoids provide three-dimensional human cellular systems that can reproduce selected features of early neural development, regional patterning, cellular diversification, and emerging neural activity more effectively than conventional two-dimensional cultures. However, their translational value depends not only on morphological resemblance to brain tissue, but also on whether construction strategies, functional validation, reproducibility, and application-specific model fitness are appropriately aligned. This structured narrative review synthesizes representative engineering strategies for brain organoid construction and examines how cell source, embryoid body formation, extracellular matrix support, patterning strategy, culture platform, vascularization, and cellular complexity influence functional validation and translational applicability. We further organize functional assessment into a hierarchical validation framework that includes morphology and growth, lineage and regional identity, tissue viability, synaptic maturation, electrophysiological activity, neurochemical signaling, BBB-like function, and omics-based benchmarking. These advances support the use of brain organoids in developmental biology, neurological disease modeling, drug screening, neurovascular research, and exploratory biohybrid interfaces, although their interpretation remains constrained by immature cellular states, incomplete vascular perfusion, batch variability, and limited standardization. Overall, this review reframes brain organoids as engineered biological platforms whose value should be judged by the alignment among construction strategy, biological benchmark, functional readout, and intended translational application. The emphasis is comparative conceptual synthesis of engineering strategies and multi-layer functional validation rather than systematic quantitative meta-analysis.

The mechanical environments endured by the human body profoundly influence life activities across different scales, from single molecules to complicated systems. Gaining insight into the mechanical factors and their biological implications is crucial for deciphering physiological and pathological processes and advancing innovations in drug development and therapeutic approaches for various diseases. Recently, we have witnessed rapid advances in biomechanics and mechanobiology, which, however, are not fully recognized by the clinical community and effectively integrated into medical decision-making, highlighting a translational gap between mechano-based discovery and therapeutic application. Here, we first provide a comprehensive review of research progress in biomechanics and mechanobiology, focusing on key areas such as the cardiovascular system, bone and joints, ocular tissues, liver, lung, the craniomandibular system, cancer, and immunology. We demonstrate how mechanical cues drive health and disease across biological levels, offering insights into complex physiological and pathological mechanisms. Further, we explore the diverse applications of biomechanics and mechanobiology in disease diagnosis, treatment, and rehabilitation. Mechanical insights fuel medical innovations through advanced diagnostic tools, novel therapies, and effective rehabilitation protocols, enhancing clinical outcomes. Looking ahead, we outline future directions of biomechanics and mechanobiology, emphasizing interdisciplinary integration, artificial intelligence, model development, and extreme environments, which hold the promise to deepen scientific understanding and propel technological innovations. This review highlights the transformative potential of biomechanics and mechanobiology in driving scientific and clinical advancements and helps bridge the long-standing gap between biomechanical research and clinical practice.

Biodegradable magnesium alloys are promising candidates for intravascular stents due to their suitable mechanical properties and biodegradability; however, their rapid corrosion in physiological environments and limited blood compatibility hinder clinical application. Developing surface modification strategies that simultaneously improve corrosion resistance and biological performance remains a critical challenge. In this work, superhydrophobic layered double hydroxide (LDH) coatings were successfully prepared on AZ31 magnesium alloy substrates, and the corrosion resistance and biological properties in phosphate-buffered saline (PBS) were investigated. The results showed that the superhydrophobic LDH coatings had good superhydrophobicity with a water contact angle of 165 degrees. The excellent corrosion resistance of the superhydrophobic LDH coating in physiological environments can be attributed to the double-anticorrosion mechanism associated with the LDH coating and the superhydrophobic structure. In addition, the superhydrophobicity of the coating could increase the stability of the corrosion resistance of magnesium alloy in PBS, inhibit platelet adhesion on the surface, and improve the hemocompatibility and migration rate of endothelial cells. These results suggest that the superhydrophobic LDH coating provides an effective approach for improving the corrosion resistance and biological performance of biodegradable magnesium alloys for regenerative vascular applications. The obtained superhydrophobic LDH coating is expected to be a potential vascular stent implant material.