Glioblastoma remains a highly aggressive brain tumor characterized by immune evasion, limiting the efficacy of immunotherapies. This study investigates the role of interleukin-1 receptor-associated kinase 4 (IRAK4) in modulating CD8+ T cell activity and immune escape in glioblastoma development. Employing high-throughput proteomics, we identified 1,205 differentially expressed proteins in glioblastoma samples, with IRAK4 significantly upregulated. Bioinformatic analyses revealed IRAK4’s involvement in the nuclear factor-kappa B (NF-κB) signaling pathway, critical for immune regulation. In vitro experiments demonstrated that IRAK4 overexpression suppressed CD8+ T cell cytotoxicity, reducing lactate dehydrogenase release and cytokine production (interferon-gamma and tumor necrosis factor-alpha), while IRAK4 knockout enhanced these functions. Co-culture assays with glioblastoma cell lines (GL261 and G422) showed that IRAK4 overexpression promoted tumor cell proliferation, migration, and invasion, while decreasing apoptosis. Conversely, IRAK4 knockout attenuated these effects. Inhibition of NF-κB signaling with Triptolide reversed IRAK4-mediated suppression of CD8+ T cell activity and tumor progression. Further investigations revealed that it can promote the phosphorylation of IκBα, leading to its ubiquitination and subsequent degradation, thereby activating the NF-κB signaling pathway and ultimately suppressing CD8⁺ T-cell activity. IN vivo, an orthotopic mouse model confirmed that IRAK4 overexpression increased tumor growth and reduced CD8+ T cell infiltration, effects mitigated by Triptolide. These findings highlight IRAK4 as a key regulator of NF-κB-mediated immune evasion in glioblastoma, suggesting its potential as a therapeutic target to enhance CD8+ T cell-based immunotherapy. This study provides novel insights into glioblastoma’s immune regulatory mechanisms and supports the development of targeted immunotherapies.

Peripheral nerve injury is a major clinical challenge that often results in incomplete functional recovery. Although nerve growth factor is a promising therapeutic molecule for nerve repair, its clinical application is limited by the high cost of recombinant protein production and the burst release associated with conventional post-loading delivery strategies. In this study, we developed an integrated design strategy termed source functionalization. Transgenic silkworms were generated to express recombinant human nerve growth factor in the silk gland under the control of the fibroin heavy chain promoter. This enabled the co-production of recombinant human nerve growth factor with endogenous silk fibroin and its physical entrapment within the fibroin matrix, allowing sustained release. Direct processing of these glands yielded an intrinsically functionalized injectable hydrogel, avoiding complex purification and reconstitution steps. In vitro, the hydrogel promoted neuronal proliferation and differentiation. In a rat sciatic nerve crush model, it significantly improved functional recovery and enhanced axonal regeneration and remyelination. These results demonstrate a cost-effective and scalable one-step strategy for preparing bioactive silk-based materials for peripheral nerve repair.

Long-term pharmacological intervention is essential for managing chronic diseases, yet continuous administration of antithrombotic agents often increases bleeding risk, posing a major clinical challenge. Here, we designed a multifunctional drug delivery platform composed of large-aperture mesoporous silica (Mas) coated with silk fibroin (SF) or sustained heparin sodium (HS) release. The well-defined mesoporous structure enables high drug loading, while the biocompatible SF coating regulates release kinetics, suppresses burst release, and prolongs therapeutic efficacy. This dual structural system enhances antithrombotic performance while mitigating hemorrhagic risk. In vitro studies demonstrated improved hemocompatibility and reduced cytotoxicity of SF-Mas/HS compared with free HS. In vivo thrombosis models further confirmed effective inhibition of thrombus formation without excessive bleeding. By integrating inorganic mesoporous carriers with natural protein coatings, SF-Mas/HS provides a safe and efficient strategy for long-term antithrombotic prevention, highlighting the potential of biomaterial-assisted delivery systems to balance efficacy and safety in chronic disease management.

Background:Cuprotosis is an emerging form of copper-dependent programmed cell death, while low-grade gliomas (LGGs) represent a common subtype of primary brain tumors. Methods:Datasets from The Cancer Genome Atlas and TargetScan were utilized to identify cuprotosis-related microRNAs (CRMs). Univariate Cox and Lasso regression analyses identified CRMs linked to prognostic outcomes. Prognostic profiles for patients with LGG were constructed using multivariate Cox regression and validated for risk stratification in the CGGA external validation cohort. The study examined clinical features, mutational status, immune cell infiltration, signaling pathways, and immune checkpoint expression across different risk groups. Functional experiments assessed the biological significance of key model genes. Results:Seven CRMs significantly associated with LGG prognosis were identified. The correlation between the CRM signature and poor prognosis in high-risk LGG cases was validated through Kaplan-Meier survival analysis, yielding a one-year area under the curve (AUC) of 0.849, indicating strong predictive accuracy. Risk scores were linked to 1p/19q co-deletion, IDH mutation, and tumor grade, with the model outperforming traditional clinicopathological criteria. Molecular enrichment analyses, including Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), revealed significant associations between high-risk subgroups and pathways related to tumorigenesis and immune dysregulation. Increased tumor mutational burden and elevated IC expression were noted in high-risk cohorts. Furthermore, miR-93-5p was validated as a critical gene, with its disruption leading to significant reductions in GBM cell proliferation, migration, and invasion. Conclusion:The novel CRM signature enhances the prognostic landscape for patients with LGG, offering a new framework for evaluating immunotherapeutic efficacy.

BackgroundWHO grade II oligodendroglioma (OG/II) is a rare primary brain tumor with various outcomes. Our study aims to investigate prognostic factors for postoperative OG/II patients and then evaluate the instructional value of tumor size.MethodsWe retrospectively studied the cases from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses and Kaplan-Meier survival curves were used to identify and assess prognostic factors. The optimal cut-off value of tumor size was determined by X-tile analysis and verified by multivariate analyses. Subsequently, Subgroup analyses were performed based on tumor size.Result676 OG/II patients were enrolled in our study. Multivariate Cox analyses revealed that age > 60 (HR 3.52), male (HR 1.48), total resection (HR 0.38), and tumor size (HR 2.04) were independent factors in predicting cancer-specific survival (CCS). The optimal cut-off value for tumor size was 60 mm. Patients with tumor size less than 60 mm, age > 60 (HR 3.82), and radiation (HR 1.58) were associated with worse CSS, while total resection (HR 0.35) was associated with better CSS. Lastly, a tumor size-based nomogram was established objectively and accurately.ConclusionOur study identified four crucial prognostic factors related to CSS in postoperative OG/II patients: age, sex, the extent of recession, and tumor size. A tumor size of 60 mm was an optimal cut-off point for dividing patients into low and high-risk groups. Patients in the low-risk group may not benefit from extended resection and radiation. Tumor size can be a valuable factor for making therapeutic schedules.

OBJECTIVE:To identify the determining factors for the use of neuronavigation in the surgical treatment of skull lesions, with the goal of establishing a standardized framework for its application in clinical practice. METHODS:A retrospective analysis was conducted on 238 consecutive cases of skull lesions treated at Sir Run Run Shaw Hospital, affiliated with Zhejiang University School of Medicine, from 2017 to 2023. Clinical data, including patient demographics, comorbidities, lesion characteristics (such as size, location, proximity to major vessels, palpable status, and skull layer involvement), and surgical parameters, were collected. First, the correlation coefficients of these variables were calculated to perform an initial screening. Then, the selected variables were incorporated into a Lasso regression model. The optimal regularization parameter (λ) was determined through 10-fold cross-validation to further refine variable selection and calculate the weights of each feature. RESULTS:By correlation coefficient analysis, the 4 factors If_cranioplasty, If_gen_anesthesia, Max_diameter, and If_invade_meninges were excluded. The optimal penalty coefficient (λ) for the model was determined to be 0.029 through cross-validation. The selected variables, ranked according to their weights, are If_vessels, Max_diam_level, If_palpable, Skull_layer, Bone_location, and Gender. CONCLUSION:The factors that influence the decision to use neuronavigation-assisted surgery for skull lesions include whether the lesion invades or is adjacent to major blood vessels, maximum diameter, palpability, skull layer, bone location, and gender. Based on the identified factors, we can develop standardized guidelines for neuronavigation-assisted surgery in patients with skull lesions.

Extracellular vesicle (EV)-incorporated hydrogels have emerged as promising scaffolds for tissue repair due to their ability to present biological cues. However, the encapsulation efficiency and distribution of EVs within hydrogels still require improvement to enhance tissue healing outcomes. In this study, a novel approach is developed that uses EVs as crosslinkers for hydrogel formation, ensuring that EVs are present at every crosslinking point and thereby achieving both functional incorporation and uniform distribution of EVs. Amphiphilic molecules with various functional groups are successfully inserted into the EV membrane, enabling crosslinking with hydrogel macromers, which is versatile for multiple crosslinking chemistries. EV-crosslinked hydrogels exhibited faster stress relaxation properties due to EV stretchability compared to hydrogels crosslinked with traditional elastic polymers, promoting enhanced cell spreading and proliferation. Additionally, it is demonstrated that EV crosslinkers could present proteins throughout the hydrogel network while maintaining their biological activity. Using VEGF-loaded EV crosslinkers, induced endothelial cell clustering and sprouting are successfully, indicating early angiogenic responses. These results underscore the potential of EV-crosslinked hydrogels for tissue engineering and regenerative medicine, offering tunable mechanical properties and the capacity for effective protein delivery.

Multi-modal medical image fusion (MMIF) aims to integrate complementary information from different modalities to obtain a fused image that contains more comprehensive details, providing clinicians with a more thorough reference for diagnosis. However, most existing deep learning-based fusion methods predominantly focus on the local statistical features within images, which limits the ability of the model to capture long-range dependencies and correlations within source images, thus compromising fusion performance. To address this issue, we propose an unsupervised image fusion method guided by stochastic structural similarity (S3IMFusion). This method incorporates a multi-scale fusion network based on CNN and Transformer modules to extract complementary information from the images effectively. During the training, a loss function with the ability to interact global contextual information was designed. Specifically, a random sorting index is generated based on the source images, and pixel features are mixed and rearranged between the fused and source images according to this index. The structural similarity loss is then computed by averaging the losses between pixel blocks of the rearranged images. This ensures that the fusion result preserves the globally correlated complementary features from the source images. Experimental results on the Harvard dataset demonstrate that S3IMFusion outperforms existing methods, achieving more accurate fusion of medical images. Additionally, we extend the method to infrared and visible image fusion tasks, with results indicating that S3IMFusion exhibits excellent generalization performance.

IntroductionGlioblastoma (GBM) represents the most aggressive and prevalent form of primary malignant brain tumor in adults, with surgical intervention being the primary treatment modality. To enhance surgical outcomes and extend patient survival, we have engineered a dual-modality MRI/FI contrast agent known as PL002 to aid in the surgical management of GBM.MethodsIn this study, an orthotopic glioma model was established in mice via intracranial injection of U-87 MG cells. Subsequently, the model animals were intravenously injected with PL002 and placed in a 7.0T magnetic resonance imaging (MRI) device to evaluate the imaging effects. After the MRI scan, fluorescence imaging techniques were employed to observe the distribution of PL002 at both the brain tissue and cellular levels. Moreover, healthy rat models were utilized to investigate the pharmacokinetic characteristics, tissue distribution, and safety profile of PL002.ResultsThe molecular structure of PL002 contains both gadolinium (Gd3+) and indocyanine green (ICG), demonstrating optimal imaging effects within the dosage range of 10-50 mg/kg, with a half-life of 2.51 to 4.87 hours. Even at relatively low concentrations in the brain, PL002 can provide stable and sustained support for MRI and fluorescence imaging for up to 72 hours. No abnormalities were observed in rats at a dosage of 100 mg/kg.DiscussionCompared to Gadavist® and ICG, PL002 provided sustained support for MRI and FI of GBM for 72 h, with a broad therapeutic window. This dual-modality contrast agent holds significant potential and promise for applications in preoperative assessment of resection margins, real-time intraoperative guidance, and postoperative verification of the extent of resection.

MXene, a novel two-dimensional (2D) transition metal carbide/nitride known for its superior electrical and mechanical properties due to size effects, has been broadly applied in various fields, including tissue engineering. Combining this conductivity material with a biopolymer such as Bombyx mori(B.mori) silk fibroin (SF) into the biological scaffold is a general approach. However, the issue on the interaction of MXene with SF has not been addressed, limiting the information on how the resultant SF/MXene matrix directs cell adhesion and neural stem cell (NSCs) fate. Herein, we present a mild and simple method by binding SF and MXene to promote the transformation of SF from nanoparticles to nanofibers guided by the MXene nanosheets. The resulting SFMSA membranes exhibit a unique nanofibrous morphology. MXene nanosheets facilitate the SF assembly into nanofibrils by triggering the structural change of SF molecules from random coils to beta-sheets, as confirmed by Fourier transform infrared spectroscopy and circular dichroism measurements. The unique nanotopographies of the SFMSA membranes were found to improve the early cell adhesion and proliferation of Pheochromocytoma cells (PC12) by activating the integrin signaling pathway and ERK/MAPK signaling pathway. Moreover, the SFMSA membrane can promote NSCs differentiation into neurons. Collectively, our study indicates that the formation of a nanofibrous structure substrates is a key factor in promoting early cell adhesion and inducing NSCs neural differentiation. Therefore, the SFMSA membrane holds great potential in the field of neural tissue engineering.

Brain damage is a common tissue damage caused by trauma or diseases, which can be life-threatening. Stem cell implantation is an emerging strategy treating brain damage. The stem cell is commonly embedded in a matrix material for implantation, which protects stem cell and induces cell differentiation. Cell differentiation induction by this material is decisive in the effectiveness of this treatment strategy. In this work, we present an injectable fibroin/MXene conductive hydrogel as stem cell carrier, which further enables in-vivo electrical stimulation upon stem cells implanted into damaged brain tissue. Cell differentiation characterization of stem cell showed high effectiveness of electrical stimulation in this system, which is comparable to pure conductive membrane. Axon growth density of the newly differentiated neurons increased by 290% and axon length by 320%. In addition, unfavored astrocyte differentiation is minimized. The therapeutic effect of this system is proved through traumatic brain injury model on rats. Combined with in vivo electrical stimulation, cavities formation is reduced after traumatic brain injury, and rat motor function recovery is significantly promoted.

Meningiomas are the most common primary intracranial tumors and account for nearly 30% of all nervous system tumors. Approximately half of meningioma patients exhibit neurofibromin 2 (NF2) gene inactivation. Here, NF2 was shown to interact with the endoplasmic reticulum (ER) calcium (Ca2+) channel inositol 1,4,5-trisphosphate receptor 1 (IP3R1) in IOMM-Lee, a high-grade malignant meningioma cell line, and the F1 subdomain of NF2 plays a critical role in this interaction. Functional assays indicated that NF2 promotes the phosphorylation of IP3R (Ser 1756) and IP3R-mediated endoplasmic reticulum (ER) Ca2+ release by binding to IP3R1, which results in Ca2+-dependent apoptosis. Knockout of NF2 decreased Ca2+ release and promoted resistance to apoptosis, which was rescued by wild-type NF2 overexpression but not by F1 subdomain deletion truncation overexpression. The effects of NF2 defects on the development of tumors were further studied in mouse models. The decreased expression level of NF2 caused by NF2 gene knockout or mutation affects the activity of the IP3R channel, which reduces Ca2+-dependent apoptosis, thereby promoting the development of tumors. We elucidated the interaction patterns of NF2 and IP3R1, revealed the molecular mechanism through which NF2 regulates IP3R1-mediated Ca2+ release, and elucidated the new pathogenic mechanism of meningioma-related NF2 variants. Our study broadens the current understanding of the biological function of NF2 and provides ideas for drug screening of NF2-associated meningioma.

Thrombotic disease poses a significant threat to human health as it blocks blood vessels and leads to severe symptoms. Effective treatment requires targeted therapy and precise localization of the thrombus, but traditional drugs are limited in their targeting ability and ability to locate the thrombus. To overcome these issues, a nanoparticle capable of both thrombus targeting and computed tomography (CT) imaging is developed. Phage display technology is used to screen for the thrombus-targeting peptide termed GK, which is then linked to the surface of macroporous silica (Mp-SiO2) with a Bi core to create Mp-Bi@SiO2-GK. The large pores of Mp-Bi@SiO2-GK enable the transport of the drug Urokinase (UK), while the Bi core provides the capabilities of CT imaging and photothermal therapy. The Mp-Bi@SiO2-GK nanoparticles precisely target thrombi in mouse carotid arteries and locate them via CT imaging. Furthermore, the combination of Bi-enabled photothermal therapy and UK-induced chemotherapy enhance the thrombolysis efficiency. Treatment with Mp-Bi@SiO2-GK nanoparticles do not harm tissues/organs or affect liver/kidney metabolism. These results show that Mp-Bi@SiO2-GK exhibits precise thrombus targeting and efficient imaging/treatment capability, making it a promising tool for the diagnosis and treatment of thrombosis.

Background Tubridge flow diverter is a widely used device aimed at reconstructing parent arteries and occluding complex aneurysms in China. The experience of Tubridge in treating small and medium aneurysms is still limited. In this study, we aimed to evaluate the safety and efficacy of the Tubridge flow diverter for the treatment of the two types of aneurysms. Methods We reviewed the clinical records of aneurysms treated with a Tubridge flow diverter between 2018 and 2021 in a national cerebrovascular disease center. Cases were divided into small and medium aneurysms according to aneurysm size. The therapeutic process, occlusion rate, and clinical outcome were compared. Results In total, 57 patients and 77 aneurysms were identified. The patients were divided into two groups: small aneurysms (39 patients, 54 aneurysms) and medium aneurysms (18 patients, 23 aneurysms). There were 19 patients with tandem aneurysms (a total of 39 aneurysms) in the two groups, among which 15 patients (30 aneurysms) were in the small aneurysm group and four patients (nine aneurysms) were in the medium aneurysm group. The results show that the mean maximal diameter/neck in the small and medium aneurysms was 3.68/3.25 and 7.61/6.24 mm, respectively. In total, 57 Tubridge flow diverters were successfully implanted without unfolding failure, and there were six patients with new mild cerebral infarction in the small aneurysm group. The complete occlusion rate on the last angiographic follow-up was achieved in 88.46% of the small aneurysms group and 81.82% of the medium aneurysms group. The complete occlusion rate of patients with tandem aneurysms in the last angiographic follow-up was 86.67% (13/15) of the small aneurysms group and 50% (2/4) of the medium aneurysm group. Intracranial hemorrhage was nonencountered in the two groups. Conclusion Our preliminary experience suggests that the Tubridge flow diverter might be a safe and effective treatment for small and medium aneurysms along the internal carotid artery. Long stents may increase the risk of cerebral infarction. Adequate evidence is required to clarify the definite indications and complications in a multicenter randomized controlled trial with a long-term follow-up.

Biophysical factors are essential in cell survival and behaviors, but constructing a suitable 3D microenvironment for the recruitment of stem cells and exerting their physiological functions remain a daunting challenge. Here, we present a novel silk fibroin (SF)-based fabrication strategy to develop hierarchical microchannel scaffolds for biomimetic nerve microenvironments in vitro. We first modulated the formation of SF nanofibers (SFNFs) that mimic the nanostructures of the native extracellular matrix (ECM) by using graphene oxide (GO) nanosheets as templates. Then, SFNF-GO systems were shaped into 3D porous scaffolds with aligned micro-lamellar structures by freeze-casting. The interconnected microchannels successfully induced cell infiltration and migration to the SFNF-GO scaffolds' interior. Meanwhile, the nano-fibrillar structures and the GO component significantly induced neural stem cells (NSCs) to differentiate into neurons within a short timeframe of 14 d. Importantly, these 3D hierarchical scaffolds induced a mild inflammatory response, extensive cell recruitment, and effective stimulation of NSC neuronal differentiation when implanted in vivo. Therefore, these SFNF-GO lamellar scaffolds with distinctive nano-/micro-topographies hold promise in the fields of nerve injury repair and regenerative medicine.

Intracerebral hemorrhage (ICH) is a high mortality and disability stroke subtype. Destruction of the blood–brain barrier (BBB) is a crucial contributor to brain edema and neurological deficit after ICH. Triggering receptor expressed on myeloid cells 1 (TREM‐1) has been reported to be expressed in endothelial cells, but its role in ICH remains unclear. This study aims to evaluate the role of TREM‐1 on BBB permeability after ICH in mice.

Glioma is the most malignant tumor in the central nervous system with a poor prognosis. The tumor immune microenvironment plays a crucial role in glioma formation and progress. TREM1, as a vital immune regulator, has not been investigated in glioma. This study aims to explore the role of TREM1 in prognosis and tumor immune microenvironment of glioma. The mRNA expression level of TREM1 was collected from TCGA and GEO databases. The correlations between the clinic-pathological features and TREM1 expression were analyzed using Cox regression analysis. Kaplan-Meier was used to evaluate the effect of TREM1 on OS. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes were performed to analyze the functional annotations and signaling pathways of the TREM1 coexpression genes. ESTIMATE and TIMER explored the correlations between TREM1 and immune cell infiltration. Spearman correlation analysis was conducted to examine the association between the TREM1 and immune checkpoint expression. The expression level of TREM1 was significantly increased in glioma. TREM1 overexpression was positively related to poor prognosis, higher World Health Organization grade, isocitrate dehydrogenase wildtype, and 1p/19q non-codeletion. TREM1 coexpression genes were mainly related to immunoregulation and inflammatory response. TREM1 participated in the initiation and progression of glioma by regulating immune cell infiltration and expression of immune checkpoints. TREM1 is an effective prognostic and diagnostic biomarker in glioma. It can be adopted as a novel predictor for clinical prognosis, pathological characteristics, and immune microenvironment in glioma patients.

Multimodal therapy requires effective drug carriers that can deliver multiple drugs to specific locations in a controlled manner. Here, the study presents a novel nanoplatform constructed using zeolitic imidazolate framework-8 (ZIF-8), a nanoscale metal-organic framework nucleated under the mediation of silk fibroin (SF). The nanoplatform is modified with the newly discovered MCF-7 breast tumor-targeting peptide, AREYGTRFSLIGGYR (AR peptide). Indocyanine green (ICG) and doxorubicin (DOX) are loaded onto the nanoplatform with high drug encapsulation efficiency (>95%). ICG enables the resultant nanoparticles (NPs), called AR-ZS/ID-P, to release reactive oxygen species for photodynamic therapy (PDT) and heat for photothermal therapy (PTT) under near-infrared (NIR) irradiation, promoting NIR fluorescence and thermal imaging to guide DOX-induced chemotherapy. Additionally, the controlled release of both ICG and DOX at acidic tumor conditions due to the dissolution of ZIF-8 provides a drug-targeting mechanism in addition to the AR peptide. When intravenously injected, AR-ZS/ID-P NPs specifically target breast tumors and exhibit higher anticancer efficacy than other groups through ICG-enabled PDT and PTT and DOX-derived chemotherapy, without inducing side effects. The results demonstrate that AR-ZS/ID-P NPs are a promising multimodal theranostic nanoplatform with maximal therapeutic efficacy and minimal side effects for targeted and controllable drug delivery.

Abstract Biological molecules such as DNA, proteins, and lipids can be assembled into naturally existing nanoparticles, such as bacterial viruses (also called bacteriophages or phages), plant viruses, nucleic acid nanoparticles (e.g., DNA origami), protein nanoparticles, and exosomes. These bionanoparticles have their own distinct properties (including compositions, structures, shapes, and functions), laying the foundation for their unique applications as probes for cancer imaging, as detectors for cancer diagnosis, or as therapeutics for cancer therapy. To highlight how the distinct properties of different bionanoparticles can be explored in cancer nanotheranostics, this review critically analyzed the use of bionanoparticles in cancer imaging, diagnosis, and treatment. Specifically, for each of these representative bionanoparticles, we describe its unique properties that render it powerful in cancer theranostics compared with synthetic inorganic nanoparticles. We also summarize how to genetically or chemically modify or redesign the bionanoparticles so that they gain new functions desired for cancer theranostics, such as tumor‐seeking or tumor‐destructive capabilities. Finally, we discussed the challenges in this exciting field. The bionanoparticles covered in this review represent different biomolecular assemblies with unique theranostic applications, showcasing the power of bionanoparticles in disease diagnosis and treatment.