Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, and while chimeric antigen receptor-T (CAR-T) cell therapy has shown promise, its efficacy remains limited by antigen heterogeneity and immune escape. Here, we investigated the expression of B7 homolog 3 (B7-H3), epidermal growth factor receptor (EGFR), and interleukin-13 receptor alpha 2 (IL-13RA2) in GBM tissues and cell lines. Although all three antigens were highly expressed, sustained exposure to B7-H3 CAR-T cells led to significant B7-H3 downregulation but concurrent EGFR upregulation, revealing a potential immune escape mechanism. To address this heterogeneity, we engineered T cells to express an anti-B7-H3 CAR and secrete an EGFR-targeting bispecific T-cell engager (EGFR-BsTe). These B7-H3-CAR-T-EGFR-BsTe cells exerted dual functionality: direct B7-H3-dependent cytotoxicity and recruitment of unmodified T cells via secreted EGFR-BsTe to eliminate EGFR-expressing tumor cells. Notably, EGFR-BsTe secretion promoted CAR-T cell proliferation and effector differentiation. In orthotopic GBM xenograft models, including mixed tumors with heterogeneous antigen expression, B7-H3-CAR-T-EGFR-BsTe cells demonstrated superior antitumor activity and prolonged survival compared to conventional B7-H3 CAR-T cells. Quantitative analysis revealed that EGFR-BsTe secretion abrogated EGFR upregulation and enhanced B7-H3 downregulation in a target-dependent manner; however, efficacy was diminished when the CAR-Target (B7-H3) was absent on a substantial fraction of tumor cells. Our findings suggest that arming B7-H3 CAR-T cells with EGFR-targeting bispecific engagers represents a promising strategy to overcome antigen heterogeneity and improve therapeutic outcomes for GBM patients.

Systemic administration of bispecific T‑cell engagers (BiTEs) targeting CEACAM6 has shown therapeutic potential but is limited by on‑target/off‑tumor toxicity and short serum half‑life. To overcome these challenges, we engineered an oncolytic herpes simplex virus (oHSV) that delivers and locally produces anti‑CEACAM6/CD3 BiTE directly within the tumor microenvironment (oHSV‑anti‑CEA6/CD3). In immunocompetent mouse models of colon (CT26) and breast (4T1) cancer, a single intratumoral injection of oHSV‑anti‑CEA6/CD3 promoted tumor regression, increased infiltration of CD8⁺CD44⁺ T cells both locally and systemically, and induced durable antitumor immunity. When combined with PD‑1 blockade, this localized BiTE‑arming strategy synergistically enhanced therapeutic efficacy, leading to superior tumor control and long‑term immunological memory without additional toxicity. Mechanistically, the virus exerts a dual action: direct oncolysis and sustained in situ BiTE production, enabling targeted T‑cell activation and tumor elimination while limiting systemic BiTE exposure. Unlike previous reports of BiTE‑armed oncolytic viruses or simple combinations with immune checkpoint inhibitors, our approach leverages the oHSV platform to achieve spatiotemporally controlled T‑cell redirection coupled with virus‑mediated innate immune stimulation. This work provides a safe, effective, and readily translatable strategy for solid tumor immunotherapy.

Nano-structured derivatives of natural organisms are enabling advances in biomaterial design, offering an innovative strategy to endow materials with specific biofunctions. In the regeneration of nervous tissue, neurogenesis and angiogenesis are intricately linked processes, yet their crosstalk in therapeutic strategies remains underexplored. This study develops an approach to produce engineered nanovisicles by pre-conditioning neural stem cells (NSCs) with brain-derived neurotrophic factor (BDNF). Compared with naive NSC exosomes, BDNF-preconditioned NSC exosomes (BNE) exhibited presented altered miRNA profiles enriched in pathways regulating neurogenesis, angiogenesis, and inflammation. In vitro assays demonstrated that BNE significantly enhanced NSC migration, neuronal/oligodendrocytic differentiation, and neuronal maturation, while promoting human umbilical vein endothelial cell (HUVEC) migration, invasion, and angiogenesis. Critically, a coculture system confirmed bidirectional crosstalk between neurogenesis and angiogenesis, which was amplified by the BNE. In a rat traumatic brain injury (TBI) model, the BNE-laden hydrogel synergistically mitigated neuroinflammation, recruited endogenous neural stem/progenitor cells (NSPCs) to the lesion, enhanced their neuronal differentiation and maturation, and stimulated angiogenesis. This pro-regenerative microenvironment, facilitated by neurovascular crosstalk, led to significant neural network reconstruction, tissue restoration, and improved functional recovery. These findings establish BDNF-preconditioned NSC exosomes delivered via a biomimetic hydrogel as a potent platform for CNS repair, harnessing the critical crosstalk between neurogenesis and angiogenesis.

Hydrocephalus is a common neurological disorder characterized by pathological dilation of the ventricular system. Its pathogenesis involves multiple factors, including cerebrospinal fluid (CSF) dynamic imbalance (encompassing overproduction, circulation obstruction, and impaired absorption) and neuroinflammatory responses. Astrocytes, as core components of the neurovascular unit, mediate CSF transport via their specialized end-foot structures and the glymphatic system formed by perivascular spaces (PVS). Simultaneously, they serve as key effector cells in neuroinflammatory regulation, participating in various disease processes. This article systematically reviews the role of astrocytes in the pathogenesis and progression of hydrocephalus, with a focus on their molecular mechanisms in CSF circulation disorders and neuroinflammatory responses. The aim is to provide novel insights for targeted therapies against hydrocephalus.

Radiotherapy remains a central component of standard treatment for glioblastoma (GBM), yet recurrence is common because GBM radioresistance is reinforced by enhanced DNA damage repair, glioma stem cells (GSCs), hypoxia, extracellular matrix remodeling, and an immunosuppressive tumor microenvironment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates, has shown reproducible normal-tissue-sparing effects in preclinical models, including the brain. In GBM models, however, available evidence indicates that FLASH-RT generally preserves tumor control at levels comparable to conventional radiotherapy rather than providing clearly superior eradication of hypoxic or stem-like tumor compartments. In parallel, endoplasmic reticulum (ER)-targeted interventions have emerged as a candidate strategy for disturbing tumor proteostasis, modulating unfolded protein response (UPR) signaling, impairing synthesis of repair-associated proteins, and promoting immunogenic cell death. This narrative review summarizes representative mechanisms of GBM radioresistance, appraises the opportunities and limitations of FLASH-RT in intracranial disease, and explains why ER targeting is discussed here as a lead but unproven biological axis for radiosensitization. We further compare ER-directed approaches with mitochondrial-, lysosomal-, and delivery-enabled radiosensitization strategies, and outline the translational variables that would determine clinical testability, including beam modality, blood-brain barrier heterogeneity, pharmacokinetics, treatment sequencing, and biomarker development. In this review, "physical precision" refers primarily to dose-rate-driven ultra-rapid delivery and the possibility of widening the normal-tissue therapeutic window under FLASH conditions, rather than to a universal depth-dose advantage shared by all FLASH platforms. Direct experimental evidence for combining FLASH-RT with ER-targeted therapy in GBM is currently lacking. We therefore present this model as a hypothesis-generating conceptual and translational framework for future preclinical testing rather than as an established therapeutic advance.

Spinal cord injury (SCI) is a severely disabling neurological disorder caused by primary mechanical trauma and subsequent secondary damage, resulting in persistent neurological deficits and imposing a significant social and economic burden. The existing treatment methods - including drug therapy, surgical treatment, and rehabilitation therapy - have limited effects in promoting functional recovery. In recent years, neural stem cells (NSCs) and their derived exosomes have emerged as highly promising innovative treatment options. NSCs promote neural repair through their multifaceted differentiation ability, secretion of neurotrophic factors, and regulation of the immune response in the injured microenvironment. However, factors such as low graft survival rate, ethical restrictions, and the risk of immune rejection have hindered their clinical translation. In contrast, NSC-derived exosomes offer an emerging cell-free alternative solution. NSC-derived exosomes can inhibit neuroinflammation, reduce glial scar formation, enhance axonal regeneration and promote angiogenesis. Compared with the transplantation of NSCs, NSC-derived exosomes may have lower immunogenicity and can avoid direct graft-related excessive proliferation. At the same time, they are convenient for loading, surface modification, and integration with hydrogels, scaffolds, or other nanomaterial delivery systems. Despite these advantages, their clinical application still faces challenges. The main challenges include vesicle heterogeneity, standardization of dosage and efficacy, target specificity of the lesion, biodistribution, timing of treatment, safety of repeated administration, storage stability, and GMP-compliant scalable manufacturing. Overall, NSCs and NSC-derived exosomes demonstrate significant therapeutic potential in the repair of SCI.

Objective: Tumor recurrence remains a major challenge in the management of pituitary neuroendocrine tumors (PitNETs). This study aimed to investigate recurrence-associated metabolic alterations in PitNETs using an integrated metabolomic approach. Methods: Untargeted gas chromatography–mass spectrometry (GC–MS)-based metabolomic profiling was performed on tumor tissues from 44 patients with PitNETs as a discovery cohort. Differential metabolites were identified using non-parametric statistical analysis. An independent validation cohort of 40 patients (20 primary and 20 recurrent PitNETs) was used for protein-level validation by multiplex immunofluorescence staining of key amino acid transporters, including L-type amino acid transporter 1 (LAT1) and alanine–serine–cysteine transporter 2 (ASCT2). Results: Metabolomic analysis revealed distinct metabolic alterations between primary and recurrent PitNETs, characterized by selective enrichment of large neutral amino acids (LNAAs) in recurrent tumors. Pathway enrichment analysis indicated that the altered metabolites were predominantly involved in amino acid-related metabolic pathways. In the validation cohort, multiplex immunofluorescence demonstrated significantly increased LAT1 expression in recurrent PitNETs compared with primary tumors, whereas ASCT2 expression did not differ significantly between groups. Conclusion: These findings indicate that recurrence of PitNETs is associated with selective remodeling of amino acid metabolism, particularly involving LNAAs, accompanied by increased expression of the corresponding transporter LAT1. Together, our results suggest that altered amino acid transport represents an important component of metabolic adaptation in recurrent PitNETs and warrants further investigation.

Tissue hypoxia and neuroinflammation are major drivers of secondary injury after traumatic brain injury (TBI). S100A8, a pro-inflammatory damage-associated molecular pattern, is involved in pathological neuron-microglia signaling and may amplify secondary damage. However, effective interventions targeting S100A8-centered neuroimmune crosstalk remain lacking. Here, we developed a multifunctional biomimetic hydrogel system, HPC@Gel, by integrating modified hemoglobin nanoparticles and curcumin-based carbon quantum dots into a hyaluronic acid-collagen hydrogel to disrupt this vicious cycle. In vitro, hypoxic HT22 neurons, LPS-stimulated BV2 microglia, and an HT22-BV2 Transwell model were used to evaluate neuroprotection and neuroimmune regulation. HPC@Gel markedly downregulated S100A8 expression and attenuated pathological neuron-microglia crosstalk. Recombinant S100A8 rescue experiments further showed that exogenous S100A8 partially reversed the protective effects of HPC@Gel, supporting the functional role of S100A8 suppression. In a rat cortical cavity TBI model, HPC@Gel reduced S100A8 expression in neurons and microglia, alleviated neuronal hypoxia, and reversed neuroinflammation. These effects improved the pathological microenvironment, promoted endogenous neural regeneration, and facilitated neurological and cognitive recovery. This study provides a promising therapeutic strategy for TBI by simultaneously targeting hypoxia and S100A8-mediated neuroimmune crosstalk.

Post-hemorrhagic hydrocephalus (PHH) represents a prevalent clinical form of hydrocephalus, where surgical interventions frequently fail or result in severe complications. While current research underscores the role of innate immunity and neuroinflammation in PHH pathogenesis, the precise mechanisms remain elusive. The cyclic guanylate adenylates synthase-stimulator of interferon genes (cGAS-STING) pathway, a pivotal component of innate immunity, has been implicated in various neuroinflammatory disorders. However, its mechanism of action in PHH has not yet been explored. Here, we propose that sustained activation of the cGAS-STING pathway in microglia following intraventricular hemorrhage (IVH) drives persistent neuroinflammation. Our results showed that dsDNA released from pyroptotic neurons and impaired mitochondrial autophagy in microglia can serve as substrates for cGAS detection, forming a cascade of interconnected pathways. Pharmacological inhibition or conditional knockout of cGAS attenuated global neuroinflammation, suppressed microglial activation, and reduced both pyroptosis-dependent (IL-1β and IL-18) and nonpyroptosis-dependent (TNF-α, IFN-β, and IL-6) cytokine release. Additionally, these interventions mitigated neuronal damage, apoptosis, and hydrocephalus-related neurological deficits after IVH Our results demonstrate that cGAS-STING pathway activation, mediated by neuronal pyroptosis and microglial mitophagy dysfunction, perpetuates post-IVH neuroinflammation. Our findings suggest that targeting cGAS may serve as a promising therapeutic approach for PHH.

Limited research has addressed how to optimally balance the risk of bleeding and thrombosis while selecting the most effective treatment strategy for chronic subdural hematoma (CSDH) in elderly patients undergoing anticoagulant (AC) or antiplatelet (AP) therapy at the time of diagnosis. We searched for studies published between January 2017 and January 2025 in PubMed, MEDLINE, EMBASE, Web of Science, and Cochrane systematic review registries involving older adults diagnosed with CSDH who are receiving AC or AP therapy. Ten studies comprising a total of 3,962 patients were included in the final analysis, with mean ages ranging from 72 to 84.4 years. Preoperative antithrombotic (AT) therapy was not significantly associated with postoperative recurrence of CSDH; however, the use of multiple AT agents may increase the risk of recurrence and the need for reoperation. Current evidence does not support a correlation between the duration of preoperative drug withdrawal and postoperative recurrence. Four studies reported that the majority of patients resumed AT therapy within two weeks postoperatively, although the optimal timing for the resumption of AP and AC therapy remains uncertain. Prolonged discontinuation or delayed resumption of AT therapy appears to increase the risk of thromboembolic events, whereas early resumption may mitigate this risk without significantly increasing the recurrence rate. Antithrombotic therapy did not significantly increase the risk of postoperative recurrence or reoperation in older patients with CSDH, and the duration of preoperative drug withdrawal was not associated with clinical outcomes. In the absence of clear contraindications or high-risk factors, AT therapy should be resumed as early as possible, as prolonged discontinuation may elevate the risk of thromboembolic events. Further studies are warranted to determine the optimal timing for the postoperative resumption of AC and AP therapy respectively.

Idiopathic normal pressure hydrocephalus (iNPH) often co-occurs with beta-amyloid deposition, both of which share a common pathophysiology involving glymphatic dysfunction. This study aimed to investigate the clinical impact of beta-amyloid co-pathology and the effects of glymphatic dysfunction on beta-amyloid deposition in patients with iNPH. Patients diagnosed with probable iNPH ( n  = 60; 28 with A+, positive amyloid PET; 32 with A-, negative amyloid PET) and Alzheimer's disease (AD) ( n  = 30, A+T+N+) were enrolled from prospective cohorts at the West China Hospital of Sichuan University. All participants underwent neuropsychological tests, magnetic resonance imaging and 18 F-AV45 PET. The choroid plexus volume/estimated total intracranial volume (CPV/eTIV) and 18 F-AV45 PET standard uptake value ratio (SUVR) were calculated based on automatic segmentation to evaluate the glymphatic function and amyloid burden. ANOVA and Kruskal-Wallis test were used for group comparison between iNPH with positive amyloid PET and other groups, and Bonferroni correction was used for post-hoc analysis. Multivariate generalized linear models were constructed to analyze the association between CPV/eTIV and 18 F-AV45 PET SUVR in patients with iNPH and AD. Patients with iNPH A+ exhibited the highest CPV/eTIV compared to the patients with iNPH A- ( p  = 0.006). Patients with iNPH A+ showed lower MMSE score compared to iNPH A- (P Bon =0.013) and AD (P Bon =0.039), while no significant difference was found between iNPH A- and AD. In iNPH patients, higher CPV/eTIV were associated with higher 18 F-AV45 PET SUVR in temporal ( p  = 0.007), parietal ( p  = 0.002), and occipital lobes ( p  = 0.004); however, no association was observed in patients with AD in these regions. Our study demonstrated that beta-amyloid co-pathology may exacerbate the cognitive symptoms of iNPH. Moreover, glymphatic dysfunction might play a distinct role in promoting beta-amyloid deposition in iNPH compared to Alzheimer's disease.

The fusion of regenerative medicine and biomaterial science, particularly in the realm of hydrogels, has emerged as a groundbreaking approach for treating neurological disorders. Hydrogels, known for their extracellular matrix-like properties, are at the forefront of neural regeneration strategies and are especially critical in the context of the limited regenerative capacities of the central and peripheral nervous systems. They play pivotal roles in the treatment of various neural disorders, such as spinal cord injuries, traumatic brain injuries, strokes, cerebral hemorrhages, and more, by creating specific microenvironments that facilitate immunomodulation, angiogenesis, and oxidative stress regulation, thereby enhancing the healing potential of stem cells and exosomes. Advancements in hydrogel fabrication, aiming for specific biophysical and biochemical properties, have enabled their role in supporting cell adhesion, proliferation, axonal regrowth, and neural repair. Although promising in preclinical models, the translation of these hydrogel-based approaches into clinical practice remains an active area of research, offering a glimpse into the future of therapeutic strategies for neural repair and regeneration.

Linear mRNA-encoded bispecific T cell engagers (BiTEs) have shown promising efficacy in cancer treatment; however, their clinical translation remains constrained by poor stability and transient protein expression. To overcome these limitations, we engineered a circular RNA (cRNA) encoding PD-L1 & times;CD3 BiTEs using permuted intron-exon splicing and CVB3-IRES elements, and encapsulated it into novel ionizable lipid nanoparticles (D1LNPs) synthesized via a streamlined one-step reaction. This platform, termed D1LNP@cRNABiTEs , achieved robust and sustained in vivo expression of the BiTEs, significantly outperforming conventional linear mRNA formulations. In murine models of colorectal cancer, monotherapy with D1LNP@cRNABiTEs potently inhibited tumor growth, enhanced CD8+ T-cell infiltration into the tumor microenvironment, and elevated levels of proinflammatory cytokines. Furthermore, ELISpot analysis confirmed the enhancement of systemic antigen-specific T cell responses. The D1LNPs delivery system also demonstrated excellent stability and favorable safety profile. In conclusion, our study provides compelling evidence for the D1LNPs@cRNA platform as a potent and scalable strategy for cancer immunotherapy, effectively addressing key challenges of RNA stability and delivery. (c) 2026 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Post-hemorrhagic hydrocephalus (PHH) is a severe complication of intraventricular hemorrhage (IVH), yet its underlying mechanisms remain unclear. The glymphatic system (GS), a key pathway involved in cerebrospinal fluid (CSF) circulation and metabolic waste clearance, has recently been implicated in the pathogenesis of PHH. In this study, we employed a mouse model of IVH (n = 6 per group, assessed from 6 h to 28 days post-IVH) to investigate the role of the CCL2/CCR2 signaling axis in GS dysfunction and PHH progression. Behavioral tests, CSF tracer imaging, immunofluorescence, and Western blot analyses were used to assess CSF dynamics, AQP4 polarization, and relevant protein levels. The results showed that IVH induced upregulation of CCL2/CCR2, endoplasmic reticulum stress, and NF-κB activation, accompanied by the loss of AQP4 polarization and impairment of GS function. Notably, CCR2 inhibition was significantly associated with restored AQP4 polarization, improved CSF clearance, reduced ventricular enlargement, and ameliorated neurological deficits. These findings suggest that the CCL2/CCR2 signaling pathway may contribute to GS dysfunction in PHH and provide a foundation for exploring its therapeutic potential.

The pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus (iNPH) remain unclear. The cerebral small vessel disease (CSVD) pathology may play a crucial role in patients with iNPH. This study aims to investigate the prevalence of CSVD in patients with probable iNPH and examined the associations between CSVD burden and clinical characteristics and prognosis after shunt surgery. We enrolled patients with iNPH from an ongoing prospective cohort study in the West China Hospital of Sichuan University from August 2021 to present. The clinical characteristics, cognitive assessment, quantitative gait analyses, and MRI were prospective collected. Those patients who underwent shunt surgery were followed up at 3 months after. CSVD imaging markers including the CSVD burden, PWMH Fazekas, DWMH Fazekas, BG-EPVS, and CSO-EPVS scores, and the presence of lacunes and CMBs were evaluated. The linear and logistic regression models were used to investigate the association between the CSVD imaging markers and clinical features and outcomes in patients with iNPH. Among the 65 patients with iNPH (Age: 74.82 ± 6.23 years, Male: 69%), 83% (54/65) patients had at least one type of CSVD imaging markers and 63% (41/65) patients had CSVD score≧2. Age and hypertension were the highest risk factors. The CSVD score was associated with poorer Stroop test scores, a shorter stride length, lower step height, a faster cadence, and a longer Timed-Up and Go test time. Adjusting for age, sex, years of education, and vascular risk factors, it remained associated with a shorter stride length. The CSVD score had increased trends for poor improvement in patients with shunt surgery. Our study showed the high occurrence of CSVD imaging abnormality in patients with iNPH, and the comorbid CSVD were associated with more severe gait disturbances and cognitive decline, suggesting that CSVD may be involved in the pathogenesis of iNPH.

Supplementary Figure 7. Molecular structure of SLC3A2/PD-L1 BsADC. VcMMAE, mc-vc-PAB-MMAE. Drug payload, MMAE, monomethyl auristatin E; Linker, mc-vc-PAB, maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl.

The vestibular schwannoma (VS) originates from the Schwann cells of the vestibular nerve myelin. For patients with growing tumors or cysts and/or clinical symptoms such as hearing loss, surgical treatment is indicated. VS treatment strategy has shifted from total tumor resection to maximal tumor resection with the preservation of nerve function. With the remarkable development of endoscopic surgery in the past 20 years, an increasing number of surgeons have begun to pursue endoscopically assisted or total endoscopic resection of VS,and have achieved remarkable clinical results. VS treatment has become more minimally invasive and better aligned with clinical needs. This article primarily focused on the application of neuroendoscopy in VS resection, including its use in different surgical approaches, such as retrosigmoid sinus approach (RSA), translabyrinthine approach (TLA), middle cranial fossa approach (MFA) and transauricular capsule approach, and also summarized the necessity and extent of drilling the posterior wall of the internal auditory meatus (IAC) during the RSA. Furthermore,the paper discussed the role of neuroendoscopy in the protection of facial and cochlear nerve function during VS operations. Finally, this study reviewed the effects of neuroendoscopy on the presence of residual VS and its limitations. The aim was to explore prospects for the application of neuroendoscopy in VS resection.