本周hzangs在最新文献中选取了11篇分享给大家，第1篇文章介绍了葡萄糖限制会引发肿瘤细胞释放外泌体TRAIL从而重塑肺部免疫微环境，促进肿瘤转移；第2篇文章介绍了一种冻干方法，可以用于保存治疗性细胞外囊泡；第4篇文章综述了目前用于制造治疗性细胞外囊泡的微流控技术进展；第6/7篇都是介绍缺氧调控细胞外囊泡调控生理过程；第11篇文章介绍了阿尔茨海默病中内皮细胞来源囊泡调控疾病发展的的机制。
- Glucose restriction shapes pre-metastatic innate immune landscapes in the lung through exosomal TRAIL.
葡萄糖限制通过外泌体 TRAIL 塑造肺内转移前的先天免疫景观。
[Cell] PMID: 40669460
Abstract: Targeting glucose metabolism has emerged as a promising strategy for inhibiting tumor growth. However, we herein uncover an unexpected paradox: while glucose deprivation through a low-carbohydrate diet or impaired in situ metabolism suppresses primary tumor growth, it simultaneously promotes lung metastasis by depleting natural killer (NK) cells via lung macrophages. Mechanistically, glucose deprivation induces endoplasmic reticulum (ER) stress, activating HMG-CoA reductase degradation protein 1 (HRD1) to catalyze K63-linked ubiquitination of TRAIL, which is then packaged into exosomes via the endosomal sorting complex required for transport (ESCRT) complex. These exosomal TRAIL molecules polarize PVR+macrophages, triggering NK cell exhaustion and establishing a pre-metastatic niche. Notably, TIGIT blockade not only prevents metastasis induced by glucose deprivation but also enhances its anti-tumor effects. Clinically, low glucose metabolism correlates with higher 2-year postoperative recurrence across 15 cancer types. Furthermore, plasma exosomal TRAIL outperforms traditional markers, such as α-fetoprotein (AFP) and tumor size, in predicting early postoperative lung metastasis, revealing both the risks and therapeutic potential of targeting glucose metabolism.
- Alleviation of dry eye disease with lyophilized extracellular vesicles.
使用冻干细胞外囊泡缓解干眼症。
[J Control Release] PMID: 40681022
Abstract: Dry eye disease (DED), a prevalent ocular condition affecting millions globally, necessitates the development of innovative therapeutic strategies for long-term management. Although extracellular vesicles (EVs) have shown therapeutic potential for DED, their clinical translation has been substantially limited by stability issues during storage. In this study, a novel lyophilization strategy incorporating ectoine - a natural osmolyte with superior bio-stabilization capabilities - was developed to address these challenges. For the first time, an ectoine-enhanced lyophilization protocol was established to preserve the key functional properties of milk-derived EVs (mEVs) during prolonged storage at 4 °C. Comprehensive characterization through hydrodynamic analysis, structural evaluation, β-galactosidase activity assessment, and functional validation demonstrated that mEVs lyophilized with 0.5 %-4 % ectoine maintained critical biological properties for over two months, representing a significant improvement compared to conventional preservation methods. The lyophilized mEVs were shown to effectively protect human corneal epithelial cells (HCECs) against hyperosmolarity-induced damage. Notably, in a benzalkonium chloride (BAC)-induced rabbit model of DED, the optimized formulation exhibited enhanced therapeutic performance, as evidenced by significant improvements in clinical parameters and ocular surface health. These findings established ectoine-based lyophilization as a transformative preservation methodology for EV-based therapeutics, providing a robust solution to persistent stability challenges in ocular drug delivery systems and facilitating the clinical translation of EV-based treatments for DED and related ocular surface disorders.
- Unveiling the role of TAM-derived extracellular vesicles in glioma progression through Treg polarization and immune suppression.
揭示 TAM 衍生的细胞外囊泡通过 Treg 极化和免疫抑制在胶质瘤进展中的作用。
[Oncogene] PMID: 40681801
Abstract: In the context of gliomas, tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) play crucial roles in shaping the tumor microenvironment (TME). This study focused on elucidating the mechanism by which TAM-derived extracellular vesicles (EVs) influence Treg differentiation and contribute to glioma progression. Through comprehensive single-cell RNA sequencing (scRNA-seq) analysis, the glioma TME was characterized by an abundance of TAMs exhibiting M2 polarization and increased Treg differentiation. Notably, TAM EVs were identified as potent inducers of Treg differentiation, with the downregulation of Bactericidal/Permeability-Increasing protein (BPI) being associated with this process. In vivo experiments utilizing a mouse model of glioma further demonstrated that TAM-derived EVs promoted glioma growth by enhancing Treg-mediated immunosuppression while dampening pro-inflammatory responses. This study highlights the critical role of TAM-derived EVs in modulating Treg differentiation and supporting glioma progression, suggesting that interventions targeting TAM EVs or regulating BPI expression could offer novel therapeutic avenues for combating immune suppression and inhibiting glioma development.
- Microfluidic Devices for Manufacture of Therapeutic Extracellular Vesicles: Advances and Opportunities.
用于制造治疗性细胞外囊泡的微流体装置：进展和机遇。
[J Extracell Vesicles] PMID: 40704561
Abstract: Extracellular vesicles (EVs) are emerging as promising candidates in therapeutic applications due to their unique ability to mediate intercellular communication and deliver biological cargo. With increasing interest in EV-based therapies, the development of scalable, cost-effective and regulatory-compliant production methods is critical. Microfluidic platforms offer transformative potential in EV manufacturing, providing precise control over production conditions, enhanced purity and seamless integration with quality control systems. This review highlights the advantages of microfluidic technologies in EV production, including fine-tuning of shear stress to optimise yield, advanced purification strategies that achieve high recovery and purity, and on-chip capabilities for EV loading and surface modification. Key challenges such as scaling up production while maintaining sterility, controlling EV release after immunoaffinity capture, and addressing clogging and fouling in microfluidic devices are discussed alongside emerging solutions. Additionally, the integration of AI-driven automation and real-time monitoring, as well as personalised EV manufacturing, is explored as pivotal innovations. Future directions emphasise the potential of combining size- and affinity-based methods for EV isolation and aligning microfluidic technologies with regulatory requirements to accelerate clinical translation. Therefore, we believe microfluidics platforms for EV isolation hold immense potential to redefine EV manufacturing by enabling scalable, reproducible and high-quality production systems essential for therapeutic applications.
- DeSUMOylation of RBMX regulates exosomal sorting of cargo to promote renal tubulointerstitial fibrosis in diabetic kidney disease.
RBMX 的去SUMO化调节外泌体货物的分选，从而促进糖尿病肾病中的肾小管间质纤维化。
[J Adv Res] PMID: 39341454
Abstract: Introduction: Diabetic kidney disease (DKD) has become the primary cause of chronic renal failure in China, and renal tubulointerstitial fibrosis plays a central role in DKD progression. Urinary exosomes, which reflect kidney changes, are largely influenced by RNA-binding proteins (RBPs) in their miRNA content. Objectives: Our research aimed to determine the effect of the RNA-binding protein RBMX on exosomal miRNA in DKD. Methods: We introduced a higher level of Rbmx into diabetic mice using an adenoassociated virus and isolated exosomes from their kidney tissue through advanced centrifugation techniques and specialized kits. We then conducted a series of tests, including qRT-PCR, Western blot, MitoSOX, ATP luminescence, coimmunoprecipitation, SUMOylation assays, RNA immunoprecipitation, and confocal microscopy. Results: RBMX is found in higher levels in DKD and contributes to worsening kidney fibrosis, mitochondrial damage, and miRNA mismanagement in exosomes. It specifically binds with miR-26a, miR-23c, and miR-874 within the exosomes. This dysfunction may be linked to changes in RBMX SUMOylation. These miRNAs seem to protect against mitochondrial damage in kidney cells by targeting CERS6. Conclusion: DeSUMOylation of RBMX plays a crucial role in determining the makeup of miRNAs in kidney cell exosomes, impacting the protective miRNAs which regulate mitochondrial damage through their interaction with CERS6 mRNA, ultimately affecting mitochondrial health in DKD.
- Hypoxic Neural Stem Cells Enhance Spinal Cord Repair Through HIF-1a/RAB17-Driven Extracellular Vesicle Release.
缺氧神经干细胞通过 HIF-1a/RAB17 驱动的细胞外囊泡释放增强脊髓修复。
[J Extracell Vesicles] PMID: 40660091
Abstract: Spinal cord injury (SCI) is a severe and complex condition that can lead to significant physical impairments and affect the life quality of patients. Neural stem cells (NSCs) transplantation holds as a promising therapeutic approach for SCI. However, the challenging post-SCI microenvironment limits NSCs effectiveness. Our current research has found that transplanted NSCs, though with lower survival and differentiation, still aided in injury repair. Hypoxia was identified as a stressor inducing the release of extracellular vesicles (EVs) from NSCs through HIF-1α/RAB17 enhancing SCI repair. By extracting and modifying these EVs derived from hypoxia treated NSCs with CAQK/Angiopep2 peptides, we were able to accurately deliver them to the injury site, enhancing recovery without relying on cell survival or differentiation. This study delved into the reparative role and underlying mechanisms of transplanted NSCs in SCI, focusing on their non-cellular contributions and developed an innovative, targeted strategy for the transplantation of EVs derived from NSCs, offering a cell-free, precision therapeutic intervention for the treatment of SCI.
- HIF-1 promotes murine breast cancer brain metastasis by increasing production of integrin β3-containing extracellular vesicles.
HIF-1通过增加含有整合素β3的细胞外囊泡的产生来促进小鼠乳腺癌脑转移。
[J Clin Invest] PMID: 40662366
Abstract: Brain metastasis is a major cause of breast cancer (BC) mortality, but the cellular and molecular mechanisms have not been fully elucidated. BC cells must breach the blood-brain barrier in order to colonize the brain. Here, we determined that integrin β3 (ITGB3) expression mediated by hypoxia-inducible factor 1 (HIF-1) plays a critical role in metastasis of BC cells to the brain. Hypoxia stimulated BC cell migration and invasion ex vivo and brain colonization in vivo. Knockdown of either HIF-1α or ITGB3 expression impaired brain colonization by human or mouse BC cells injected into the cardiac left ventricle. Exposure of BC cells to hypoxia increased expression of ITGB3 and its incorporation into small extracellular vesicles (EVs). EVs harvested from the conditioned medium of hypoxic BC cells showed increased retention in the brain after intracardiac injection that was HIF-1α and ITGB3 dependent. EVs from hypoxic BC cells showed binding to brain endothelial cells (ECs), leading to increased EC-BC cell interaction, increased vascular endothelial growth factor receptor 2 signaling, increased EC permeability, and increased transendothelial migration of BC cells. Taken together, our studies implicate HIF-1-stimulated production of ITGB3+ EVs as a key mechanism by which hypoxia promotes BC brain metastasis.
- ADAM Sheddase Activity Promotes the Detachment of Small Extracellular Vesicles From the Plasma Membrane.
ADAM 脱落酶活性促进小细胞外囊泡从质膜上分离。
[J Extracell Vesicles] PMID: 40673783
Abstract: Small extracellular vesicles (SEVs) are involved in diverse functions in normal and pathological situations, including intercellular communication, immunity, metastasis and neurodegeneration. Cell release of SEVs is assumed to occur passively right after multivesicular bodies of the endocytic pathway fuse with the plasma membrane. We show here that the completion of SEV release depends on membrane-bound ADAM10 and ADAM17 sheddases that promote the detachment of SEVs from the cell surface by catalysing the cleavage of adhesion proteins of the SEV membrane. The intensity of ADAM10/17-mediated release of SEVs depends on a balanced control of 3-phosphoinositide-dependent kinase 1 (PDK1) and ERK1/2 signalling pathways converging on 90-kDa ribosomal S6 kinase-2 (RSK2), which, in turn, fine-tunes ADAM17 bioavailability and ADAM10/17 enzymatic activities at the plasma membrane, according to a mechanism that relies, at least in part, on variation of the rhomboid-like pseudoprotease iRhom2 cell surface level. By identifying a new proteolytic step involved in the basal release of SEVs, our work may help understand how the deregulation of ADAM10/17-mediated discharge of SEVs contributes to several pathological states.
- Dynamic Profiling of Penicillin-Binding Protein 2a (PBP2a)-Positive Extracellular Vesicles: Implications for Early Diagnosis and Treatment Monitoring of Methicillin-Resistant Staphylococcus Aureus Infections.
青霉素结合蛋白 2a (PBP2a) 阳性细胞外囊泡的动态分析：对耐甲氧西林金黄色葡萄球菌感染的早期诊断和治疗监测的意义。
[J Extracell Vesicles] PMID: 40673893
Abstract: Infections caused by methicillin-resistant staphylococci (MRS), such as methicillin-resistant Staphylococcus aureus (MRSA), pose significant challenges to public health. The early detection of MRS infections and monitoring of antibiotic resistance profiles are critical for patient management and infection control strategies. Extracellular vesicles (EVs) have emerged as promising biomarkers in infectious disease. By combining single-particle nano-flow cytometry and immunoelectron microscopy (immuno-TEM), we discovered that PBP2a is present on the surface of EVs extracted from MRS. However, whether PBP2a can serve as an EVs-associated protein marker for diagnosing bacterial infections remains unexplored. Using MRSA as a model strain, mouse models of localized and systemic infections were established, alongside a clinical cohort study, to investigate the dynamics of PBP2a-positive (PBP2a+) EVs in plasma following bacterial infection, infection progression, and in response to antimicrobial therapy. In mouse infection models, PBP2a+EVs were detected in plasma, with variable detection rates observed across different infection models. The study found a progressive correlation between increasing plasma PBP2a+ EVs levels and non-specific inflammation markers (CRP, IL-6) during infection progression. Antimicrobial therapies, however, inversely affected the ratio of PBP2a+ EVs. Furthermore, a clinical cohort study confirmed a direct association between the magnitude of PBP2a+ EVs in the plasma of patients with MRSA infection and the severity of infection. The investigation highlights the potential of PBP2a+ EVs as plasma biomarkers of MRSA antibiotic resistance, particularly during the early stages of resistant infections. Their persistence in plasma throughout the infectious episode makes them valuable indicators for monitoring disease progression and evaluating the efficacy of antibiotic treatments.
- Proteomic Analysis of Extracellular Vesicles Identifies CDCP1 as Critical Metastasis-Related Glycoprotein in Lung Cancer.
细胞外囊泡的蛋白质组学分析表明 CDCP1 是肺癌中关键的转移相关糖蛋白。
[J Extracell Vesicles] PMID: 40693605
Abstract: Lung cancer is the most prevalent malignancy worldwide, with the majority of fatalities attributed to metastasis. Recent studies have demonstrated the pivotal role of extracellular vesicles (EVs) and glycoproteins in tumor progression. In this study, we compared the glycoproteome of EVs from 95C (low metastatic) and 95D (high metastatic) lung cancer cells to discover key targets in metastasis. Through coupling lectin affinity chromatography with quantitative proteomics, 1562 glycoproteins were identified. Compared to 95C EVs, 23 glycoproteins were significantly upregulated more than 20-fold in 95D EVs, including CDCP1, TNC, NCAM2, and ITGA4. CUB-domain containing protein 1 (CDCP1) was upregulated 143-fold in 95D EVs, which is significantly correlated with poor prognosis of lung cancer patients in the TCGA database. We subsequently performed site-specific glycoform profiling of CDCP1 using intact glycopeptide enrichment. Then we generated CDCP1 knockout (KO) 95D cell lines and revealed that the absence of CDCP1 reduced cell migration ability, which was also confirmed by EVs and cell co-culture experiments. We further performed Ti4+-IMAC-based phosphoproteomic analysis to investigate the changes in signaling pathways in CDCP1 KO cell lines. 147 differentially expressed phosphoproteins were revealed. Verification experiments confirmed that the levels of phosphorylated SRC and JUN proteins, markers of ErbB signaling pathway, were decreased 5.5-fold and 4.2-fold, respectively. Glycosylation site mutagenesis identified N339 and N386 as critical functional determinants of CDCP1. Collectively, our data demonstrate that glycoprotein CDCP1 was selectively packed into EVs and potentially contributed to cancer metastasis, which is a critical target for anti-metastasis research and cancer therapy.
- Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer's disease.
内皮特异性内皮因子通过阿尔茨海默病小鼠模型中的细胞外囊泡触发星形胶质细胞反应性。
[Mol Neurodegener] PMID: 40702549
Abstract: Background: Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. Methods: We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. Results: The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. Conclusions: This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.
今天的整理就到这里。希望大家可以有所收获。大家下周见！
