Journal of Extracellular Vesicles最新文献

Stem cell niches are complex multi-signalling networks comprised of molecular cues and physical interactions, orchestrated by niche-resident cells and the extracellular factors they produce. The bone niche specifically houses haematopoietic stem cells (HSCs), a critical cell type responsible for producing all blood and immune cells throughout life. Currently, how niches facilitate an ideal environment with simultaneously coordinating both intrinsic and extrinsic cellular signals is unknown. Studies presented here identify the existence of unique extracellular vesicle (EV)-defined niches within the haematopoietic system of human individuals. Bridging studies using proteomic signatures, nanoparticle characterization at single-vesicle resolution and machine learning-based techniques reveal that EVs can be grouped by blood, bone marrow and trabeculae within a human individual. Stem cell assays demonstrate that these niche-defined EVs impart functional effects on stem cells/progenitors based on location within the haematopoietic system. Finally, using single-cell transcriptomic analyses, results identify for the first time how niche-sourced EVs differentially affect the most primitive human HSCs and progenitors. This study highlights the significance of nanoparticles on human immunity and blood production and provides evidence for a new role for EVs, namely the demarcation of distinct nano-niches within biological systems.

Extracellular Vesicles (EVs), nanoscale membrane-bound cell-released structures, are vital for intercellular communication and material transport. Their role in musculoskeletal health and diseases has recently drawn significant attention. This review focuses on the latest EV research in musculoskeletal diseases, including their roles in disease progression and potential as biomarkers and therapies. Musculoskeletal disorders are the third-leading cause of global disability-adjusted life-years among adolescents and young adults. Current treatments face issues like limited tissue regeneration and poor drug targeting. With their natural messenger function and low immunogenicity, EVs have become a research focus. However, their action mechanisms in the musculoskeletal system remain un-systematically understood. This paper reviews EVs’ role in musculoskeletal diseases. It covers classification, biogenesis, release, internalization, cargo and their involvement in muscle cell processes, joint diseases, bone metabolism and disc degeneration. It also explores EVs’ role in musculoskeletal crosstalk and their potential as therapeutic agents and drug carriers through engineering with biomaterials. Future research should delve deeper into EV action mechanisms for better treatments. Overall, while EVs offer new treatment strategies for musculoskeletal diseases, more research is needed to overcome technical and clinical barriers.

For the past decade, the field of extracellular vesicle (EV) research has vastly expanded (Bazzan et al. 2021). Our knowledge of EV biogenesis, their various roles in intercellular communication, and significant contributions to disease initiation and regulation has quickly developed (Möller and Lobb 2020, Kalluri and LeBleu 2020). The burgeoning of EV research is notable in the rapid parallel advancement of appropriate, cutting-edge isolation and analysis techniques (Qiu et al. 2023, De Sousa et al. 2023). Whilst there is a consensus amongst the field on certain aspects of EV function and biology, one crucial, trending topic of controversy is the significance of EV nomenclature.

Accurate and appropriate naming is paramount within and outside the scientific community for several reasons. Firstly, researchers must be able to refer to the same entity properly to ensure that the same phenomenon is evaluated in their specific fields, as well as across fields, to allow legitimate comparisons and improvement. Iterative publications of MISEV guidelines and similar initiatives over the years have enabled significant progress (Welsh et al. 2024). Within the past decade, researchers used over 25 names for EVs, often describing the same entity across different diseases or source materials, with different labels (Choi et al. 2015). Precise designation of EVs is not only a matter of scientific uniformity, but also of scientific integrity. If research groups isolate the same EV but use different terms for it, determining whether the findings are providing deeper insights into a certain topic or contradicting each other can be difficult. In 2023, an average of ∼170 publications per week were deposited with PubMed in the EV field, increasing to about 195 in 2024, a trend that is likely to continue. Thus, it is possible that repeated work has been published without cross-referencing, and that this happens not by ignorance or deceit, but by a difficulty of finding related studies due to discrepancies in EV naming. The nomenclature of EVs was clearly and unambiguously defined in MISEV2018 (Théry et al. 2018) and more recently in MISEV2023 (Welsh et al. 2024). The MISEV guidelines, not only for researchers in the EV field but across disciplines, provide a unified and comparable platform.

Using accurate and specific EV terms is also important for early-career researchers and those new to the field. As numerous publications show, EVs obtained by current experimental methods are not EVs generated by a single mechanism, but rather a mixture of EVs secreted by multiple mechanisms (Di Bella 2022). Hence, a precise understanding of the EV source material used helps to design appropriate experiments and conduct accurate research. MISEV2023 provides an appropriate framework by defining the terms for EV subpopulations and the require

The seminal work by Shi et al. unveils a novel cytoprotective mechanism in intervertebral disc degeneration, whereby USP5-rich apoptotic extracellular vesicles (ApoEVs) stabilize the transcription factor E2F1 to suppress apoptosis and enhance DNA repair in nucleus pulposus cells. While this study elegantly reframes the reparative potential of ApoEVs, its conceptual and translational premises invite critical scrutiny. This letter highlights several overlooked challenges. We argue that the contextual duality of E2F1—a well-established regulator of both cell survival and senescence—poses a considerable therapeutic hazard, as sustained E2F1 stabilization may inadvertently trigger a senescent phenotype. Moreover, the generalizability of this mechanism remains uncertain: ApoEV cargo and functionality are highly dependent on the apoptotic stimulus, and vesicles derived from etoposide-induced apoptosis may not mirror those produced under pathophysiological disc conditions. Crucially, the proposed pathway—from vesicle internalization and endosomal escape of luminal USP5 to its nuclear trafficking and engagement with E2F1—represents a mechanistic black box requiring rigorous validation. Resolving these issues is essential to translating this compelling discovery into a safe and effective therapeutic strategy.

Extracellular vesicles (EVs) are nanosized particles secreted by all cell types. As EVs are naturally occurring carriers of biological cargo, they serve as a promising candidate for drug delivery applications. Potential advantages of EVs as drug delivery systems include biological stability, intrinsic targeting properties and ability to overcome natural barriers. However, limitations such as cumbersome production and isolation procedures, batch-to-batch variability, and challenges related to efficient cargo loading limit their potential for clinical applications. Here, we introduce EV mimetics, prepared by incorporating full-length membrane proteins in the lipid bilayer of liposomes, using cell-free protein synthesis. These structures mimic functional characteristics of EVs, while offering advantages in terms of ease of manufacture, controllability and potential for efficient cargo loading. To demonstrate the feasibility of producing proteoliposomes as EV mimetics, we selected EV-associated CD47, CD39 and N-Cadherin as model proteins. We show successful production and purification of CD47, CD39 and N-Cadherin containing EV mimetics. Additionally, for CD47, we show that reaction conditions can be tailored to enhance EV mimetic yield. Furthermore, proteinase K protection assays and immuno-labelling electron microscopy revealed that correct membrane protein topology is preserved for CD47 and CD39. N-Cadherin EV mimetics show enhanced uptake by N-Cadherin-expressing MDA-MB-231 cells, proving membrane protein functionality is preserved. We demonstrate the versatility of the methodology by producing EV mimetics using a wide variety of liposomal formulations. Finally, we show that two distinct membrane proteins can be inserted in the same EV mimetic, further indicating versatility and broad applicability. This study presents a modular and controllable strategy for cell-free synthesis of functional EV mimetics, which provides a meaningful step toward addressing challenges in EV-inspired drug delivery development.

Current antidepressants face limitations due to the blood–brain barrier (BBB), systemic side effects and delayed onset. Here, we engineered an intranasal thermosensitive hydrogel (EVs@IN) encapsulating Chlorella vulgaris-derived extracellular vesicles (EVs) for sustained nose-to-brain delivery. EVs@IN significantly enhanced nasal mucosal retention and facilitated targeted transport of EVs to the hippocampus via olfactory pathways, while minimizing pulmonary exposure and clearance. In mouse models of depression (LPS-induced and CUMS), intranasal EVs@IN elicited rapid and potent alleviation of depressive- and anxiety-like behaviours. Mechanistically, EVs modulated astrocyte phenotypic transformation, reducing the release of neurotoxic complement C3 and suppressing neuroinflammation. Concurrently, they activated the Nrf2-Pgc-1α pathway, enhanced antioxidant defences (elevated SOD and GSH), mitigated oxidative stress and restored synaptic plasticity and neurogenesis in the hippocampus. Furthermore, we demonstrated the capacity of EVs to serve as efficient drug carriers for brain delivery. EVs@IN exhibited excellent long-term biocompatibility in vivo. Our findings establish plant-derived EVs within a sustained-release intranasal platform as a promising, scalable and BBB-bypassing strategy for the rapid treatment of depression and potentially other neuropsychiatric disorders.

Gastric cancer (GC) persists as one of the most lethal malignancies globally, primarily due to late-stage diagnosis, limited therapeutic targeting options, and inherent resistance to conventional therapies. While molecular profiling has advanced our understanding of GC, the development of effective delivery systems capable of precise tumour targeting and enhanced treatment response remains an unmet need. In this work, we explored targeted therapeutic approaches for GC by leveraging patient-derived organoid models. Firstly, we confirmed claudin-4 (CLDN4) as an overexpressed target in malignant epithelial cells in GC through comprehensive analysis of multiple single-cell RNA sequencing datasets. Capitalising on this discovery, we developed an innovative nano-therapeutic biomaterial, designated NESC (NK-sEV-SpoVM-c-CPE^Q317I), by engineering natural killer cell-derived small extracellular vesicles (NK-sEVs) with a CLDN4-targeting peptide and a membrane-curvature-sensing domain. Multimodal imaging further confirmed tumour-specific accumulation of NESC, underscoring its targeting precision. Proteomic profiling and functional assays revealed that NK-sEVs possessed intrinsic radiosensitising properties, which were significantly augmented upon conjugation with the targeting peptide. The resulting NESC platform demonstrated robust tumour-suppressive activity and enhanced radiosensitisation in both GC organoids and organoid-derived xenograft models. Collectively, by harnessing patient-derived organoids for functional validation, this study not only establishes a versatile framework for developing targeted sEV-based therapeutics but also provides a translational foundation for future clinical applications in GC management.

Extracellular vesicles (EVs) are increasingly recognized as mediators of central nervous system (CNS) function and pathologies, including multiple sclerosis (MS). While plasma-derived EVs have been explored as biomarkers in MS, little is known about EVs in CNS tissue. Here, we characterize EVs from postmortem normal-appearing white matter (NAWM) of MS and control brains. EVs were separated by differential centrifugation followed by size exclusion chromatography and characterized using nanoflow cytometry, single-particle reflectance imaging sensing (SP-IRIS) and transmission electron microscopy. EV size, yield and morphology did not differ significantly between MS and control samples. Despite the small sample size (n = 4 per group), proteomic analyses revealed downregulation of synaptic and mitochondrial proteins and upregulation of complement and inflammatory proteins and pathways in MS NAWM EVs. This suggests that EVs reflect ongoing synaptic pathology, metabolic dysfunction and CNS-compartmentalized inflammation and that they may actively contribute to these pathological processes. Deconvolution analyses suggest a shift in EV cellular origin, with an increased astrocytic and decreased neuronal EV contribution in MS. Several proteomic changes we observed in CNS-derived EVs have also been reported in circulating EVs of people with MS, establishing this CNS tissue EV study as a valuable resource for identifying biomarker candidates for brain-derived plasma EV studies.

Intercellular communication is essential for healthy embryo development, yet the role and dynamics of extracellular space in the maternal-embryonic dialogue remain unclear. Furthermore, little is known of maternal and embryonic metabolic states during early endometrial preparation and after the embryo enters the uterine cavity. Using a human in vitro co-culture model and extracellular vesicle (EV)-specific tools, we dynamically tracked EV secretion, uptake and processing between embryonic and endometrial cells at early stages of cell-to-cell communication. Hormonal stimulation altered endometrial secretory output, producing distinct EV populations. Stimulated EVs (St-EVs) differed from non-stimulated EVs (NSt-EVs) in size, secretion dynamics, uptake efficiency and metabolic cargo, selectively packaging energy-related metabolites and aryl hydrocarbon receptor (AhR) ligands. AhR inhibition increased spheroid attachment, suggesting that AhR signalling regulates implantation by modulating the endometrial environment. Additionally, lipid droplets (LDs) affected by endometrial- and embryo-derived EVs were actively secreted and taken up by embryonic cells, highlighting their role in implantation. EVs were not only exchanged between the embryo and endometrium but were also rapidly internalized, influencing mitochondrial activity, lipid metabolism and extracellular matrix remodelling. Translation of EV-derived mRNA occurred within 1 h of uptake, driving cellular changes and enhancing embryo attachment. These findings suggest EVs, extracellular metabolites and LDs mobilized between the endometrium and embryo coordinate to promote embryo attachment and implantation. This study advances our understanding of embryo-maternal EV-mediated communication and provides a valuable model for investigating EV-mediated simultaneous intercellular bidirectional crosstalk in other biological contexts.