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Extracellular vesicles (EVs) have emerged as important means of cell–cell communication, having the potential to transfer various cargoes – encompassing proteins, nucleic acids, metabolites or even entire organelles — between cells. By now, the importance of EV-mediated cell–cell communication has been documented in a plethora of physiological and pathological situations, across the different kingdoms. In addition, their secretion and cargo composition can change depending on the biological context, making EVs suitable biomarkers for several diseases. EVs have also been harnessed as drug delivery agents and standalone therapeutics.
In this Collection, we have put together selected articles from across the Nature Portfolio that document the recent progress in understanding the biology of EV-mediated cell–cell communication and advances in clinical translation of EVs. The Collection has been divided into four parts: 1) Basic mechanisms, which overview the biogenesis and regulation of EV secretion; 2) Examples of biological function of EVs; 3) Techniques that improve the studies of EVs; and 4) Examples of various clinical applications of EVs. The breadth of this Collection further underlines the cross-disciplinary nature of this field of research and the importance of collaborative work in unleashing the full potential of EVs.
Extracellular vesicles (EVs) are lipid-bound nanoscale mediators of intercellular communication. This Review discusses EVs in the context of the extracellular matrix, highlighting how the understanding of their interactions inspires materials design to control the release, retention and production of EVs for various biological and therapeutic applications.
In this Review, Toyofuku, Schild, Kaparakis-Liaskos and Eberl discuss the different types of bacterial membrane vesicle, how they are formed, their structure and composition and their diverse functions.
Extracellular vesicles (EVs) have emerged as important players in intercellular communication, carrying proteins, lipids, nucleic acids and various signalling molecules between cells. Unravelling how these different cargoes are sorted into EVs in a regulated and context-specific manner is essential to understanding the specificity of EV-mediated signalling.
Extracellular vesicles (EVs) mediate cell–cell communication in physiology and pathology but many questions remain about the mechanisms governing their delivery to recipient cells. This Expert Recommendation article highlights areas of progress and challenges in establishing the importance of EV-mediated communication in vivo.
Wu et al. report that a stiff extracellular matrix stimulates the release of exosomes from cancer cells under the control of Akt and Rab8. These exosomes in turn promote tumour growth.
Arya et al. identify a pathway for exosome generation in immune cells that originates at the nuclear envelope and is facilitated by nSMase1-mediated generation of ceramide.
MicroRNAs encode sorting sequences that determine whether they are secreted in exosomal vesicles to regulate gene expression in distant cells or retained in cells that produced them, with different sequences used by individual cell types.
Extracellular vesicles (EV) are known to be released from the primary cilium, but the role ciliary proteins play in EV biogenesis remains unexplored. Here, the authors demonstrate increased secretion of small EVs with altered cargo composition from cells with known ciliarelated mutations. Wnt related molecules made up a majority of altered cargo
Mitochondrial content in extracellular vesicles (EVs) can enhance inflammation, although its role in noninflammatory conditions is unclear. Here, the authors show that mitochondria-derived vesicles target material to EVs, whereas Parkin directs damaged mitochondrial content to lysosomes, providing insight into mitochondria-driven immune responses.
Plants use extracellular vesicles to deliver small RNAs that could silence fungal virulence genes to their fungal pathogens. In this study, the authors profile the components of these extracellular vesicles and investigate regulators contributing to the specific RNA loading and stabilization.
Extracellular vesicles (EVs) are increasingly recognized as having ubiquitous roles in the immune system. This Review focuses on the progress made in the field in the past 5 years, including the roles of EVs in innate and adaptive immunity and their potential use in diagnosis and therapy.
In this Review, the authors discuss the roles of extracellular vesicles in kidney physiology and disease as well as the beneficial effects of stem cell-derived extracellular vesicles in preclinical models of acute kidney injury and chronic kidney disease. They also highlight current and future clinical applications of extracellular vesicles in kidney diseases.
Exerkines are signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.
The authors review the evidence for a biological role of RNA as a form of cell–cell communication in mammals as well as proposed roles for extracellular RNAs in health and disease. Moreover, this Review emphasizes and provides guidance on the experimental rigor that is required to definitively show that extracellular RNAs are functional in recipient cells in vivo.
Kuang, Dou et al. show that upon Salmonella Typhimurium infection in mice, macrophages release extracellular vesicles (EVs) that harbor iron-uptake receptors. By sequestering iron via a humoral mechanism, these EVs limit bacterial growth and thereby protect against infection.
Hexokinase 1 is found to be secreted from hepatic stellate cells in large extracellular vesicles in response to TGF-β, and is subsequently taken up by hepatocellular carcinoma cells, where it promotes tumor progression and metastasis.
Lanna and colleagues discover extracellular vesicle-mediated transfer of telomeres from antigen-presenting cells to T cells, which enables elongation of chromosomes, protection against replicative senescence and long-term immune defence.
The DEAD box protein DDX1 is known to form large aggregates in the cytoplasm of early mouse embryos. Here the authors identify DDX1-containing vesicles and show that loss of Ddx1 affects their integrity, compromising mitochondria function and causing embryonic lethality.
Cao et al. show that miR-122 encapsulated in breast cancer-derived extracellular vesicles targets PKM to downregulate β-cell insulin secretion, leading to dysregulated glucose homeostasis and enhanced tumour growth.
Suberizing plant cells export suberin monomers outside of the cell to form a hydrophobic barrier. Here the authors propose a role for extracellular vesiculo-tubular structures in the deposition of suberin monomers.
Peinado and colleagues show that small extracellular vesicles and secreted NGFR cargo induce lymphangiogenesis and develop the lymph node pre-metastatic niche to promote melanoma metastasis, which could be targeted pre-clinically with NGFR inhibition.
This study shows that miRNAs produced by plants act as signalling molecules that affect gene expression in nearby plants. This RNAi induced by exogenous miRNAs enables communication between plants and requires the production of secondary siRNAs.
Here, Goss et al. explore the diagnostic potential of male reproductive small extracellular vesicles and the practical approaches of implementing point-of-need and multianalyte diagnostics in infertility treatment, detailing microfluidic small extracellular vesicle isolation and analysis as an accessible and effective approach to achieving this outcome.
This Review describes the state of the art in imaging extracellular vesicles in animals to study their release, biodistribution and uptake, and covers labeling strategies, microscopy methods and discoveries made in model organisms.
Understanding the heterogeneity of extracellular vesicles is crucial for unraveling their functions. This review describes the benefits, challenges and contributions of the state-of-the art methods used in single-vesicle analysis.
Bacterial extracellular vesicles (BEVs) in human body fluids are analyzed using ultrafiltration, size-exclusion chromatography and density-gradient centrifugation to separate the BEVs, followed by post-separation characterization with orthogonal biochemical methods.
iNTA combines interferometric detection of scattering with nanoparticle tracking analysis for determining the size and refractive index distributions of nanoparticles in suspension with high sensitivity and precision.
A device that integrates the enrichment and electrochemical detection, in less than one hour, of tumour extracellular vesicles bearing clinically relevant tumour biomarkers accurately classifies patients with colorectal cancer.
A prior live-cell exosome reporter showed dim fluorescence and could not be expressed stably, limiting its usefulness. Here the authors stabilise the reporter to allow long-term tracking of exosomes, and incorporate a second fluorophore to visualise the entire exosome lifecycle.
The past decade has witnessed rapid growth in the field of extracellular vesicle (EV) research, and the potential of harnessing EVs in the treatment and diagnosis of diseases is now well recognized. Here, Cheng and Hill provide an overview of the physiological and pathological roles of EVs, discuss how they could be therapeutically exploited and consider the associated challenges.
In this Review the authors discuss the biological role of extracellular vesicles and how they can be applied as drug carriers, focusing on the current state of their manufacturing and existing challenges.
This Review discusses the potential use of cancer-derived extracellular vesicles for cancer biomarkers and novel therapeutics, with a focus on evolving translational applications, and their roles during cancer progression.
Extracellular vesicles are a heterogeneous group of natural particles that can deliver their biologically active molecular cargo to recipient cells. In this Review, the authors outline the endogenous properties of extracellular vesicles that make them natural delivery agents and the features that can be improved by bioengineering for the treatment of cardiovascular diseases.
Extracellular vesicles transfer a variety of cellular components between cells — including proteins, lipids and nucleic acids. There is now evidence indicating that these cargoes, in particular RNAs, can affect the function of recipient cells. Extracellular vesicles are now being actively tested as biomarkers and delivery vehicles for therapeutic agents.
Cancer vaccines based on endogenous modified dendritic cells can activate cytotoxic T cells in an antigen-specific manner, but the short life of dendritic cells on injection in the body limits the efficacy of the strategies. Here the authors design biomimetic nanovesicles derived from antigen-presenting dendritic cell membranes for cancer vaccination and the simultaneous delivery of immune co-stimulatory molecules, showing robust antitumour activity in animal models.
Celià-Terrassa and colleagues identify LCOR-low cancer stem cells driving tumor immunity and propose LCOR induction with mRNA therapy as an enhancer of immunotherapy response.
Milbank et al. show that specific targeting of AMPKα1 in SF1 neurons of the VMH through systemic injection of small extracellular vesicles causes weight loss via increased brown adipose tissue thermogenesis.
The loading of two different protein therapeutics onto extracellular vesicles can be optimized by genetically engineering the parent cells, as shown for extracellular vesicles displaying decoy receptors for two pro-inflammatory cytokines.
Measuring the levels of circulating SARS-CoV-2 RNA in plasma might represent a more accurate way to detect lower respiratory tract and extrapulmonary infections, which classical COVID-19 detection assays based on nasopharyngeal swabs might miss. Here, the authors accurately detect SARS-CoV-2 RNA in plasma-circulating extracellular vesicles using a CRISPR–Cas-based strategy that shows promising characteristics for potential clinical application.
In response to infection with Staphylococcus aureus in vitro and in vivo, host cells increase their secretion of exosomes containing ADAM10—vesicular structures that can provide protection by sequestering bacterial toxins.