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Trends in Cell Biology Aug 2023The study of extracellular vesicles (EVs) and nanoparticles (NPs) is rapidly expanding because recent discoveries have revealed a much greater complexity and diversity... (Review)
Review
The study of extracellular vesicles (EVs) and nanoparticles (NPs) is rapidly expanding because recent discoveries have revealed a much greater complexity and diversity than was appreciated only a few years ago. New types of EVs and NPs have recently been described. Proteins and nucleic acids previously thought to be packaged in exosomes appear to be more enriched in different types of EVs and in two recently identified amembranous NPs, exomeres and supermeres. Thus, our understanding of the cell biology and intercellular communication facilitated by the release of EVs and NPs is in a state of flux. In this review, we describe the different types of EVs and NPs, highlight recent advances, and present major outstanding questions.
Topics: Humans; Extracellular Vesicles; Exosomes; Cell Communication; Nucleic Acids
PubMed: 36737375
DOI: 10.1016/j.tcb.2023.01.002 -
Nature Reviews. Molecular Cell Biology Jul 2023To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell-cell communication involves secretion... (Review)
Review
To coordinate, adapt and respond to biological signals, cells convey specific messages to other cells. An important aspect of cell-cell communication involves secretion of molecules into the extracellular space. How these molecules are selected for secretion has been a fundamental question in the membrane trafficking field for decades. Recently, extracellular vesicles (EVs) have been recognized as key players in intercellular communication, carrying not only membrane proteins and lipids but also RNAs, cytosolic proteins and other signalling molecules to recipient cells. To communicate the right message, it is essential to sort cargoes into EVs in a regulated and context-specific manner. In recent years, a wealth of lipidomic, proteomic and RNA sequencing studies have revealed that EV cargo composition differs depending upon the donor cell type, metabolic cues and disease states. Analyses of distinct cargo 'fingerprints' have uncovered mechanistic linkages between the activation of specific molecular pathways and cargo sorting. In addition, cell biology studies are beginning to reveal novel biogenesis mechanisms regulated by cellular context. Here, we review context-specific mechanisms of EV biogenesis and cargo sorting, focusing on how cell signalling and cell state influence which cellular components are ultimately targeted to EVs.
Topics: Proteomics; Biological Transport; Extracellular Vesicles; Protein Transport; Signal Transduction; Cell Communication
PubMed: 36765164
DOI: 10.1038/s41580-023-00576-0 -
Molecular Cancer Dec 2023Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles... (Review)
Review
Tumor immunotherapy has transformed neoplastic disease management, yet low response rates and immune complications persist as major challenges. Extracellular vesicles including exosomes have emerged as therapeutic agents actively involved in a diverse range of pathological conditions. Mounting evidence suggests that alterations in the quantity and composition of extracellular vesicles (EVs) contribute to the remodeling of the immune-suppressive tumor microenvironment (TME), thereby influencing the efficacy of immunotherapy. This revelation has sparked clinical interest in utilizing EVs for immune sensitization. In this perspective article, we present a comprehensive overview of the origins, generation, and interplay among various components of EVs within the TME. Furthermore, we discuss the pivotal role of EVs in reshaping the TME during tumorigenesis and their specific cargo, such as PD-1 and non-coding RNA, which influence the phenotypes of critical immune cells within the TME. Additionally, we summarize the applications of EVs in different anti-tumor therapies, the latest advancements in engineering EVs for cancer immunotherapy, and the challenges encountered in clinical translation. In light of these findings, we advocate for a broader understanding of the impact of EVs on the TME, as this will unveil overlooked therapeutic vulnerabilities and potentially enhance the efficacy of existing cancer immunotherapies.
Topics: Humans; Neoplasms; Extracellular Vesicles; Exosomes; Cell Communication; Immunotherapy; Tumor Microenvironment
PubMed: 38087360
DOI: 10.1186/s12943-023-01898-5 -
Advanced Materials (Deerfield Beach,... Sep 2023Immunomodulation of tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like phenotype is a promising but challenging strategy. Cleverly, tumor cells...
Immunomodulation of tumor-associated macrophages (TAMs) into tumor-inhibiting M1-like phenotype is a promising but challenging strategy. Cleverly, tumor cells overexpress CD47, a "don't eat me" signal that ligates with the signal regulatory protein alpha (SIRPα) on macrophages to escape phagocytosis. Thus, effective re-education of TAMs into the "eat me" type and blocking the CD47-SIRPα signaling play pivotal roles in tumor immunotherapy. Herein, it is reported that hybrid nanovesicles (hEL-RS17) derived from extracellular vesicles of M1 macrophages and decorated with RS17 peptide, an antitumor peptide that specifically binds to CD47 on tumor cells and blocks CD47-SIRPα signaling, can actively target tumor cells and remodel TAM phenotypes. Consequently, more M1-like TAMs infiltrate into tumor tissue to phagocytize more tumor cells due to CD47 blockade. By further co-encapsulating chemotherapeutic agent shikonin, photosensitizer IR820, and immunomodulator polymetformin in hEL-RS17, an enhanced antitumor effect is obtained due to the combinational treatment modality and close synergy among each component. Upon laser irradiation, the designed SPI@hEL-RS17 nanoparticles exert potent antitumor efficacy against both 4T1 breast tumor and B16F10 melanoma models, which not only suppresses primary tumor growth but also inhibits lung metastasis and prevents tumor recurrence, exhibiting great potential in boosting CD47 blockade-based antitumor immunotherapy.
Topics: Humans; CD47 Antigen; Neoplasm Recurrence, Local; Phagocytosis; Neoplasms; Immunotherapy; Extracellular Vesicles
PubMed: 37384818
DOI: 10.1002/adma.202303835 -
ACS Nano Jul 2023Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical...
Ionizing radiation (IR) is associated with the occurrence of enteritis, and protecting the whole intestine from radiation-induced gut injury remains an unmet clinical need. Circulating extracellular vesicles (EVs) are proven to be vital factors in the establishment of tissue and cell microenvironments. In this study, we aimed to investigate a radioprotective strategy mediated by small EVs (exosomes) in the context of irradiation-induced intestinal injury. We found that exosomes derived from donor mice exposed to total body irradiation (TBI) could protect recipient mice against TBI-induced lethality and alleviate radiation-induced gastrointestinal (GI) tract toxicity. To enhance the protective effect of EVs, profilings of mouse and human exosomal microRNAs (miRNAs) were performed to identify the functional molecule in exosomes. We found that miRNA-142-5p was highly expressed in exosomes from both donor mice exposed to TBI and patients after radiotherapy (RT). Moreover, miR-142 protected intestinal epithelial cells from irradiation-induced apoptosis and death and mediated EV protection against radiation enteritis by ameliorating the intestinal microenvironment. Then, biomodification of EVs was accomplished via enhancing miR-142 expression and intestinal specificity of exosomes, and thus improved EV-mediated protection from radiation enteritis. Our findings provide an effective approach for protecting against GI syndrome in people exposed to irradiation.
Topics: Humans; Extracellular Vesicles; MicroRNAs; Exosomes; Enteritis
PubMed: 37399352
DOI: 10.1021/acsnano.3c04578 -
Signal Transduction and Targeted Therapy Feb 2024Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and... (Review)
Review
Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.
Topics: Humans; Extracellular Vesicles; MicroRNAs; Biomarkers; Virus Diseases; Neoplasms; Tumor Microenvironment
PubMed: 38311623
DOI: 10.1038/s41392-024-01735-1 -
Cell Reports. Medicine Sep 2023The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers...
The bone microenvironment promotes cancer cell proliferation and dissemination. During periodic bone remodeling, osteoclasts undergo apoptosis, producing large numbers of apoptotic bodies (ABs). However, the biological role of osteoclast-derived ABs, which are residents of the bone-tumor niche, remains largely unknown. Here, we discover that AB-null MRL/lpr mice show resistance to breast cancer cell implantation, with more CD8 T cell infiltrations and a higher survival rate. We uncover that the membranous Siglec15 on osteoclast-derived ABs binds with sialylated Toll-like receptor 2 (TLR2) and blocks downstream co-stimulatory signaling, leading to the inhibition of naive CD8 T cell activation. In addition, our study shows that treatment with Siglec15 neutralizing antibodies significantly reduces the incidence of secondary metastases and improves the survival rate of mice with advanced breast cancer bone metastasis. Our findings reveal the immunosuppressive function of osteoclast-derived ABs in the bone-tumor niche and demonstrate the potential of Siglec15 as a common target for anti-resorption and immunotherapy.
Topics: Animals; Mice; CD8-Positive T-Lymphocytes; Extracellular Vesicles; Melanoma; Mice, Inbred MRL lpr; Osteoclasts; Tumor Microenvironment; Melanoma, Cutaneous Malignant
PubMed: 37607544
DOI: 10.1016/j.xcrm.2023.101165 -
Biological Reviews of the Cambridge... Jun 2024Neutrophils are considered 'first-line defence' cells as they can be rapidly recruited to the site of the immune response. As key components of non-specific immune... (Review)
Review
Neutrophils are considered 'first-line defence' cells as they can be rapidly recruited to the site of the immune response. As key components of non-specific immune mechanisms, neutrophils use phagocytosis, degranulation, and formation of neutrophil extracellular traps (NETs) to fight pathogens. Recently, immunoregulatory abilities of neutrophils associated with the secretion of several mediators, including cytokines and extracellular vesicles (EVs) containing, among other components, microRNAs (miRNAs), have also been reported. EVs are small structures released by cells into the extracellular space and are present in all body fluids. Microvesicles show the composition and status of the releasing cell, its physiological state, and pathological changes. Currently, EVs have gained immense scientific interest as they act as transporters of epigenetic information in intercellular communication. This review summarises findings from recent scientific reports that have evaluated the utility of miRNA molecules as biomarkers for effective diagnostics or even as start-points for new therapeutic strategies in neutrophil-mediated immune reactions. In addition, this review describes the current state of knowledge on miRNA molecules, which are endogenous regulators of gene expression besides being involved in the regulation of the immune response.
Topics: Humans; Extracellular Vesicles; MicroRNAs; Neutrophils
PubMed: 38148491
DOI: 10.1111/brv.13048 -
Nature Communications Jul 2023The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered...
The transplantation of mesenchymal stem cells-derived secretome, particularly extracellular vesicles is a promising therapy to suppress spinal cord injury-triggered neuroinflammation. However, efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains a challenge. Here we present a device for the delivery of extracellular vesicles to treat spinal cord injury. We show that the device incorporating mesenchymal stem cells and porous microneedles enables the delivery of extracellular vesicles. We demonstrate that topical application to the spinal cord lesion beneath the spinal dura, does not damage the lesion. We evaluate the efficacy of our device in a contusive spinal cord injury model and find that it reduces the cavity and scar tissue formation, promotes angiogenesis, and improves survival of nearby tissues and axons. Importantly, the sustained delivery of extracellular vesicles for at least 7 days results in significant functional recovery. Thus, our device provides an efficient and sustained extracellular vesicles delivery platform for spinal cord injury treatment.
Topics: Humans; Porosity; Spinal Cord Injuries; Spinal Cord; Axons; Extracellular Vesicles
PubMed: 37419902
DOI: 10.1038/s41467-023-39745-2 -
Trends in Endocrinology and Metabolism:... Sep 2023The body partially maintains metabolic homeostasis through interorgan communication between metabolic organs under physiological conditions. This crosstalk is known to... (Review)
Review
The body partially maintains metabolic homeostasis through interorgan communication between metabolic organs under physiological conditions. This crosstalk is known to be mediated by hormones or metabolites, and has recently been expanding to include extracellular vesicles (EVs). EVs participate in interorgan communication under physiological and pathological conditions by encapsulating various bioactive cargoes, including proteins, metabolites, and nucleic acids. In this review we summarize the latest findings about the metabolic regulation of EV biogenesis, secretion, and components, and highlight the biological role of EV cargoes in interorgan communication in cancer, obesity, diabetes, and cardiovascular disease. We also discuss the potential application of EVs as diagnostic markers, and corresponding therapeutic strategies by EV engineering for both early detection and treatment of metabolic disorders.
Topics: Humans; Extracellular Vesicles; Metabolic Diseases; Neoplasms; Cell Communication; Communication
PubMed: 37394346
DOI: 10.1016/j.tem.2023.06.002