Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis.

Introduction: Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). Method: A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. Results: 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). Conclusion: MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.

Isolation and Characterization of Extracellular Vesicles to Activate Retina Regeneration.

Mammals do not possess the ability to spontaneously repair or regenerate damaged retinal tissue. In contrast to teleost fish which are capable of retina regeneration through the action of Müller glia, mammals undergo a process of reactive gliosis and scarring that inhibits replacement of lost neurons. Thus, it is important to discover novel methods for stimulating mammalian Müller glia to dedifferentiate and produce progenitor cells that can replace lost retinal neurons. Inducing an endogenous regenerative pathway mediated by Müller glia would provide an attractive alternative to stem cell injections or gene therapy approaches. Extracellular vesicles (EVs) are now recognized to serve as a novel form of cell-cell communication through the transfer of cargo from donor to recipient cells or by the activation of signaling cascades in recipient cells. EVs have been shown to promote proliferation and regeneration raising the possibility that delivery of EVs could be a viable treatment for visual disorders. Here, we provide protocols to isolate EVs for use in retina regeneration experiments.

Surface modification of extracellular vesicles with polyoxazolines to enhance their plasma stability and tumor accumulation.

Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo, we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation.

Maternal stress during pregnancy alters circulating small extracellular vesicles and enhances their targeting to the placenta and fetus.

BACKGROUND: Maternal psychological distress during pregnancy can negatively impact fetal development, resulting in long-lasting consequences for the offspring. These effects show a sex bias. The mechanisms whereby prenatal stress induces functional and/or structural changes in the placental-fetal unit remain poorly understood. Maternal circulating small extracellular vesicles (sEVs) are good candidates to act as "stress signals" in mother-to-fetus communication. Using a repetitive restraint-based rat model of prenatal stress, we examined circulating maternal sEVs under stress conditions and tested whether they could target placental-fetal tissues. RESULTS: Our mild chronic maternal stress during pregnancy paradigm induced anhedonic-like behavior in pregnant dams and led to intrauterine growth restriction (IUGR), particularly in male fetuses and placentas. The concentration and cargo of maternal circulating sEVs changed under stress conditions. Specifically, there was a significant reduction in neuron-enriched proteins and a significant increase in astrocyte-enriched proteins in blood-borne sEVs from stressed dams. To study the effect of repetitive restraint stress on the biodistribution of maternal circulating sEVs in the fetoplacental unit, sEVs from pregnant dams exposed to stress or control protocol were labeled with DiR fluorescent die and injected into pregnant females previously exposed to control or stress protocol. Remarkably, maternal circulating sEVs target placental/fetal tissues and, under stress conditions, fetal tissues are more receptive to sEVs. CONCLUSION: Our results suggest that maternal circulating sEVs can act as novel mediators/modulators of mother-to-fetus stress communication. Further studies are needed to identify placental/fetal cellular targets of maternal sEVs and characterize their contribution to stress-induced sex-specific placental and fetal changes.

Optimizing Conditions of Polyethylene Glycol Precipitation for Exosomes Isolation From MSCs Culture Media for Regenerative Treatment.

Mesenchymal stem cell (MSC)-derived exosomes, as a cell-free alternative to MSCs, offer enhanced safety and significant potential in regenerative medicine. However, isolating these exosomes poses a challenge, complicating their broader application. Commonly used methods like ultracentrifugation (UC) and tangential flow filtration are often impractical due to the requirement for costly instruments and ultrafiltration membranes. Additionally, the high cost of commercial kits limits their use in processing large sample volumes. Polyethylene glycol (PEG) precipitation offers a more convenient and cost-effective alternative, but there is a critical need for optimized and standardized isolation protocols using PEG precipitation across different cell types and fluids to ensure consistent quality and yield. In this work, we optimized the PEG precipitation method for exosomes isolation and compared its effectiveness to two commonly used methods: UC and commercial exosome isolation kits (ExoQuick). The recovery rate of the optimized PEG method (about 61.74%) was comparable to that of the commercial ExoQuick kit (about 62.19%), which was significantly higher than UC (about 45.80%). Exosome cargo analysis validated no significant differences in miRNA and protein profiles associated with the proliferation and migration of exosomes isolated by UC and PEG precipitation, which was confirmed by gap closure and CCK8 assays. These findings suggest that PEG-based exosomes isolation could be a highly efficient and high-quality method and may facilitate the development of exosome-based therapies for regenerative medicine.

Exosome-like nanoparticles derived from fruits, vegetables, and herbs: innovative strategies of therapeutic and drug delivery.

Over the past ten years, significant advancements have been made in exploring plant-derived exosome-like nanoparticles (PELNs) for disease therapeutics and drug delivery. PELNs, as inherent nanoscale particles comprised of proteins, lipids, nucleic acids, and secondary metabolites, exhibit the capacity for cellular uptake by human cells. This intercellular interaction transcends biological boundaries, effectively influencing biological functions in animals. PELNs have outstanding biocompatibility, low immunogenicity, enhanced safety, and environmentally friendly sustainability. This article summarized the preparation methods and characteristics of PELNs. It provided a systematic review of the varied roles of PELNs derived from fruits, vegetables, and herbs in disease therapeutics and drug delivery. The challenges in their production and application were discussed, and future prospects in this rapidly evolving field were explored.

Brain incoming call from glia during neuroinflammation: Roles of extracellular vesicles.

The functionality of the central nervous system (CNS) relies on the connection, integration, and the exchange of information among neural cells. The crosstalk among glial cells and neurons is pivotal for a series of neural functions, such as development of the nervous system, electric conduction, synaptic transmission, neural circuit establishment, and brain homeostasis. Glial cells are crucial players in the maintenance of brain functionality in physiological and disease conditions. Neuroinflammation is a common pathological process in various brain disorders, such as neurodegenerative diseases, and infections. Glial cells, including astrocytes, microglia, and oligodendrocytes, are the main mediators of neuroinflammation, as they can sense and respond to brain insults by releasing pro-inflammatory or anti-inflammatory factors. Recent evidence indicates that extracellular vesicles (EVs) are pivotal players in the intercellular communication that underlies physiological and pathological processes. In particular, glia-derived EVs play relevant roles in modulating neuroinflammation, either by promoting or inhibiting the activation of glial cells and neurons, or by facilitating the clearance or propagation of pathogenic proteins. The involvement of EVs in neurodegenerative diseases such as Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD), and Multiple Sclerosis (MS)- which share hallmarks such as neuroinflammation and oxidative stress to DNA damage, alterations in neurotrophin levels, mitochondrial impairment, and altered protein dynamics- will be dissected, showing how EVs act as pivotal cell-cell mediators of toxic stimuli, thereby propagating degeneration and cell death signaling. Thus, this review focuses on the EVs secreted by microglia, astrocytes, oligodendrocytes and in neuroinflammatory conditions, emphasizing on their effects on neurons and on central nervous system functions, considering both their beneficial and detrimental effects.

Adipocyte derived exosomes promote cell invasion and challenge paclitaxel efficacy in ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest gynaecological cancer with high mortality rates driven by the common development of resistance to chemotherapy. EOC frequently invades the omentum, an adipocyte-rich organ of the peritoneum and omental adipocytes have been implicated in promoting disease progression, metastasis and chemoresistance. The signalling mechanisms underpinning EOC omentum tropism have yet to be elucidated. METHODS: Three-dimensional co-culture models were used to explore adipocyte-EOC interactions. The impact of adipocytes on EOC proliferation, response to therapy and invasive capacity was assessed. Primary adipocytes and omental tissue were isolated from patients with ovarian malignancies and benign ovarian neoplasms. Exosomes were isolated from omentum tissue conditioned media and the effect of omentum-derived exosomes on EOC evaluated. Exosomal microRNA (miRNA) sequencing was used to identify miRNAs abundant in omental exosomes and EOC cells were transfected with highly abundant miRNAs miR-21, let-7b, miR-16 and miR-92a. RESULTS: We demonstrate the capacity of adipocytes to induce an invasive phenotype in EOC populations through driving epithelial-to-mesenchymal transition (EMT). Exosomes secreted by omental tissue of ovarian cancer patients, as well as patients without malignancies, induced proliferation, upregulated EMT markers and reduced response to paclitaxel therapy in EOC cell lines and HGSOC patient samples. Analysis of the omentum-derived exosomes from cancer patients revealed highly abundant miRNAs that included miR-21, let-7b, miR-16 and miR-92a that promoted cancer cell proliferation and protection from chemotherapy when transfected in ovarian cancer cells. CONCLUSIONS: These observations highlight the capacity of omental adipocytes to generate a pro-tumorigenic and chemoprotective microenvironment in ovarian cancer and other adipose-related malignancies.

Characterization of Exosomes Released from Mycobacterium abscessus-Infected Macrophages.

Extracellular vesicles (EVs), such as exosomes, play a critical role in cell-to-cell communication and regulating cellular processes in recipient cells. Non-tuberculous mycobacteria (NTM), such as Mycobacterium abscessus, are a group of environmental bacteria that can cause severe lung infections in populations with pre-existing lung conditions, such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge of the engagement of EVs in the host-pathogen interactions in the context of NTM infections. In this study, we found that M. abscessus infection increased the release of a subpopulation of exosomes (CD9, CD63, and/or CD81 positive) by mouse macrophages in cell culture. Proteomic analysis of these vesicles demonstrated that M. abscessus infection affects the enrichment of host proteins in exosomes released by macrophages. When compared to exosomes from uninfected macrophages, exosomes released by M. abscessus-infected macrophages significantly improved M. abscessus growth and downregulated the intracellular level of glutamine in recipient macrophages in cell culture. Increasing glutamine concentration in the medium rescued intracellular glutamine levels and M. abscessus killing in recipient macrophages that were treated with exosomes from M. abscessus-infected macrophages. Taken together, our results indicate that exosomes may serve as extracellular glutamine eliminators that interfere with glutamine-dependent M. abscessus killing in recipient macrophages.

Surface protein analysis of breast cancer exosomes using visualized strategy on centrifugal disk chip.

Breast cancer, the most common cancer among women worldwide, lacks specific tumor markers for accurate diagnosis. Recent advances have highlighted tumor-derived exosomes as a promising non-invasive biomarker for cancer detection. Continuous monitoring of surface protein markers on exosomes in the blood could offer valuable insights for breast cancer diagnosis. However, integrating the isolation and detection of exosomes from whole blood is bulky, time-consuming, and requires professional operations. To address this difficulty, we developed a method of integrated centrifugal disk chip (CD chip) exosome enrichment directly from whole blood followed by a colorimetric visualization strategy for multiplex analysis. The disc consists of multi-chambers and multi-microchannels with immediate smartphone-enabled processing of colorimetric results. The combination of CEA + CA125 + EGFR on-chip detection could significantly differentiate the different stages of cancer in tumor-bearing mice and successfully distinguish between breast cancer patients and healthy individuals. Crucially, small volumes (100 µL) of blood samples were adequate. In addition, the chip was simple and fast, with results within 10 min, which provides immediate exosomal information through consecutive blood sampling, which could potentially result in a more timely and well-informed clinical breast cancer diagnosis.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p.

BACKGROUND: Cancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth. METHODS: twenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence. RESULTS: Western blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics. CONCLUSION: Our results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

IL-1ß-induced mesenchymal stem cell-derived exosomes inhibit neuronal ferroptosis in intracerebral hemorrhage through the HSPA5/GPX4 axis.

BACKGROUND: Neuronal cell ferroptosis following intracerebral hemorrhage (ICH) is a crucial factor contributing to the poor prognosis of ICH patients. The objective of this investigation was to investigate the molecular mechanism of IL-1ß-induced mesenchymal stem cell-derived exosomes (IL-1ß-Exo) in mitigating ICH injury. METHODS: Exo and IL-1ß-Exo were obtained and identified. Hemin was used to induce an ICH model, and an ICH mouse model was established using Collagenase. Exo and IL-1ß-Exo interventions were conducted to study their impact and molecular mechanisms on neuronal ferroptosis in ICH. RESULTS: Vesicular structure Exo and IL-1ß-Exo, with an average particle size of 141.7 ± 38.8 nm and 138.8 ± 37.5 nm, respectively, showed high expression of CD63, CD9 and CD81 could be taken up by SH-SY5Y cells. These Exos reversed Hemin-induced abnormalities in neuronal cells, including elevated iron, Fe2+, ROS, MDA, 4-HNE, and decreased SOD, GSH-Px, GSH, FTH1 levels, and cell vitality. The RNA content of IL-1ß-Exo was linked to its ability to reduce iron accumulation. There was an interaction between HSPA5 and GPX4. Exo and IL-1ß-Exo reversed Hemin-induced downregulation of HSPA5 and GPX4 expression. Overexpression and knockdown of HSPA5 respectively potentiate or counteract the impacts of Exo and IL-1ß-Exo. IL-1ß-Exo was more effective than Exo. These findings were further validated in ICH mice. Moreover, both Exo and IL-1ß-Exo reduced the modified neurological severity score and brain water content, as well as alleviated pathological damage in ICH mice. CONCLUSION: IL-1ß-Exo inhibited neuronal ferroptosis in ICH through the HSPA5/GPX4 axis.

Exosomal Drug Delivery Systems: A Novel Therapy Targeting PD-1 in Septic-ALI.

BACKGROUND: The cytokine storm triggered by sepsis can lead to the development of acute lung injury (ALI). Human umbilical cord Mesenchymal stem cells derived exosomes (HucMSCs-EXOs) have been demonstrated to possess immunosuppressive and anti-inflammatory properties. Programmed cell death receptor 1 (PD-1) plays a crucial role in maintaining the inflammatory immune homeostasis. The aim of this study is to investigate the synergistic therapeutic effect of EXOs loaded with anti-PD-1 peptide on septic-ALI. METHODS: This study prepares a novel EXOs-based drug, named MEP, by engineering modification of HucMSCs-EXOs, which are non-immunogenic extracellular vesicles, loaded with anti-PD-1 peptide. The therapeutic effect and potential mechanism of MEP on septic-ALI are elucidated through in vivo and in vitro experiments, providing experimental evidence for the treatment of septic acute lung injury with MEP. RESULTS: We found that, compared to individual components (anti-PD-1 peptide or EXOs), MEP treatment can more effectively improve the lung injury index of septic-ALI mice, significantly reduce the expression levels of inflammatory markers CRP and PCT, as well as pro-inflammatory cytokines TNF-α and IL-1ß in serum, decrease lung cell apoptosis, and significantly increase the expression of anti-inflammatory cytokine IL-10 and CD68+ macrophages. In vitro, MEP co-culture promotes the proliferation of CD206+ macrophages, increases the M2/M1 macrophage ratio, and attenuates the inflammatory response. GEO data analysis and qRT-PCR validation show that MEP reduces the expression of inflammasome-related genes and M1 macrophage marker iNOS. CONCLUSION: In both in vitro and in vivo settings, MEP demonstrates superior therapeutic efficacy compared to individual components in the context of septic-ALI.

Sensitive and reliable lab-on-paper biosensor for label-free detection of exosomes by electrochemical impedance spectroscopy.

A new, sensitive, and cost-effective lab-on-paper-based immunosensor was designed based on electrochemical impedance spectroscopy (EIS) for the detection of exosomes. EIS was selected as the determination method since there was a surface blockage in electron transfer by binding the exosomes to the transducer. Briefly, the carbon working electrode (WE) on the paper electrode (PE) was modified with gold particles (AuPs@PE) and then conjugated with anti-CD9 (Anti-CD9/AuPs@PE) for the detection of exosomes. Variables involved in the biosensor design were optimized with the univariate mode. The developed method presents the limit of detection of  8.7 × 102 exosomes mL-1, which is lower than that of many other available methods under the best conditions. The biosensor was also tested with urine samples from cancer patients with high recoveries. Due to this  a unique, low-cost, biodegradable technology is presented that can directly measure exosomes without labeling them for early cancer or metastasis detection.

An injectable decellularized extracellular matrix hydrogel with cortical neuron-derived exosomes enhances tissue repair following traumatic spinal cord injury.

Traumatic spinal cord injury (SCI), known for its limited intrinsic regeneration capacity, often results in considerable neurological impairment. Studies suggest that therapeutic techniques utilizing exosomes (Exo) to promote tissue regeneration and modulate immune responses are promising for SCI treatment. However, combining exosome therapy with biomaterials for SCI treatment is not very effective. This study developed an adhesive hydrogel using exosomes secreted by cortical neurons derived from human induced pluripotent stem cells (iPSCs) and decellularized extracellular matrix (dECM) from human umbilical cord mesenchymal stem cells (hUCMSCs) to enhance motor function recovery post-SCI. In vitro assessments demonstrated the excellent cytocompatibility of the dECM hydrogel. Additionally, the Exo-dECM hydrogel facilitated the polarization of early M2 macrophages, reduced neuronal apoptosis, and established a pro-regenerative microenvironment in a rodent SCI model. Subsequent analyses revealed significant activation of endogenous neural stem cells and promotion of axon regeneration and remyelination at eight weeks post-surgery. The Exo-dECM hydrogel also promoted the functional recovery and preservation of urinary tissue in SCI-afflicted rats. These findings highlighted that the Exo-dECM hydrogel is a promising therapeutic strategy for treating SCI.

Low-Grade Activation of the Extrinsic Coagulation Pathway in Patients with Ulcerative Colitis.

BACKGROUND: Ulcerative colitis (UC) increases the risk for venous thromboembolism. Tissue factor (TF) initiates the extrinsic coagulation pathway (ECP). AIMS: To investigate the correlation of UC severity with latent ECP activation and TF expression in primary colonic stromal cells (PCSC). METHODS: In plasma of 38 UC patients (31 males, disease duration 151 ± 25 months) and 28 healthy controls, exosomes and microparticles (EM) were counted. Moreover, TF protein concentration, activities of EM-bound TF (EM-TFa) and coagulation factor VII (FVIIa) were assessed. In PCSC in culture, TF mRNA (F3) from 12 patients with active UC and 7 controls was evaluated. RESULTS: UC patients had 4- and 3.7- times more exosomes and microparticles, respectively, than controls. TF protein in UC was correlated with several disease severity indices, such as partial Mayo score (pMs; r 0.443), albumin (- 0.362), ESR (0.353), PLT (0.575), and endoscopic Ms (eMs 0.468). EM-TFa was also significantly higher in UC and was correlated to SIBDQ (- 0.64), albumin (- 0.624), disease extent and eMs (0.422). Refractory-to-treatment patients had significantly higher TF protein, EM-TFa and FVIIa. Even within responders, the need for steroids or biologics correlated with a 2.2-times higher EM-TFa. PCSC from active UC maintained higher F3 than controls, which was correlated to pMs (0.56), albumin (- 0.543) and eMs. Treatment with cytokines further upregulated F3. P for all comparisons was < 0.05. CONCLUSION: Low-grade activation of the ECP associates with clinical, endoscopic UC activity and response to treatment. TF in PCSC mirrors its systemic activity and points to them as a source.

Exosome-based drug delivery systems for enhanced neurological therapeutics.

Exosomes are small extracellular vesicles naturally secreted by cells into body fluids, enriched with bioactive molecules such as RNAs, proteins, and lipids. These nanosized vesicles play a crucial role in physiological and pathological processes by facilitating intercellular communication and modulating cellular responses, particularly within the central nervous system (CNS). Their ability to cross the blood-brain barrier and reflect the characteristics of their parent cells makes exosomal cargo a promising candidate for biomarkers in the early diagnosis and clinical assessment of neurological conditions. This review offers a comprehensive overview of current knowledge on the characterization of mammalian-derived exosomes, their application as drug delivery systems for neurological disorders, and ongoing clinical trials involving exosome-loaded cargo. Despite their promising attributes, a significant challenge remains the lack of standardized isolation methods, as current techniques are often complex, costly, and require sophisticated equipment, affecting the scalability and affordability of exosome-based therapies. The review highlights the engineering potential of exosomes, emphasizing their ability to be customized for targeted therapeutic delivery through surface modification or conjugation. Future advancements in addressing these challenges and leveraging the unique properties of exosomes could lead to innovative and effective therapeutic strategies in neurology.

Exosomal miR-502-5p suppresses the progression of gastric cancer by repressing angiogenesis through the Wnt/ß-catenin pathway.

BACKGROUND: Gastric cancer (GC) is a significant global health concern, ranking as the fifth most common cancer and the third leading cause of cancer-related deaths. The role of miR-502-5p in various cancers has been studied, but its specific impact on gastric cancer through exosomes is not well understood. This study aimed to investigate the role and mechanism of exosome-derived miR-502-5p in gastric cancer. METHODS: Differential expression of miR-502-5p in tissues or serum of GC patients was determined using qRT-PCR. The impact of miR-502-5p on cell proliferation, migration, and invasion was assessed through in vitro and in vivo experiments. The potential of exosome-miR-502-5p to inhibit metastatic ability was also explored by using vivo and vitro assay. Furthermore, the underlying mechanism of miR-502-5p in gastric cancer was investigated using western blotting. RESULTS: It was found that miR-502-5p suppressed the proliferation, migration, and invasion of gastric cancer cells. Exosome-miR-502-5p expression was negatively linked to metastatic ability and demonstrated inhibition of metastasis in vitro and in vivo. Additionally, miR-502-5p appeared to inhibit angiogenesis through the Wnt/ß-catenin pathway in gastric cancer. CONCLUSIONS: Exosomal miR-502-5p acts as a suppressor in the development and progression of gastric cancer, suggesting its potential as a target for anti-cancer therapy or as a diagnostic biomarker.

High glucose induces DNA methyltransferase 1 dependent epigenetic reprogramming of the endothelial exosome proteome in type 2 diabetes.

In response to hyperglycemia, endothelial cells (ECs) release exosomes with altered protein content and contribute to paracrine signalling, subsequently leading to vascular dysfunction in type 2 diabetes (T2D). High glucose reprograms DNA methylation patterns in various cell/tissue types, including ECs, resulting in pathologically relevant changes in cellular and extracellular proteome. However, DNA methylation-based proteome reprogramming in endothelial exosomes and associated pathological implications in T2D are not known. Hence, in the present study, we used Human umbilical vein endothelial cells (HUVECs), High Fat Diet (HFD) induced diabetic mice (C57BL/6) and clinical models to understand epigenetic basis of exosome proteome regulation in T2D pathogenesis . Exosomes were isolated by size exclusion chromatography and subjected to tandem mass tag (TMT) labelled quantitative proteomics and bioinformatics analysis. Immunoblotting was performed to validate exosome protein signature in clinically characterized individuals with T2D. We observed ECs cultured in high glucose and aortic ECs from HFD mouse expressed elevated DNA methyltransferase1 (DNMT1) levels. Quantitative proteomics of exosomes isolated from ECs treated with high glucose and overexpressing DNMT1 showed significant alterations in both protein levels and post translational modifications which were aligned to T2D associated vascular functions. Based on ontology and gene-function-disease interaction analysis, differentially expressed exosome proteins such as Thrombospondin1, Pentraxin3 and Cystatin C related to vascular complications were significantly increased in HUVECs treated with high glucose and HFD animals and T2D individuals with higher levels of glycated hemoglobin. These proteins were reduced upon treatment with 5-Aza-2'-deoxycytidine. Our study shows epigenetic regulation of exosome proteome in T2D associated vascular complications.

Exosomal non-coding RNAs (ncRNAs) as potential biomarkers in tumor early diagnosis.

Exosomes, extracellular vesicles carrying a cargo rich in various non-coding RNAs (ncRNAs), have emerged as crucial mediators of intercellular communication. Their stability, abundance, and specificity make exosomal ncRNAs promising candidates for biomarker discovery. The discovery of exosomal ncRNAs has unveiled a novel avenue for the exploration of biomarkers in tumor early diagnosis. This review consolidates current knowledge on the role of exosomal ncRNAs as potential biomarkers in the early detection of various tumors. We provide an overview of recent studies demonstrating the diagnostic potential of exosomal ncRNAs across multiple cancer types, highlighting their sensitivity, specificity, and feasibility for early detection. This review underscores the potential of exosomal ncRNAs as non-invasive biomarkers for early tumor diagnosis, paving the way for improved clinical outcomes through timely intervention and personalized management strategies.