Nano-sized Vesicles Research Articles

Plasma membrane-coated nanoparticles and membrane vesicles to orchestrate multimodal antitumor immunity

BackgroundA number of immunotherapeutic approaches have been developed and are entering the clinic. Bispecific antibodies (BsAbs) are one of these modalities and induce robust efficacy by endogenous T cells in...

Emerging Strategies for Revascularization: Use of Cell-Derived Extracellular Vesicles and Artificial Nanovesicles in Critical Limb Ischemia.

Critical limb ischemia (CLI) poses a substantial and intricate challenge in vascular medicine, necessitating the development of innovative therapeutic strategies to address its multifaceted pathophysiology. Conventional revascularization approaches often fail to adequately address the complexity of CLI, necessitating the identification of alternative methodologies. This review explores uncharted territory beyond traditional therapies, focusing on the potential of two distinct yet interrelated entities: cell-derived extracellular vesicles (EVs) and artificial nanovesicles. Cell-derived EVs are small membranous structures naturally released by cells, and artificial nanovesicles are artificially engineered nanosized vesicles. Both these vesicles represent promising avenues for therapeutic intervention. They act as carriers of bioactive cargo, including proteins, nucleic acids, and lipids, that can modulate intricate cellular responses associated with ischemic tissue repair and angiogenesis. This review also assesses the evolving landscape of CLI revascularization through the unique perspective of cell-derived EVs and artificial nanovesicles. The review spans the spectrum from early preclinical investigations to the latest translational advancements, providing a comprehensive overview of the current state of research in this emerging field. These groundbreaking vesicle therapies hold immense potential for revolutionizing CLI treatment paradigms.

Stem Cell-Derived Extracellular Vesicle-Mediated Therapeutic Signaling in Spinal Cord Injury.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising therapeutic strategy for spinal cord injury (SCI). These nanosized vesicles possess unique properties such as low immunogenicity and the ability to cross biological barriers, making them ideal carriers for delivering bioactive molecules to injured tissues. MSC-EVs have been demonstrated to exert multiple beneficial effects in SCI, including reducing inflammation, promoting neuroprotection, and enhancing axonal regeneration. Recent studies have delved into the molecular mechanisms underlying MSC-EV-mediated therapeutic effects. Exosomal microRNAs (miRNAs) have been identified as key regulators of various cellular processes involved in SCI pathogenesis and repair. These miRNAs can influence inflammation, oxidative stress, and apoptosis by modulating gene expression. This review summarized the current state of MSC-EV-based therapies for SCI, highlighting the underlying mechanisms and potential clinical applications. We discussed the challenges and limitations of translating these therapies into clinical practice, such as inconsistent EV production, complex cargo composition, and the need for targeted delivery strategies. Future research should focus on optimizing EV production and characterization, identifying key therapeutic miRNAs, and developing innovative delivery systems to maximize the therapeutic potential of MSC-EVs in SCI.

Bridging brain and blood: a prospective view on neuroimaging-exosome correlations in HIV-associated neurocognitive disorders.

HIV-associated neurocognitive disorder (HAND) is a complex neurological complication resulting from human immunodeficiency virus (HIV) infection, affecting about 50% of individuals with HIV and significantly diminishing their quality of life. HAND includes a variety of cognitive, motor, and behavioral disorders, severely impacting patients' quality of life and social functioning. Although combination antiretroviral therapy (cART) has greatly improved the prognosis for HIV patients, the incidence of HAND remains high, underscoring the urgent need to better understand its pathological mechanisms and develop early diagnostic methods. This review highlights the latest advancements in neuroimaging and exosome biomarkers in HAND research. Neuroimaging, particularly magnetic resonance imaging (MRI), offers a non-invasive and repeatable method to monitor subtle changes in brain structure and function, potentially detecting early signs of HAND. Meanwhile, exosomes are nano-sized vesicles secreted by cells that serve as key mediators of intercellular communication, playing a crucial role in the neuropathology of HIV and potentially acting as a critical bridge between peripheral blood and central nervous system lesions. Thus, combining plasma exosome biomarkers with indicators derived from neuroimaging scans may enhance the early diagnosis of HAND. This review summarizes evidence supporting the role of exosomes as reliable biomarkers for early detection and management of HAND. Furthermore, we emphasize the correlation between neuroimaging biomarkers and exosome biomarkers and explore their potential combined use. This review discusses the technical challenges and methodological limitations of integrating these two types of biomarkers and proposes future research directions. This multidisciplinary integrative approach not only promises to improve the neurocognitive health management of HIV patients but may also offer valuable insights for research into other neurodegenerative diseases.

Mesenchymal Stem Cell-Sourced Exosomes as Potentially Novel Remedies for Severe Dry Eye Disease.

Severe dry eye disease (DED) is an inflammatory condition characterized by a lack of sufficient moisture or lubrication on the surface of the eye, significantly impacting the quality of life and visual function. Since detrimental immune response is crucially responsible for the development and aggravation of DED, therapeutic agents which modulate phenotype and function of eye-infiltrated inflammatory immune cells could be used for the treatment of severe DED. Due to their potent immunomodulatory properties, mesenchymal stem cells (MSCs) represent potentially new remedies for the treatment of inflammatory eye diseases. The majority of MSC-sourced bioactive factors are contained within MSC-derived exosomes (MSC-Exos), nano-sized extracellular vesicles which, due to their nanosize dimension and lipid envelope, easily by pass all biological barriers in the body and deliver their cargo directly into the target immune cells. MSC-Exos contain a variety of bioactive proteins (growth factors, immunoregulatory molecules, cytokines, and chemokines) lipids, and microRNAs (miRNAs) which affect viability, proliferation, phenotype, and function of eye-infiltrated immune cells. Accordingly, MSC-Exos may modulate the progression of inflammatory eye diseases, including DED. Therefore, in this review article, we summarized the current knowledge regarding molecular and cellular mechanisms which were responsible for trophic, anti-inflammatory, immunoregulatory, and regenerative properties of MSC-Exos in the treatment of severe DED. For this purpose, an extensive literature review was carried out in February 2024 across several databases (Medline, Embase, and Google Scholar), from 2000 to the present. Eligible studies delineated molecular and cellular mechanisms responsible for the MSC-Exos-based modulation of immune cell-driven eye inflammation in DED, and their findings were analyzed in this review. Results obtained in these studies demonstrated beneficial effects of MSC-Exos in the treatment of severe DED, paving the way for their future clinical use in ophthalmology. Trial Registration: ClinicalTrials.gov identifier: NCT04213248, NCT06475027, NCT06543667, NCT05738629.

Nanovesicles derived from edible plants: a new player that contributes to the function of foods.

Nano-sized vesicles are ubiquitous in vegetables, fruits, and other edible plants. We have successfully prepared nanovesicles (NVs) from over 150 edible plants. These results suggest that the daily intake of NVs from various foods and their roles in food function are promising novel approaches for explaining the health-promoting properties of edible plants. These vesicles contain RNAs, including miRNAs, similar to extracellular NVs, which play pivotal roles in cell-cell communication. Intriguingly, NVs also contain phytochemicals such as polyphenols and carotenoids that are specific to each edible plant. In conclusion, these dietary NVs have the potential to serve as functional packages to deliver RNAs or phytochemicals to target cells across species from plants to humans.

Exosome-derived proteins in gastric cancer progression, drug resistance, and immune response.

Gastric cancer (GC) represents a prevalent malignancy globally, often diagnosed at advanced stages owing to subtle early symptoms, resulting in a poor prognosis. Exosomes are extracellular nano-sized vesicles and are secreted by various cells. Mounting evidence indicates that exosomes contain a wide range of molecules, such as DNA, RNA, lipids, and proteins, and play crucial roles in multiple cancers including GC. Recently, with the rapid development of mass spectrometry-based detection technology, researchers have paid increasing attention to exosomal cargo proteins. In this review, we discussed the origin of exosomes and the diagnostic and prognostic roles of exosomal proteins in GC. Moreover, we summarized the biological functions of exosomal proteins in GC processes, such as proliferation, metastasis, drug resistance, stemness, immune response, angiogenesis, and traditional Chinese medicine therapy. In summary, this review synthesizes current advancements in exosomal proteins associated with GC, offering insights that could pave the way for novel diagnostic and therapeutic strategies for GC in the foreseeable future.

Molecular Profiling of A549 Cell-Derived Exosomes: Proteomic, miRNA, and Interactome Analysis for Identifying Potential Key Regulators in Lung Cancer.

Exosomes, nano-sized extracellular vesicles released by all cells, play a key role in intercellular communication and carry tumorigenic properties that impact surrounding or distant cells. The complexity of the exosomal molecular interactome and its effects on recipient cells still remain unclear. This study aims to decipher the molecular profile and interactome of lung adenocarcinoma A549 cell-derived exosomes using multi-omics and bioinformatics approaches. We performed comprehensive morphological and physicochemical characterization of exosomes isolated from cell culture supernatant of A549 cells in vitro, using DLS, cryo-TEM, Western blot, and flow cytometry. Proteomic and miRNA high-throughput profiling, coupled with bioinformatics network analysis, were applied to elucidate the exosome molecular cargo. A comparative miRNA analysis was also conducted with exosomes derived from normal lung fibroblast MRC-5 cells. Exosomes exhibited an average size of ~40 nm and disk-shaped lipid bilayer structures, with tetraspanins CD9 and CD63 validated as exosomal markers. Proteomic analysis identified 68 proteins, primarily linked to the extracellular matrix organization and metabolic processes. miRNA sequencing revealed 72 miRNAs, notably hsa-miR-619-5p, hsa-miR-122-5p, hsa-miR-9901, hsa-miR-7704, and hsa-miR-151a-3p, which are involved in regulating metabolic processes, gene expression, and tumorigenic pathways. Th integration of proteomic and miRNA data through a proteogenomics approach identified dually affected genes including ERBB2, CD44, and APOE, impacted by both exosomal miRNA targeting and protein interactions through synergistic or antagonistic interactions. Differential analysis revealed a distinct miRNA profile in A549 exosomes, associated with cancer-related biological processes, compared to MRC-5 exosomes; notably, hsa-miR-619-5p emerged as a promising candidate for future clinical biomarker studies. The network analysis also revealed genes targeted by multiple upregulated tumor-associated miRNAs in potential exosome-recipient cells. This integrative study provides insights into the molecular interactome of lung adenocarcinoma A549 cell-derived exosomes, providing a foundation for future research on exosomal cargo and its role in tumor cell communication, growth, and progression.

Circulating small extracellular vesicles as blood-based biomarkers of muscle health in aging nonhuman primates.

Age-associated loss of muscle mass and function and subsequent mobility decline define poor health outcomes, reduced quality of life, and mortality risk. The rate and extent of aging-related muscle loss varies across older adults. It is challenging to understand the molecular pathogenesis of mobility decline, as anthropometric and imaging techniques, primarily used in muscle function assessment, do not offer much molecular information. Small extracellular vesicles (sEV) are lipid membrane-bound, nano-sized (≤ 200nm) vesicles which carry a wide array of biomolecules as their cargo. sEV contain cell/tissue-specific signatures on their surface and can be isolated from biofluids. These properties pose sEV as a minimally invasive means to monitor the functional and biological health of difficult-to-access tissues, establishing them as a promising liquid biopsy tool. Here, we first isolated skeletal muscle-derived sEV (sEVSKM) from the serum of vervet monkeys (16 to < 25years old) using alpha sarcoglycan (SGCA) as a muscle-specific sEV surface marker. sEVSKM were extensively characterized for size, concentration, purity, and specificity. Further, sEVSKM isolated from young (11-15years) and old (25-29years) monkeys' serum were characterized for oxidized proteins by mass spectrometry and miRNAs by small-RNAseq. Notably, the analysis of oxidized proteins indicated perturbation of metabolic pathways, actin cytoskeleton, muscle cytoskeleton regulation, and HIF-1 signaling in older monkeys. Furthermore, small-RNAseq analysis identified differential expression of several miRNAs regulating metabolic pathways, inflammation, and stress signaling. Altogether, these results suggest that it is feasible to isolate sEVSKM and use them to identify molecular biomarkers that reflect the physiological state of muscle tissue.

DEVELOPMENT, CHARACTERIZATION, AND OPTIMIZATION OF REPAGLINIDE LOADED SPANLASTICS ALONG WITH INVESTIGATION OF DRUG SOLUBILITY IN VARIOUS MEDIA

Objective: This study seeks to explore the solubility of an antidiabetic drug with poor water solubility, Repaglinide (RPG), in various media, and develop and optimize RPG-loaded spanlastic formulations. Methods: A 72-hours solubility study was conducted for RPG in different media, followed by UV spectrum analysis. Spanlastics containing RPG were prepared through the thin-film hydration (TFH) method combined with ultrasonication, incorporating varying concentrations ofthe lipophilic, non-ionic surfactant agents, Span 60 and Tween 80. Characterization was performed To assess particle size (PS), polydispersity index (PDI), zeta potential (ZP), and entrapment efficiency (EE%). Optimization was achieved by analysing characterization results and using a mixture design of Design Expert software which predicted the optimized formula. Results: RPG exhibited the highest solubility in phosphate buffer saline (PBS, pH 6.8) incorporating 0.5% Tween 20 (168.595 µg/mL), followed by PBS with 0.1% Tween 80 (80.355 µg/mL), PBS alone (56.163 µg/mL), and PBS with 0.1% sodium lauryl sulphate (SLS) (53.706 µg/mL). UV scanning in methanol revealed three characteristic absorption bands for RPG, with peak selection optimized for molar absorptivity in each medium. The RPG-loaded spanlastic formulations demonstrated nano-sized vesicles with uniform size distribution, high stability, and efficient drug encapsulation. Optimized spanlastics predicted a particle size 126.162 nm, PDI 0.416, ZP-43.258 mV, and EE% 77.753%. Conclusions: This research emphasizes the potential of optimized RPG-loaded spanlastics, developed through the thin-film hydration method, as a promising approach for improving the solubility and stability of poorly water-soluble drugs. RPG showed the highest solubility in PBS (pH 6.8) containing 0.5% Tween 20, and the formulation achieved desirable nanosize, uniformity, and high encapsulation efficiency. Peer Review History: Received 12 July 2024; Reviewed 16 September 2024; Accepted 23 October; Available online 15 November 2024 Academic Editor: Dr. Asia Selman Abdullah, Pharmacy institute, University of Basrah, Iraq, asia_abdullah65@yahoo.com Average Peer review marks at initial stage: 6.0/10 Average Peer review marks at publication stage: 7.5/10 Reviewers: Antonio José de Jesus Evangelista, Federal University of Ceará, UFC, Brazil, tony_biomed@hotmail.com Asmaa Ahmed Mohamed Ahmed Khalifa, Pharos University, Alexandria, Egypt, asmaa.khalifa@pua.edu.eg

Implications of glioblastoma-derived exosomes in modifying the immune system: state-of-the-art and challenges.

Glioblastoma is a brain cancer with a poor prognosis. Failure of classical chemotherapy and surgical treatments indicates that new therapeutic approaches are needed. Among cell-free options, exosomes are versatile extracellular vesicles (EVs) that carry important cargo across barriers suchas the blood-brain barrier (BBB) to their target cells. Thismakes exosomes an interesting option for the treatment ofglioblastoma. Moreover, exosomes can comprise many therapeutic cargos, including lipids, proteins, and nucleic acids,sampled from special intercellular compartments of their origin cell. Cells exposed to various immunomodulatory stimulican generate exosomes enriched in specific therapeutic molecules. Notably, the secretion of exosomes could modify theimmune response in innate and adaptive immune systems. For instance, glioblastoma-associated exosomes (GBex) uptake bymacrophages could influence macrophage dynamics (e.g., shifting CD markers expression). Expression of critical immunoregulatory proteins such as cytotoxic T-lymphocyte antigen-1 (CTLA1) and programmed death-1 (PD-1) on GBex indicates the direct crosstalk of these nano-size vesicles with the immune system. The present study reviews the role of exosomes in immune system cells, including Bcells, Tcells, natural killer (NK) cells, and dendritic cells (DCs), as well as novel technologies in the field.

MSCs–derived EVs protect against chemotherapy-induced ovarian toxicity: role of PI3K/AKT/mTOR axis

Chemotherapy detrimentally impacts fertility via depletion of follicular reserves in the ovaries leading to ovarian failure (OF) and development of estrogen deficiency-related complications. The currently proposed options to preserve fertility such as Oocyte or ovarian cortex cryopreservation are faced with many technical obstacles that limit their effective implementation. Therefore, developing new modalities to protect ovarian function remains a pending target. Exosomes are nano-sized cell-derived extracellular vesicles (EVs) with documented efficacy in the field of regenerative medicine. The current study sought to determine the potential beneficial effects of mesenchymal stem cells (MSCs)-derived EVs in experimentally induced OF. Female albino rats were randomly allocated to four groups: control, OF group, OF + MSCs-EVs group, OF + Rapamycin (mTOR inhibitor) group, and OF + Quercetin (PI3K/AKT inhibitor) group. Follicular development was assessed via histopathological and immunohistochemical examination, and ovarian function was evaluated by hormonal assay. PI3K/Akt/mTOR signaling pathway as a key modulator of ovarian follicular activation was also assessed. MSCs-EVs administration to OF rats resulted in restored serum hormonal levels, preserved primordial follicles and oocytes, suppressed ovarian PI3K/AKT axis and downstream effectors (mTOR and FOXO3), modulated miRNA that target this axis, decreased expression of ovarian apoptotic markers (BAX, BCl2) and increased expression of proliferation marker Ki67. The present study validated the effectiveness of MSCs-EVs therapy in preventing ovarian insufficiency induced by chemotherapy. Concomitant MSCs-EVs treatment during chemotherapy could significantly preserve ovarian function and fertility by suppressing the PI3K/Akt axis, preventing follicular overactivation, maintaining normal ovarian cellular proliferation, and inhibiting granulosa cell apoptosis.

Immune System Modulation by Extracellular Vesicles: Implications for Disease Treatment

Extracellular vesicles (EVs), including exosomes and microvesicles, have emerged as crucial mediators of intercellular communication, playing a significant role in immune system modulation. These nanosized vesicles transfer bioactive molecules such as proteins, lipids, and nucleic acids, influencing immune responses and contributing to various disease processes, including cancer, autoimmune disorders, and infections. The dual functionality of EVs capable of either activating or suppressing immune responses depending on their origin and cargo highlights their therapeutic potential. This review explores the mechanisms through which EVs modulate immune functions, their implications in disease pathogenesis, and their innovative applications in therapeutic strategies. In oncology, tumor-derived EVs can promote immune evasion, while engineered EVs show promise as vehicles for targeted drug delivery and cancer immunotherapy. In autoimmune diseases, EVs can either exacerbate inflammation or facilitate tolerance, offering new avenues for treatment. Furthermore, EVs hold potential as biomarkers for disease diagnosis and monitoring due to their stability in bodily fluids and ability to reflect cellular states. However, challenges remain in standardizing EV isolation, characterization, and clinical application. Future advancements in bioengineering, along with improved understanding of EV biology, are crucial for harnessing their therapeutic potential. This review emphasizes the importance of EVs in immune modulation and their promising implications for innovative disease treatment strategies. Keywords: Extracellular vesicles, immune modulation, cancer therapy, autoimmune diseases, biomarkers

Exosomal Delivery of miR-155 Inhibitor can Suppress Migration, Invasion, and Angiogenesis Via PTEN and DUSP14 in Triple-negative Breast Cancer.

Triple-Negative Breast Cancer (TNBC) is the most common type of breast cancer (BC). In order to develop effective treatments for TNBC, it is vital to identify potential therapeutic targets. Angiogenesis stimulates tumor growth and metastasis in TNBC, and miR-155 plays a crucial role in this process. The exosome is a nano-sized vesicle that carries many cargoes, including miRNAs. The present study investigated the effect of exosomal delivery of miR-155 antagomir on tumor migration, invasion, and angiogenesis in TNBC. From MDA-MB-231 cells, exosomes were extracted, characterized, and loaded with miR-155 antagomir using electroporation. The expression of miR-155 and its target genes, including PTEN and DUSP14, was analyzed using RTqPCR. The wound-healing and transwell assays were used to measure cell migration and invasion. Furthermore, angiogenesis was evaluated by tube formation and chorioallantoic membrane (CAM) assays. The results indicated that exosomal delivery of miR-155 antagomir to HUVEC cells significantly suppressed miR-155 expression while upregulating PTEN and DUSP14. The tube formation properties of HUVEC cells were also significantly reduced following treatment with exosomes containing miR-155 antagomirs, and these results were confirmed using CAM assay. The migration and invasion of MDA-MB-231 cells were significantly reduced after treatment with miR-155 antagomir-loaded exosomes. It was found that miR-155 antagomir delivery using exosomes can inhibit migration, invasion, and angiogenesis viaPTEN and DUSP14 in TNBC.

Advances in therapies using mesenchymal stem cells and their exosomes for treatment of peripheral nerve injury: state of the art and future perspectives.

"Peripheral nerve injury" refers to damage or trauma affecting nerves outside the brain and spinal cord. Peripheral nerve injury results in movements or sensation impairments, and represents a serious public health problem. Although severed peripheral nerves have been effectively joined and various therapies have been offered, recovery of sensory or motor functions remains limited, and efficacious therapies for complete repair of a nerve injury remain elusive. The emerging field of mesenchymal stem cells and their exosome-based therapies hold promise for enhancing nerve regeneration and function. Mesenchymal stem cells, as large living cells responsive to the environment, secrete various factors and exosomes. The latter are nano-sized extracellular vesicles containing bioactive molecules such as proteins, microRNA, and messenger RNA derived from parent mesenchymal stem cells. Exosomes have pivotal roles in cell-to-cell communication and nervous tissue function, offering solutions to changes associated with cell-based therapies. Despite ongoing investigations, mesenchymal stem cells and mesenchymal stem cell-derived exosome-based therapies are in the exploratory stage. A comprehensive review of the latest preclinical experiments and clinical trials is essential for deep understanding of therapeutic strategies and for facilitating clinical translation. This review initially explores current investigations of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in peripheral nerve injury, exploring the underlying mechanisms. Subsequently, it provides an overview of the current status of mesenchymal stem cell and exosome-based therapies in clinical trials, followed by a comparative analysis of therapies utilizing mesenchymal stem cells and exosomes. Finally, the review addresses the limitations and challenges associated with use of mesenchymal stem cell-derived exosomes, offering potential solutions and guiding future directions.

Differential abundance of microRNAs in seminal plasma extracellular vesicles (EVs) in Sahiwal cattle bull related to male fertility.

Sahiwal cattle, known for their high milk yield, are propagated through artificial insemination (AI) using male germplasm, largely contingent on semen quality. Spermatozoa, produced in the testes, carry genetic information and molecular signals essential for successful fertilization. Seminal plasma, in addition to sperm, contains nano-sized lipid-bound extracellular vesicles (SP-EVs) that carry key biomolecules, including fertility-related miRNAs, which are essential for bull fertility. The current study focused on miRNA profiling of SP-EVs from high-fertile (HF) and low-fertile (LF) Sahiwal bulls. SP-EVs were isolated using size exclusion chromatography (SEC) and characterized by dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). Western blotting detected the EV-specific protein markers TSG101 and CD63. The DLS analysis showed SP-EV sizes of 170-180nm in HF and 130-140nm in LF samples. The NTA revealed particle concentrations of 5.76 × 1010 to 5.86 × 1011 particles/mL in HF and 5.31 × 1010 to 2.70 × 1011 particles/mL in LF groups, with no significant differences in size and concentration between HF and LF. High-throughput miRNA sequencing identified 310 miRNAs in SP-EVs from both groups, with 61 upregulated and 119 downregulated in HF bull. Further analysis identified 41 miRNAs with significant fold changes and p-values, including bta-miR-1246, bta-miR-195, bta-miR-339b, and bta-miR-199b, which were analyzed for target gene prediction. Gene Ontology (GO) and KEGG pathway analyses indicated that these miRNAs target genes involved in transcription regulation, ubiquitin-dependent endoplasmic reticulum-associated degradation (ERAD) pathways, and signalling pathways. Functional exploration revealed that these genes play roles in spermatogenesis, motility, acrosome reactions, and inflammatory responses. qPCR analysis showed that bta-miR-195 had 80% higher expression in HF spermatozoa compared to LF, suggesting its association with fertility status (p < 0.05). In conclusion, this study elucidates the miRNA cargoes in SP-EVs as indicators of Sahiwal bull fertility, highlighting bta-miR-195 as a potential fertility factor among the various miRNAs identified.

Global Trends of Exosomes Application in Clinical Trials: A Scoping Review.

Exosomes, nano-sized extracellular vesicles, have emerged as a promising tool for the diagnosis and treatment of various intractable diseases, including chronic wounds and cancers. As our understanding of exosomes continues to grow, their potential as a powerful therapeutic modality in medicine is also expanding. This systematic review aims to examine the progress of exosome-based clinical trials and provide a comprehensive overview of the therapeutic perspectives of exosomes. This systematic review strictly follows PRISMA guidelines and has been registered in PROSPERO, the International Prospective Register of Systematic Reviews. It encompasses articles from January 2000 to January 2023, sourced from bibliographic databases, with targeted search terms targeting exosome applications in clinical trials. During the screening process, strict inclusion and exclusion criteria were applied, including a focus on clinical trials utilizing different cell-derived exosomes for therapeutic purposes. Among the 522 publications initially identified, only 10 studies met the stringent eligibility criteria after meticulous screening. The selection process involved systematically excluding duplicates and irrelevant articles to provide a transparent overview. According to our systematic review, exosomes have promising applications in a variety of medical fields, including cell-free therapies and drug delivery systems for treating a variety of diseases, especially cancers and chronic wounds. To ensure safety, potency, and broader clinical applications, further optimization of exosome extraction, loading, targeting, and administration is necessary. While cell-based therapeutics are increasingly utilizing exosomes, this field is still in its infancy, and ongoing clinical trials will provide valuable insights into the clinical utility of exosomes.

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.

Molecular and Functional Cargo of Plasma-Derived Exosomes in Patients with Hereditary Hemorrhagic Telangiectasia.

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is a genetic disorder leading to frequent bleeding in several organs. As HHT diagnosis is demanding and depends on clinical criteria, liquid biopsy would be beneficial. Exosomes from biofluids are nano-sized vesicles for intercellular communication. Their cargo and characteristics represent biomarkers for many diseases. Here, exosomes of HHT patients were examined regarding their biosignature. Methods: Exosomes were isolated from the plasma of 20 HHT patients and 17 healthy donors (HDs). The total exosomal protein was quantified, and specific proteins were analyzed using Western blot and antibody arrays. Human umbilical vein endothelial cells (HUVECs) co-incubated with exosomes were functionally examined via immunofluorescence, proliferation, and scratch assay. Results: The levels of the angiogenesis-regulating protein Thrombospondin-1 were significantly higher in HHT compared to HD exosomes. Among HHT, but not HD exosomes, a negative correlation between total exosomal protein and soluble Endoglin (sENG) levels was found. Other exosomal proteins (ALK1, ALK5) and the particle concentration significantly correlated with disease severity parameters (total consultations/interventions, epistaxis severity score) in HHT patients. Functionally, HUVECs were able to internalize both HD and HHT exosomes, inducing a similar change in the F-Actin structure and a reduction in migration and proliferation. Conclusions: This study provided first insights into the protein cargo and function of HHT-derived exosomes. The data indicate changes in sENG secretion via exosomes and reveal exosomal Thrombospondin-1 as a potential biomarker for HHT. Several exosomal characteristics were pointed out as potential liquid biomarkers for disease severity, revealing a possible new way of diagnosis and prognosis of HHT.

Enhancing Cartilage Repair: Surgical Approaches, Orthobiologics, and the Promise of Exosomes.

Treating cartilage damage is challenging as its ability for self-regeneration is limited. Left untreated, it can progress to osteoarthritis (OA), a joint disorder characterized by the deterioration of articular cartilage and other joint tissues. Surgical options, such as microfracture and cell/tissue transplantation, have shown promise as techniques to harness the body's endogenous regenerative capabilities to promote cartilage repair. Nonetheless, these techniques have been scrutinized due to reported inconsistencies in long-term outcomes and the tendency for the defects to regenerate as fibrocartilage instead of the smooth hyaline cartilage native to joint surfaces. Orthobiologics are medical therapies that utilize biologically derived substances to augment musculoskeletal healing. These treatments are rising in popularity because of their potential to enhance surgical standards of care. More recent developments in orthobiologics have focused on the role of exosomes in articular cartilage repair. Exosomes are nano-sized extracellular vesicles containing cargo such as proteins, lipids, and nucleic acids, and are known to facilitate intercellular communication, though their regenerative potential still needs to be fully understood. This review aims to demonstrate the advancements in cartilage regeneration, highlight surgical and biological treatment options, and discuss the recent strides in understanding the precise mechanisms of action involved.