Unveiling the promise: Exosomes as game‐changers in anti‐infective therapy

Exploration, Journal Year: 2024, Volume and Issue: 4(5)

Published: March 12, 2024

Abstract Extracellular vesicles (EVs)‐based intercellular communication (through exosomes, microvesicles, and apoptotic bodies) is conserved across all kingdoms of life. In recent years, exosomes have gained much attention for targeted pharmaceutical administration due to their unique features, nanoscale size, capacity significantly contribute cellular communication. As drug delivery vehicles, several advantages over alternative nanoparticulate technologies. A key advantage lies in comparable makeup the body's cells, which makes them non‐immunogenic. However, face challenges, including a lack an effective standard production technique, decreased loading capacity, limited characterization techniques, underdeveloped isolation purification procedures. Exosomes are well known long‐term safety natural ability transport nucleic acids medicinal compounds blood‐brain‐barrier (BBB). Therefore, addition revealing new insights into exosomes’ distinctiveness, growing availability analytical tools may drive development next‐generation synthetic systems. Herein, light shed on as vehicles anti‐infective therapy by reviewing literature primary articles published between 2002 2023. Additionally, benefits limitations employing therapeutic also discussed.

Language: Английский

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CD66b⁺/CD68⁺ circulating extracellular vesicles, lactate dehydrogenase and neutrophil‐to‐lymphocyte ratio can differentiate coronavirus disease 2019 severity during and after infection

Journal of Extracellular Vesicles, Journal Year: 2024, Volume and Issue: 13(7)

Published: July 1, 2024

Abstract Coronavirus disease 2019 (COVID‐19) has been a major public health burden. We hypothesised that circulating extracellular vesicles (cEVs), key players in and disease, could trace the cell changes during COVID‐19 infection recovery. Therefore, we studied temporal trend of cEV inflammatory marker levels plasma samples patients were collected within 24 h patient admission (baseline, n = 80) after hospital discharge at day‐90 post‐admission ( 59). Inflammatory markers measured by standard biochemical methods. cEVs quantitatively phenotypically characterized high‐sensitivity nano flow cytometry. In recovered from lower detected. vascular (endothelial cells) blood (platelets, distinct immune subsets) cells significantly reduced compared to levels, pattern also observed for progenitor, perivascular epithelial cells. The best discriminatory power severity was found lactate dehydrogenase neutrophil‐to‐lymphocyte ratio granulocyte/macrophage‐released CD66b + /CD68 ‐cEVs. Albeit good indicators systemic response discriminators remission, they do not completely reveal stress organ damage states. reaching baseline pre‐infection 90 days post‐infection discriminate parental affected disease.

Language: Английский

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Intranasal delivery of extracellular vesicles: A promising new approach for treating neurological and respiratory disorders

Journal of Controlled Release, Journal Year: 2025, Volume and Issue: 379, P. 489 - 523

Published: Jan. 18, 2025

Language: Английский

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Consistency in bacterial extracellular vesicle production: key to their application in human health

Extracellular Vesicles and Circulating Nucleic Acids, Journal Year: 2025, Volume and Issue: 6(1), P. 1 - 20

Published: Jan. 17, 2025

Bacterial extracellular vesicles (BEVs) are naturally occurring functional structures that play critical roles in bacterial life processes. These vesicles, commonly known as outer membrane (OMVs), were first found to be released by Gram-negative bacteria; however, it has since been confirmed Gram-positive bacteria also secrete BEVs. As research advances, BEVs increasingly utilized diverse applications, including vaccine development and drug delivery. Nevertheless, the effective employment of these contexts requires acquisition with consistent properties functions through appropriate culture, isolation, purification methods. This review examines advantages disadvantages various techniques alongside heterogeneity they may introduce. We utilize a framework critically analyze barriers their application factors influencing characteristics. Additionally, we constructively propose solutions enhance consistency BEVs, thereby facilitating further application.

Language: Английский

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Challenging the notion of endothelial infection by SARS-CoV-2: insights from the current scientific evidence

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 4, 2025

IntroductionCoronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is a public health emergency with phenotypes ranging from asymptomatic to severe sequelae that can lead multiple organ failure and death (1, 2). SARS-CoV-2 efficiently infects airway epithelial cells alveolar pneumocytes, causing in high viral loads inflammatory responses, including the interferon response (3). In hospitalized patients, COVID-19 increases risk of venous arterial thromboembolic events due vascular barrier failure, edema, endotheliitis, thrombosis, cell infiltration (4, 5). Hypercoagulation micro- macro-circulatory thrombosis are major causes (6). Although many people have survived without long-term symptoms, considerable portion survivors reportedly continuing cardiovascular issues such as coagulopathy or bleeding disorders (7). This suggests that, addition respiratory epithelium, endothelium lining blood vessels may also be impacted infection. The pathophysiology has been explored recent reviews (reviewed (8, 9)). Due conflicting data, there ongoing controversy about endothelial tropism (refers ability interact cells) productive infection (viral replication within ECs) SARS-CoV-2. Here, we share our perspective on challenging notion infection, drawing insights current scientific evidence.Endothelial dysfunction hypercoagulation COVID-19The endothelium, which lines inside arteries, crucial for controlling tone preserving homeostasis (10). Disseminated intravascular coagulation (DIC), vasculitis, all attributable damage (11, 12). Numerous prevalent viruses bacteria found directly infect ECs, necrosis, apoptosis and/or vessel wall (13-15). Upon Dengue, Hantaan, Marburg, Lassa, Ebola, both immune non-immune (including cells, monocytes, macrophages) express tissue factor (TF), leading often culminating disseminated (DIC) (16-20). Studies demonstrated Marburg (ECs) replicate them, reviewed detail elsewhere (13, 21, 22). However, it remains unclear whether exhibits similar phenomenon observations. less studied than epithelium pneumocytes (10, 23-25). Despite thromboprophylaxis, 31-49% care patients had thromboembolism (26-30). shows impairment must addressed aggressively prevent thrombosis. driven lung-induced systemic inflammation upon injury direct Several pro-inflammatory cytokines TNF-α, IL-1α, IL-1β, IL-6, IL-8, MCP-1, IFN- responsible cytokine storm (31, 32) induce COVID-19-associated (CAC) via expression TF macrophages T (33-40). IL-6 signaling complex damages liver sinusoidal ECs produces injury, suggesting cause (41). Syrian hamster model showed type I dysregulation non-respiratory tissues like heart kidney, shedding light multiorgan possible post-acute (42). Spike Nucleocapsid protein activate inducing mitochondrial dysfunction, vasculopathy, (43, 44) (Figure 1). Furthermore, study early host declines aging, potentially contributing increased severity (45).Proposed novel (co)-receptors entry SARS-CoV utilize human ACE2 an receptor TMPRSS2, primarily expressed digestive tracts, co-factor degrade extracellular matrix proteins (46). variably smooth muscle pericytes across organs, facilitating dissemination into circulatory system. studies, in-house immunohistochemistry, humanized mice hACE2 brain but not lung, gastrointestinal, renal vessels, employ hACE2-dependent independent mechanisms (47) 1B). Low TMPRSS2 limits (48). Thus, variations different microvascular beds, alternative receptors facilitate infectious particles. Supporting this concept, numerous additional identified over past three years relevant particle ECs. Endosomal cysteine peptidases cathepsins B L spike (S) protein, enhancing (49-51). binds heparan sulfate, sialic acid-containing glycoproteins, gangliosides (52, 53). Proteolytic cleavage at furin-type sites S exposes conserved motif interacts Neuropilin-1/2 receptors, significantly increasing infectivity (54, 55). Vimentin, CD147, TMEM106B co-receptors though role pathology lacks experimental validation (56-59). Further research needed confirm these vivo relevance.Controversies Endotheliitis regarded immune-inflammatory forming inner surface association consequence pathogen invasion. Systemic endotheliitis (60). Human autopsies, non-human primates (NHPs) models sporadic consistently observed hamsters (61, 62). Compared healthy individuals, circulating markers platelet activation elevated (63). Evidence myeloid polarization, levels shed CD16 CD163, linked proinflammatory related poor clinical outcomes (64). Elevated D-dimer thrombocytopenia could explained dysregulated microthrombus formation complicated (65). Consecutively, COVID-19, hypoxia pulmonary might classic acute distress syndrome (ARDS) (66). compared controls, isolated lungs challenged lipopolysaccharide tumor necrosis alpha pro-coagulant activity PAI-1, decreased fibrinolytic potential, emphasizing features ARDS (67).Earlier studies support particles were detected highly vascularized organs plays fundamental (24, 68-76). Initial transmission electron microscopy (TEM) revealed presence kidney autopsy samples (76-78). owing challenges interpreting TEM variability experience those images, debatable (76, 79, 80). Irrespective controversies, evidence indicate coated vesicles multivesicular bodies closely mimic even lung uncommonly misinterpreted (81). thrombo-inflammatory phenotype, no definitive animal biopsies yet shown (82-85). macrovascular resistant overexpression necessary (86-89). Montezano et al. recombinant protein-1 induced enzymatic vitro (90). On ex cultures patient who signs virus following immunohistochemical labeling (91). primed (IL-1) produced more cytokines, (92). two separate investigations (MOI=0.5-3 after 2 hours adsorption) (93, 94).Based findings, hypothesize prior reports universal hallmark illness restricted certain groups episodes. this, carefully evaluated immunoreactivity (N) Protein slices translational preclinical (transgenic K18-hACE2 (expression cells), hACE2-KI (global knock-in replacing mouse ACE2), hamsters, African green monkeys (AGM) postmortem samples. A board-certified veterinary pathologist (N.A.C.) immunohistochemically analyzed hundreds previous each species (45, 61, 62, 69, 95-99). PCR-positive clear hyaline membrane AGMs 7 days post-infection (dpi) N Protein, antigen only present during phase 2A 2B). K18-hACE2, NHPs, ACE2-KI varying decreasing hamsters. No antigens 2C-E). To further absence performed duplex fluorescent IHC targeting (CD34 CD31) protein. AGM mouse, luminal exclusively displayed evidenced colocalization 4DPI 2F-G). EC mediators COVID-19Collectively, findings group others question universality SARS- CoV-2's infectivity. Because active associated pro-inflammation, activating immunothrombosis complement activation, antiphospholipid antibodies, so on. treated sera (n=118) anti-cardiolipin IgG/IgM anti-phosphatidlyserine/prothrombin (anti-PS/PT) IgG/IgM-driven elevation adhesion E-selectin, VCAM-1, ICAM-1 (100-102). Infection-induced IL1β, TNFα, stimulate coagulation, influence thrombin generation, fibrin formation, TF-dependent responses protease-activated (PARs) (6, 103-107) 2H). induces production superoxide anion release DNA (mtDNA), Toll-like 9 (TLR9) NFκ-B. Consequently, orchestrates genes, pathological processes (108). highlighted changes lipid profiles COVID-19. Among most commonly reductions serum cholesterol ApoA1 levels, coupled triglycerides (109). Lipidomic analysis eicosanoids potential contributor dysfunction. aberrant (ECM) controls balance repair (110). confirmed Hyaluronan important compound ECM vital systems (111). characterized MMP-1 growth (VEGF)-A, correlated (112). More 50% experienced moderate cases reduced diffusion fibrotic changes, (113). detailed (114).The glycocalyx (EG) maintaining homeostasis, (115). EG surface, plasma components syndecan-1, hyaluronan. These biomarkers, along hsCRP, procalcitonin, mortality (116-118). despite underlying still fully understood (118-122). several drugs, heparin tocilizumab, already being used treatment protect (123-126). Marine algae extracts, fucoidan rhamnan sulfate (RS) restore (127, 128). Specifically, fucoidan, (HS) mimetic, reduce restoration serum(125). Vascular targeted therapy (84, 129, 130). drugs exhibit multifunctional properties; however, agents specifically aimed improving structure integrity reported date. Nevertheless, regimens protection applied practice patients. approaches comprehensively (129, 131). Most extracellularvesicles (EVs) originate platelets erythrocytes (132). Under physiological conditions, proportion EVs secreted relatively low, notably conditions marked released contain markers, endoglin/CD105, E-selectinCD62E, S-endo/CD146, cadherin/CD144, molecule 1/ CD31, intercellular 1 /CD54 (133). carrying bloodstream thereby COVID-19-related (134, 135). Given critical prospective appears preexisting various states (e.g., diabetes, atherosclerosis, hypertension) vulnerable course (136). For instance, among comorbidities, diabetes mellitus (DM) was frequently (10.9% cases) condition (137). China, Europe, UK US when DM acquire they likely develop complications, require ICU hospitalization, die (138-140). root chronic together SARS-CoV-2-mediated result microcirculation multi-organ failure.ConclusionExperimental unlikely productively cells. Instead, mediators, components, vesicles, lipids/lipoproteins, thrombin, primary drivers Additionally, accumulating indicates disrupts altering permeability, adhesion, mechanosensing, antithrombotic anti-inflammatory functions.Given mixed involvement (co)-receptors, needed. First, developing better demonstrate help identify validate Second, possibility enters effective replication. trigger significant signaling, rapid RNA degradation render undetectable. hypotheses warrant investigation.Besides, variation detection methodological differences, sampling techniques, sensitivity methods, models. addition, biological variability, differences population severity, lay studies. systematic review required contributes discrepancies. tested researchers dissect out pathogen-host interactions effects interventions, progression, between animals humans relevance findings.Alternatively, infected cleared system mechanisms, phagocytosis macrophages, through responses. make detect infections layer, removed before adequately identified. considering typically sample time points, likelihood occurring low. investigate draw well-informed conclusion, ensuring clearance accounted analysis.Nonetheless, confirms making therapeutic target. Addressing individuals hyperinflammation hypercoagulation. mitigate pro-thrombotic International Society Thrombosis Haemostasis (ISTH) recommends standard thromboprophylaxis low molecular weight unfractionated (LMWH/UFH) unless contraindicated (141).

Language: Английский

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Extracellular vesicles for infectious diseases: a game-changer in infectious disease control

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown, P. 157 - 174

Published: Jan. 1, 2025

Language: Английский

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Targeting Atf4 for enhanced neuroprotection: Role of quercetin-loaded evs in ischemic stroke

Journal of Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown, P. 101312 - 101312

Published: April 1, 2025

Language: Английский

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Extracellular Vesicles as Delivery Systems in Disease Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(24), P. 17134 - 17134

Published: Dec. 5, 2023

Extracellular vesicles (EVs)/exosomes are nanosized membrane-bound structures that released by virtually all cells. EVs have attracted great attention in the scientific community since discovery of their roles cell-to-cell communication. EVs’ enclosed structure protects bioactive molecules from degradation extracellular space and targets specific tissues according to topography membrane proteins. Upon absorption recipient cells, EV cargo can modify transcription machinery alter cellular functions these playing a role disease pathogenesis. been tested as delivery system for mRNA COVID-19 vaccine. Recently, different therapeutic strategies designed use microRNAs mRNA. In this review, we will focus on exciting various platforms related using vehicles, mainly gene editing CRISPR/Cas9, cancer therapy, drug delivery, vaccines. We also touch upon

Language: Английский

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Extracellular vesicles as the next‐generation modulators of pharmacokinetics and pharmacodynamics of medications and their potential as adjuvant therapeutics

Clinical and Translational Medicine, Journal Year: 2024, Volume and Issue: 14(8)

Published: Aug. 1, 2024

Pharmacokinetics (PK) and pharmacodynamics (PD) are central concepts to guide the dosage administration of drug therapies essential consider for both healthcare professionals researchers in therapeutic planning discovery. PK/PD properties a significantly influence variability response treatment, including failure or excessive medication-related harm. Furthermore, suboptimal PK constitute significant barrier further development some candidate treatments This article describes how extracellular vesicles (EVs) affect different aspects PD medications their potential modulate address problematic profiles drugs. We reviewed EVs' intrinsic effects on cell behaviours medication responses. also described surface cargo modifications can enhance EV functionalities enable them as adjuvants optimise profile conventional medications. we demonstrated that various bioengineering strategies be used modify EVs, hence enhancing

Language: Английский

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Beyond Borders of the Cell: How Extracellular Vesicles Shape COVID-19 for People with Cystic Fibrosis

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 3713 - 3713

Published: March 27, 2024

The interaction between extracellular vesicles (EVs) and SARS-CoV-2, the virus causing COVID-19, especially in people with cystic fibrosis (PwCF) is insufficiently studied. EVs are small membrane-bound particles involved cell-cell communications different physiological pathological conditions, including inflammation infection. CF airway cells release that differ from those released by healthy may play an intriguing role regulating inflammatory response to SARS-CoV-2. On one hand, activate neutrophils exacerbate inflammation. other block IL-6, a pro-inflammatory cytokine associated severe protect PwCF adverse outcomes. regulated TGF-β signaling, essential disease states, COVID-19. Here, we review knowledge, identify gaps understanding, suggest future research directions elucidate of during

Language: Английский

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