Search Results (110)

The magnitude and quality of adaptive immune responses are fundamentally influenced by the efficiency of antigen presentation. Traditional vaccine platforms, such as live–attenuated or inactivated pathogens, although immunogenic, often present safety concerns. Conversely, subunit vaccines, despite being safer, generally exhibit poor immunogenicity due to inadequate delivery of antigens to professional antigen–presenting cells (APCs). To address this issue, the development of innovative delivery systems has become a pivotal strategy to overcome significant biological barriers, including extracellular antigen degradation, suboptimal lymph node targeting, and inefficient cross–presentation necessary for CD8+ T cell activation. This review systematically explores recent advancements in delivery technologies aimed at enhancing antigen presentation, encompassing rationally engineered nanocarriers and sophisticated biomimetic platforms. We first examine how nanoparticle properties like size, surface charge, and ligand density affect intracellular trafficking and the transition from MHC–II to MHC–I cross–presentation. Then, we explore bioinspired systems such as extracellular vesicles, virus–like particles, and cell–membrane–coated nanoparticles that utilize natural biological traits for enhanced targeting and immune modulation. Additionally, we review new physical delivery methods like microneedle arrays and in situ electroporation for direct, minimally invasive antigen delivery to dendritic cells. Lastly, we discuss the potential of these platforms in personalized cancer vaccines and combination immunotherapies. By combining insights from materials science, immunology, and bioengineering, these next–generation delivery tools could enhance antigen presentation and transform precision vaccination and immune intervention. Full article

Background/Objectives: African Swine Fever (ASF) represents one of the most serious threats to animal health and global food security. The causative agent of ASF is the African swine fever virus (ASFV), a DNA virus belonging to the Asfarviridae family. Here, we describe ex vivo results for an original anti-ASFV vaccine approach based on the cellular immune response induced by extracellular vesicles (EVs) engineered to express four ASFV proteins. EV engineering was achieved by expressing a DNA vector encoding a biologically inactive HIV-1 Nef protein (Nef^mut), which exhibits unusually high efficiency of incorporation into EVs, even when fused to foreign proteins. Previous studies have demonstrated that intramuscular injection of Nef^mut-based vectors leads to the engineering of Evs, spontaneously released by muscle cells, and induction of antigen-specific CD8⁺ T cell immunity. Methods: We designed DNA vectors expressing the fusion products between Nef^mut and each of the four ASFV structural proteins p30, p54, pp62, and p72. Engineered EVs were molecularly characterized by Western blot and nanotrack analysis, and their potential immunogenicity was assessed by priming and cross-presentation assays. Results: We assessed that the four fusion proteins were successfully expressed in transfected mammalian cells, with the release of valuable amounts of engineered EVs. When immature swine dendritic cells were challenged with the engineered EVs and then co-cultivated with autologous peripheral blood lymphocytes in priming assays, lymphocyte subpopulations specifically reacting against each ASFV antigen were elicited, as detected by an IFN-γ ELISpot assay. In addition, we provide evidence that the Nef^mut-based fusion products incorporated into the engineered EVs can be cross-presented by professional antigen-presenting cells, leading to cross-priming of autologous lymphocytes. Conclusions: These results represent the best premise to go forward with experiments examining immunogenicity and antiviral efficiency in pigs. Full article

Successful embryo implantation requires dynamic, bidirectional communication between a developmentally competent blastocyst and a receptive endometrium, integrating hormonal, molecular, and immunologic signals. Increasing evidence indicates that endometrial receptivity is critically dependent on a specialized immune microenvironment that supports trophoblast invasion while maintaining maternal tolerance. This review synthesizes current knowledge on the immunologic regulation of implantation, with emphasis on uterine natural killer (uNK) cells, regulatory T cells (Tregs), macrophages, dendritic cells, and cytokine networks. We further examine intracellular signaling pathways—including JAK/STAT, PI3K/AKT, NF-κB, and MAPK—that integrate immune and decidual responses. The bidirectional embryo–endometrium dialogue is explored through embryo-derived mediators such as human chorionic gonadotropin (hCG), cytokines, growth factors, and extracellular vesicles. The endometrium is increasingly recognized as a biosensor of embryo quality, selectively supporting viable embryos. Disruption of this complex communication network is implicated in recurrent implantation failure and early pregnancy loss. Despite substantial mechanistic advances, clinical translation remains limited. Emerging strategies, including immune profiling, microbiome modulation, and extracellular vesicle-based diagnostics, hold promise for precision reproductive medicine. Full article

Leishmaniasis caused by Leishmania infantum is a zoonotic disease endemic in many regions worldwide. The antigen-presenting dendritic cells (DCs) bridge the innate and adaptive immune response by activating T lymphocytes. Therefore, the present study examines whether T lymphocyte activation can be directed by autologous DCs primed by extracellular vesicles (EVs) derived from L. infantum. For this, lymphocytes were co-cultured with monocyte-derived DCs (moDCs) that were primed by EVs. moDC signaling and activation were examined by gene expression of toll-like receptors and cytokines. The antigen-presentation ability was analyzed through major histocompatibility complex molecules, and T cell subpopulations were explored by immunophenotyping. In co-cultures, EV-primed moDCs upregulated TLR2, TLR4, and TLR9, along with overexpression of MHC molecules. Co-cultures involving moDCs primed by EVs promoted the upregulation of both pro-inflammatory and regulatory cytokines associated with the expansion of non-conventional regulatory and central memory T cell subsets within the CD8⁺ T cell subpopulation. These findings suggest that activated moDCs can modulate cytotoxic lymphocytes, thereby promoting a balanced inflammatory microenvironment counterbalanced by a concurrent regulatory immune response. Thus, cell-based immune strategies using moDCs loaded with Leishmania-derived EVs represent a potential first step toward the development of innovative and personalized immune prophylactic and therapeutic approaches for leishmaniasis. Full article

The utilization of immunomodulatory nanomaterials, i.e., leveraging their unique properties to enhance immune responses, represents a transformative approach for the treatment of various diseases. Recent advancements in nanotechnology have enabled the design of nanomaterials capable of delivering immunomodulatory agents in a targeted manner, such as cytokines, antibodies, and nucleic acids, to specific cells or tissues involved in immune regulation. These nanomaterials, including nanoparticles, liposomes, nanogels, nanoemulsions, dendrimers, MXenes and extracellular vesicles, have been increasingly tailored to modulate immune responses with precision and efficacy. This targeted approach not only enhances therapeutic outcomes but also reduces off-target effects, minimizing systemic toxicity. In this review, an overview of immunomodulatory nanomaterials and their biomedical applications are highlighted. Herein, we have discussed different types of nanomaterials and their design strategies, interactions with different immune system components (macrophages, dendritic cells (DCs), neutrophils, T lymphocytes (CD4⁺ helper T-cells, CD8⁺ cytotoxic T-cells, regulatory T-cells/Tregs, and memory T-cells), and B lymphocytes), and immunomodulation mechanisms. Furthermore, nanomaterial-based immunomodulation strategies to enhance cancer immunotherapy, wound healing, and bone regeneration and the treatment of infectious diseases, autoimmune diseases, and allergy and are discussed in detail. In addition to therapeutic applications, selected nanomaterial platforms demonstrate significant potential in pharmaceutical formulations by improving drug stability, controlled release, and bioavailability, as well as in cosmetology through skin-targeted delivery, anti-inflammatory activity, immune protection, and enhanced tissue regeneration. Finally, clinical trial updates, challenges and future prospects are outlined. Key findings indicate that lipid-based, polymeric, inorganic nanoparticles and dendrimers provide complementary advantages for immunomodulation, including efficient delivery, controlled release, multifunctionality, and precise immune targeting. Despite safety, regulatory, and scalability challenges, these systems show strong potential for advancing precision and personalized medicine. Taken together, these innovations hold great promise for personalized medicine approaches, wherein nanomaterials can be tailored to individual patient profiles for more effective and precise disease treatment and prevention strategies. This review focuses primarily on the mechanistic interactions between immunomodulatory nanomaterials and immune cells, including macrophages, dendritic cells, neutrophils, T lymphocytes, and B lymphocytes, rather than providing an exhaustive treatment of physicochemical optimization parameters such as particle size or surface modification chemistry, which fall outside the defined scope of this work. Full article

Background and Objectives: Cutaneous melanoma (CM) is one of the most aggressive skin malignancies due to its rapid progression and high therapeutic resistance. Growing evidence demonstrates that the tumor microenvironment (TME)—comprising diverse immune, stromal, vascular, and epidermal cell populations alongside various cytokines and growth factors, as well as extracellular matrix (ECM) components—plays a crucial role in tumor heterogeneity, metastatic potential, and response to therapy. This review aims to synthesise current knowledge on the cellular and non-cellular constituents of the CM microenvironment and clarify their contributions to tumor progression, immune evasion, and treatment resistance. Materials and Methods: We conducted a narrative review of recent experimental, clinical, and translational studies investigating melanoma–microenvironment interactions, integrating evidence from in vitro, in vivo, and human tissue analyses. Results: Melanoma exhibits marked intra-tumoral heterogeneity driven by genetic, epigenetic, and microenvironmental influences. Cancer-associated fibroblasts, adipocytes, endothelial cells, and keratinocytes are reprogrammed by melanoma cells to promote invasion, angiogenesis, and metastasis. Immune subsets play divergent roles: neutrophils, M2 macrophages, myeloid-derived suppressor cells, and tolerogenic dendritic cells foster immune suppression, while lymphocytes—particularly CD8⁺ T cells, TFH cells, and B cells —are associated with improved outcomes but often become dysfunctional. ECM remodeling, including collagen deposition, integrin signaling, and increased matrix stiffness, actively remodels the tissue to support tumor growth and immune evasion. Hypoxia-inducible factor (HIF)-mediated signaling drives cell dedifferentiation, angiogenesis, and metabolic changes that contribute to treatment resistance. Consequently, emerging therapeutic strategies are moving beyond targeting tumor cells alone to focus on modulating TME components, counteracting immunosuppression, hypoxia, metabolic reprogramming, and extracellular vesicle signaling. Conclusions: The TME profoundly modulates tumor behavior and therapeutic response. A deeper understanding of the reciprocal interactions between melanoma cells and their microenvironmental components may enable the development of more effective strategies for early detection, prognosis, and personalized therapies. Full article

Objectives: This study aimed to investigated the role of Giardia extracellular vesicles (EVs) in intercellular communication and to evaluated their potential as vaccine candidates. Methods: The immunomodulatory effects of Giardia EVs were assessed in mouse macrophages and human monocyte-derived dendritic cells (Mo-DCs), with a particular focus on key inflammatory signaling pathways. In vivo immunogenicity was evaluated following EV administration, and the antigenic composition of EV cargo was characterized by proteomic analysis. Results: Giardia EVs activated pro-inflammatory signaling pathways in mouse macrphages, including SAPK/JNK, ERK1/2, and NF-κB. This activation was associated with IκB-α degradation and nuclear translocation of p65. Furthermore, EV stimulation significantly upregulated the expression of pro-inflammatory genes, including Il1β, Il6, Il4, Ptgs2, Nos2, and Tnf, with log₂ fold changes ranging from 3.9 to 15.8. Consistently, EVs increased iNOS protein expression (28–45%) and nitrite production (9.6–12.3-fold). In human Mo-DCs, Giardia EVs promoted cellular maturation, as evidenced by increased expression of MHC-II, CD80, and CD86, and enhanced T-cell proliferation with a Th1-skewed profile. In vivo immunization induced antigen-specific antibody responses, with IgG subclass distribution indicative of a balanced Th1/Th2 response. Proteomic analysis identified immunoreactive EV-associated proteins, including elongation factor 1-alpha, α-7.3 giardin, tubulin, and variant surface proteins (VSPs), which are well-established antigens in Giardia infection, with prominent bands observed at approximately 22 kDa and 50 kDa. Conclusions: Collectively, these findings demonstrate that Giardia EVs modulate innate immune responses in vitro, elicit antigen-specific humoral immunity in vivo, and contain conserved immunogenic proteins. These properties support their potential as a promising cell-free vaccine platform against giardiasis. Full article

Cow’s milk allergy (CMA) is characterized by an exaggerated immune response where dendritic cells (DCs) play a crucial role. Additionally, extracellular vesicles (EVs) can be released by immune cells, modulating this allergic response. Moreover, eosinophils also contribute to tissue damage and perpetuate inflammation in allergic reactions. Therefore, the aim of this work was to study the role of EVs from monocyte-derived dendritic cells (moDCs) on eosinophil and lymphocytes in CMA. Sixteen infants with IgE-mediated cow’s milk allergy (CMAIE) and three non-allergic controls were recruited. Peripheral blood monocytes were purified and differentiated to moDCs. EVs were obtained from the culture supernatant by ultracentrifugation and characterized by nanoparticle tracking analysis and Western blot. Interaction among EVs, eosinophils and peripheral blood mononuclear cells (PBMCs) were analyzed with confocal microscopy. Additionally, these cells were incubated with EVs to assess lymphocyte proliferation, as well as eosinophil migration and reactive oxygen species (ROS) production by flow cytometry. Moreover, multiplex analysis was performed to evaluate the cytokines released by PBMCs following stimulation with EVs. Proteins characteristic of EVs were identified (CD9, CD63, CD81 and Alix). Furthermore, the size of the nanovesicles was ~185 nm, which is consistent with previously published reports. Confocal microscopy revealed that EVs internalized and localized in the cytoplasm of eosinophils, while in PBMCs, EVs were located in the perinuclear region. A proliferation assay revealed an increase in the proliferation of Th1 and Th2 lymphocytes, with higher levels of IL-4. Moreover, EVs were able to significantly increase eosinophil ROS production and migration. However, these effects were not observed after stimulation with EVs from non-allergic controls. This exploratory study shows that EVs from the moDCs of children with CMAIE could induce chemotactic and stimulatory functions on eosinophils and lymphocytes, which could perpetuate inflammation and contribute to tissue damage in this type of allergy. Full article

Outer membrane vesicles (OMVs) are tractable, cell-free microbial outputs that can shape innate immune programs. Here, we compared OMVs from the probiotic Escherichia coli Nissle 1917 (EcN) and the commensal strain ECOR12 in a paired within-donor model of human monocyte-derived dendritic cells (Mo-DCs) (N = 20). In the core integrated arm, Mo-DCs were exposed to iDC control, EcN OMVs, or ECOR12 OMVs (10 µg/mL, 24 h) and profiled for maturation markers (CD14, CD83, CD209), cytokines (IL-6, TNF-α, IL-10), and a targeted miRNA panel (miR-155-5p, let-7i-3p, miR-146b-5p, miR-29a-5p). Both OMV types promoted maturation (increased CD83 and reduced CD14), but generated distinct cytokine–miRNA configurations, with ECOR12 tending toward an IL-10–high profile and EcN toward higher IL-6/TNF-α tendencies. Multivariate integration separated conditions into reproducible, strain-specific immune fingerprints, supporting the key take-home that probiotic versus commensal E. coli OMVs imprint distinguishable coordinated response states in human DCs. In an extended phenotyping arm, ECOR63 OMVs were evaluated by ELISA and flow cytometry only and were not included in miRNA profiling or integrated PCA due to unavailable matched miRNA measurements. Full article

Atopic allergy is rising globally and placing a significant strain on healthcare systems, yet the understanding of the underpinning mechanisms of allergic sensitization remains incomplete. Extracellular vesicles (EVs) have recently emerged as important mediators of immune modulation, due to their diverse cargo, and therefore may play a mechanistic role in allergic sensitization development. Thus, this study investigated whether EVs released by activated dendritic cells (DCs) contribute to allergic sensitization of the common egg allergen, ovalbumin (OVA). DCs were generated from human monocytes cultured with GM-CSF and IL-4, then stimulated with LPS and/or OVA. EVs were subsequently isolated using size-exclusion chromatography and added to freshly isolated naive T cells at defined time points. T cell responses were then analyzed using spectral flow cytometry. The results highlight that EVs derived from LPS or LPS + OVA-stimulated DCs enhanced IL-4 production and reduced IFN-γ production in naive T cells from egg-allergic donors, indicating a shift toward a Th2 profile. In healthy donors, LPS-induced DC EVs also suppressed IFN-γ expression. Notably, EVs alone were insufficient to activate T cells without CD3/CD28 co-stimulation, suggesting that EVs may function as a “third signal” shaping T cell polarization. These findings highlight a potential role for DC-derived EVs in initiating allergic sensitization. Full article

Neuronal synapses are the functional units of communication in the central nervous system. This review describes the molecular mechanisms regulating synaptic transmission, plasticity, and circuit refinement. At the presynaptic active zone, scaffolding proteins including bassoon, piccolo, RIMs, and munc13 organize vesicle priming and the localization of voltage-gated calcium channels. Neurotransmitter release is mediated by the SNARE complex, comprising syntaxin-1, SNAP25, and synaptobrevin, and triggered by the calcium sensor synaptotagmin-1. Following exocytosis, synaptic vesicles are recovered through clathrin-mediated, ultrafast, bulk, or kiss-and-run endocytic pathways. Postsynaptically, the postsynaptic density (PSD) serves as a protein hub where scaffolds such as PSD-95, shank, homer, and gephyrin anchor excitatory (AMPA, NMDA) and inhibitory (GABA-A, Glycine) receptors are observed. Synaptic strength is modified during long-term potentiation (LTP) and depression (LTD) through signaling cascades involving kinases like CaMKII, PKA, and PKC, or phosphatases such as PP1 and calcineurin. These pathways regulate receptor trafficking, Arc-mediated endocytosis, and actin-dependent remodeling of dendritic spines. Additionally, synapse formation and elimination are guided by cell adhesion molecules, including neurexins and neuroligins, and by microglial pruning via the complement cascade (C1q, C3) and “don’t eat me” signals like CD47. Molecular diversity is further expanded by alternative splicing and post-translational modifications. A unified model of synaptic homeostasis is required to understand the basis of neuropsychiatric and neurological disorders. Full article

Mesenchymal stem/stromal cells (MSCs) exhibit broad differentiation capability and strong immunoregulatory potential mediated through intercellular communication and the release of diverse paracrine mediators. They represent a promising but still investigational therapeutic approach for managing complications associated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This review provides an updated synthesis of MSC biology, their bidirectional interaction with immune cells, and their functional contribution to the hematopoietic niche. It also evaluates current clinical evidence regarding the therapeutic roles of MSCs and MSC-derived extracellular vesicles (EVs) in acute and chronic graft-versus-host disease (aGVHD/cGVHD), as well as in poor graft function. Mechanistic insights encompass macrophage polarization toward an anti-inflammatory phenotype, inhibition of dendritic cell maturation, enhancement of regulatory T-cell expansion, and modulation of cytokine signaling pathways. Within the bone marrow milieu, MSCs contribute to stromal restoration and angiogenic repair. Recent phase II/III trials in steroid-refractory (SR)-aGVHD have demonstrated overall response rates ranging from 48 to 71%. Efficacy appears particularly enhanced in pediatric patients and with early MSC administration. Across studies, MSC therapy shows a favorable safety profile; however, heterogeneity in response and inconsistent survival outcomes remain notable limitations. For poor graft function, limited prospective studies indicate hematopoietic recovery following third-party MSC infusions, and combination approaches such as co-administration with thrombopoietin receptor agonists are under investigation. MSC-derived EVs emulate many immunomodulatory effects of their parental cells with a potentially safer profile, though clinical validation remains in its infancy. MSC-oriented interventions hold substantial biological and therapeutic promise, offering a favorable safety margin; however, clinical translation is hindered by product variability, suboptimal engraftment and persistence, and inconsistent efficacy across studies. Future directions should emphasize standardized manufacturing and potency assays, biomarker-driven patient and timing selection, optimized conditioning and dosing strategies, and the systematic appraisal of EV-based or genetically modified MSC products through controlled trials. Full article

BST2 has emerged as a multifunctional molecule that bridges antiviral defense, membrane architecture, and tumor immunity. Originally characterized as an interferon-inducible restriction factor that tethers virions to the plasma membrane, BST2 is now recognized as an oncogenic driver and immunoregulatory hub in diverse malignancies. In cancer, BST2 expression is frequently upregulated through promoter hypomethylation and transcriptional activation. Functionally, BST2 promotes proliferation, epithelial–mesenchymal transition, anoikis resistance, and chemoresistance, whereas its loss sensitizes tumor cells to proteotoxic and metabolic stresses. Beyond tumor cells, BST2 modulates the tumor microenvironment by promoting M2 macrophage infiltration, dendritic cell exhaustion, and natural killer (NK)-cell resistance, thereby contributing to immune evasion. Elevated BST2 expression correlates with poor prognosis in glioblastoma, breast, nasopharyngeal, and pancreatic cancers, and it serves as a circulating biomarker within small extracellular vesicles. In conclusion, BST2 is a dual-function molecule that integrates oncogenic signaling and immune regulation, making it an attractive diagnostic and therapeutic target for hematological and solid tumors. Full article

Synapses, abundant in the brain, are structures needed for life. Our Introduction, based on the forms of such structures published few decades ago, helped in developing recent concepts of health and diseases. Growing axons govern their growth by cell-to-cell communication, axon guidance, and synapse orientations. The assembly of synapses requires the organization and function of pre-synaptic and post-synaptic neuronal terminals with a liquid–liquid phase, governed by Ca²⁺ responses of thin astrocyte domains. Upon synapse stimulation, the clefts expand up to several folds while pre- and post-synaptic thickness remains unchanged. In additional responses, neurons co-operate with astrocytes and extracellular vesicles (EVs), the latter dependent on extracellular and intracellular spaces. Astrocyte and microglia cells and/or EV secretions induce neurons by various effects including traveling changes. Pre-synaptic responses are defined as canonical if based on neurotransmitter release; non-canonical if they are without release and are discharged by EVs, not neurotransmitters. Health and diseases depend on other general properties, such as those defined molecularly. Among neurodegenerative diseases, attention is specified by various properties of Alzheimer’s and other diagnoses. Critical identifications can be due to astrocyte and microglia cells or multiple effects induced by EVs. At present, the complexity of therapies, although of limited success, is developing innovative initiatives. Full article

Extracellular vesicles, encompassing eukaryotic exosomes and bacterial outer membrane vesicles (OMVs), play multifaceted roles in mediating host–pathogen interactions. These nanoscale structures act as critical mediators of intercellular communication, transporting diverse bioactive cargo such as miRNAs, cytokines, proteins, and bacterial components. Exosomes contribute to host immunity by delivering antimicrobial agents and modulating inflammatory responses, but they can also be hijacked by pathogens to suppress defenses and promote persistent infection. OMVs, on the other hand, enable bacteria to disseminate virulence factors, deliver toxins directly into host cells, and modulate immune signaling. For example, exosomes from infected macrophages can stimulate dendritic cell activation and T-cell priming, whereas bacterial OMVs have been shown to suppress host immunity or trigger excessive inflammation depending on their molecular cargo. Importantly, OMVs facilitate horizontal gene transfer and nutrient exchange within microbial communities, thereby influencing microbiome composition and adaptation. Together, these complex dynamics position both exosomes and OMVs as central players in immunity and pathogenesis. This review synthesizes recent insights into how host- and pathogen-derived vesicles modulate infection biology and immune responses, while also exploring their potential as diagnostic biomarkers and therapeutic carriers, and discussing current limitations in their clinical translation. Full article