Search Results (1,276)

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: Among primary intracranial neoplasms in adults, glioblastoma multiforme stands out for both its prevalence and its exceptionally invasive character. Uric acid-related genes (UARGs) may enhance tumor cell invasiveness and drug resistance by promoting oxidative stress responses. This study aimed to elucidate uric acid-driven mechanisms in glioblastoma, focusing on risk stratification and therapeutic vulnerability. Methods: Transcriptomic profiles of GBM were retrieved from TCGA and GEO repositories, followed by performing differentially expressed analysis, univariate Cox and LASSO regression, in order to screen prognostic UARGs and construct a risk model. Then, prognostic analyses were expanded by performing immune microenvironment analysis, drug sensitivity analysis, tumor mutation analysis, independent prognostic analysis, and nomogram construction. Additionally, dataset GSE162631 was interrogated to pinpoint pivotal cell subsets and to map intercellular communication as well as pseudo-time analysis. Results: A risk model incorporating six prognostic UARGs (TIMP1, PLAUR, CTSB, KLF10, RARRES2, and PTPRN) was constructed and identified as a favorable prognostic signature. Resting dendritic cells and drugs (including acetalax and trametinib) were found to be associated with GBM patients’ risk stratification. Low-risk patients showed relatively higher mutation rates of PTEN and TP53. A nomogram was developed based on RARRES2 and PTPRN, which exhibited favorable predictive performance for GBM prognosis. Furthermore, scRNA-seq profiling identified dendritic cells (DCs), macrophages, and T cells as key populations in the tumor microenvironment. Intercellular communication inference indicated relatively strong DCs-macrophage crosstalk, and pseudo-time analysis linked prognostic UARG expression to the differentiation trajectory of critical cell subsets. Conclusions: This study identified uric acid-related genes as potential independent indicators of clinical outcomes in glioblastoma progression. A novel prognostic UARG-associated signature was developed and validated, which showed potential in predicting GBM patient outcomes. Full article

Metal ion-based chemo-immunotherapy is often limited by rigid intracellular metal homeostasis, insufficient reactive oxygen species (ROS) accumulation, and an immunosuppressive tumor microenvironment (TME). To overcome these limitations, we engineered an ATP-responsive, core–shell bimetallic nanoreactor (Cu/ZIF@PDA, termed CZP) featuring a precisely controlled ~25 nm biomimetic polydopamine (PDA) coating. Triggered by elevated tumoral ATP levels, CZP undergoes coordination-induced disassembly and promotes oxidative stress amplification. Specifically, the PDA shell acts as a superoxide dismutase (SOD) mimetic to continuously supply H₂O₂, fueling Cu²⁺-mediated Fenton-like reactions to unleash highly toxic hydroxyl radicals (•OH) while aggressively depleting the intracellular glutathione (GSH) pool. This irreversible oxidative damage, coupled with Zn²⁺-induced mitochondrial dysfunction, triggers profound mitochondrial DNA (mtDNA) leakage. Crucially, this cytosolic DNA robustly activates the cGAS-STING signaling axis, driving a massive surge in immunogenic cell death (ICD) and significantly promoting dendritic cell (DC) maturation. Furthermore, CZP markedly inhibited primary tumor growth in vivo and showed protection in a tumor re-challenge model, accompanied by enhanced dendritic cell maturation. These findings support the potential of this ATP-responsive bimetallic nanoplatform to promote antitumor immune activation. Full article

Background/Objectives: High-grade serous ovarian cancer (HGSOC) is usually discovered in advanced stages and often relapses shortly after initial conventional therapy. Survival in HGSOC patients might be improved with the use of novel immune therapies, which potentiate autologous anti-tumor responses. Dendritic cells (DCs) are potent antigen-presenting cells that can initiate immune responses, activate cytotoxic T cells and drive T-cell differentiation. This pilot trial evaluated the safety and efficacy of a unique DC vaccine (α-DC-1) in relapsed, advanced HGSOC patients with minimal tumor burden. Methods: Monocytes from patient leukaphereses were used to propagate a unique autologous DC, the α-DC-1, generated with granulocyte–macrophage colony-stimulating factor and interleukin-4, pulsed with keyhole limpet hemocyanin (KLH) and tumor lysate (from debulking surgery) on day 5, and matured with a cocktail of cytokines and chemokines on day 6. Mature α-DC-1 were harvested on day 7 and administered intranodally (inguinal nodes) every other week for three doses/cycle for up to three DC vaccine cycles (nine vaccines). The primary endpoints were progression-free survival (PFS) and overall survival (OS). Results: In 19 patients treated, the median PFS was 9.7 months (95% CI: (5, NA)) and the median OS was 42.2 months (95% CI: (31.2, 68.3)). In 5/19 (26.3%) patients, OS exceeded five years. Administration of six or more vaccines was associated with a significant improvement in PFS. No grade 2 or higher toxicities were noted. Conclusions: Our α-DC-1 vaccine was safe, and 94.2% elicited an immune response to KLH. The long OS, exceeding 5 years in some patients, suggests this DC vaccine may improve survival for some with relapsed HGSOC. Full article

Dendritic cells (DCs) integrate innate immune sensing with adaptive immune priming through coordinated transcriptional programs that regulate antiviral defense, inflammatory signaling, and antigen presentation. However, the hierarchical organization and interdependence of these pathways following stimulation remain incompletely defined. Here, we performed an in silico re-analysis with full reproducibility of publicly available RNA-sequencing data (GSE108526) to characterize the temporal architecture and associations of immune transcriptional modules in human dendritic cells at 6 h and 16 h following innate immune activation. Principal component analysis revealed stimulation status as the dominant source of transcriptomic variance. Differential expression analysis confirmed robust induction of interferon-stimulated genes (ISGs) alongside modulation of inflammatory mediators and antigen presentation-associated genes. Module-level quantification showed that interferon signaling constituted the primary early transcriptional axis, whereas inflammatory cytokine programs displayed moderate induction and antigen presentation-associated genes exhibited distinct temporal dynamics. Association analysis demonstrated strong relationships between CIITA and downstream MHC class II genes, supporting coordinated antigen presentation regulation, while relationships between interferon and inflammatory modules were positive but non-proportional, indicating partial modular independence. Collectively, these findings reveal a structured yet non-uniform transcriptional organization in stimulated human dendritic cells, characterized by dominant interferon responses accompanied by context-dependent inflammatory activation and differentially associated antigen presentation programs. This integrative framework provides a reproducible systems-level approach for dissecting immune transcriptional architecture in human dendritic cell activation. Full article

Background: Aralia echinocaulis has therapeutic effects on rheumatoid arthritis (RA), with total polysaccharide and glycoside (TPGs) as main active components. RA pathogenesis involves gut microbiota dysbiosis and immune–metabolic crosstalk, but the role of microbiota-derived succinate in RA remains unclear. Objective: This study explored the role of succinate-GPR91 signaling in intestinal dendritic cells (DCs) in the context of RA and the therapeutic mechanism of A. echinocaulis TPGs. Methods: Collagen-induced arthritis (CIA) mice were treated with TPGs or exogenous succinate. Paw edema, inflammation, gut succinate levels, the Th17/regulatory T (Treg) balance, and DC activation via succinate-GPR91 were detected, and GPR91-targeting siRNA and CD4+ T-cell coculture assays for verification. Results: TPGs alleviated symptoms in CIA mice and restored the Th17/Treg balance by reducing intestinal succinate levels. Succinate activated DCs via GPR91 to promote Th17 differentiation, while TPGs suppressed DC maturation and Th17-driven inflammation, supporting the involvement of a gut-centric immunometabolic axis in RA. Conclusions: TPGs ameliorate RA by targeting the succinate-GPR91-Th17 pathway, identifying succinate as a novel RA target and TPGs as a potential microbiota-modulating agent. 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

Understanding host cell response to viral infection could lead to the identification of molecular targets that can be used for the development of diagnostics and therapeutics. In this study, we investigated human dendritic cell (DC) response to infections with Vaccinia (VAC) virus, a highly immunogenic poxvirus, and Venezuelan Equine Encephalitis (VEE) virus, a single-stranded positive-strand RNA alphavirus, using human gene expression microarrays. Comparative changes in DC mRNA expression resulting from infection by the two viruses at 1, 8, and 12 h post-infection (hpi) revealed distinct temporal dynamics. VAC infection triggered early and robust activation of pathways related to chromatin organization, DNA damage, and antigen presentation, while VEE infection exhibited delayed activation of immune signaling pathways, including interferon signaling and cytokine production. Shared pathways, such as interferon signaling and inflammasome activation, highlight universal antiviral responses and potential therapeutic targets. These findings provide a molecular framework affected by VAC and VEE that need to be validated with additional experiments, such as functional assays or in vivo studies. The specific up- or downregulation of these pathways at different time points likely dictates the overall outcome of the viral infection and could potentially lead to better understanding of the temporal regulatory dynamics of virus host response. Full article

Objectives: To analyze changes in ocular dendritic cells and their correlation with signs of keratitis in patients with herpes simplex stromal keratitis (HSK) using in vivo confocal microscopy (IVCM). Methods: This was a retrospective, cross-sectional, controlled, single-center study. Fifty-nine eyes from 59 patients with HSK and 40 eyes from 40 control subjects were studied. Each patient underwent IVCM and slit-lamp examinations. The density, area, size, and number of dendritic cells (DCs) in the corneas of both groups were analyzed. The severity of HSK was assessed, and the morphology and density of DCs in the cornea in the HSK group, categorized by ocular parameter severity levels, were compared with those in the control group. Results: DC density was significantly greater in patients with HSK than in controls. The DC field and size and the number of branches were also significantly greater in the HSK group. Furthermore, the DC density increased and morphological changes were exacerbated with increasing degree of corneal edema. The DC density was significantly increased and morphological changes were significantly exacerbated in the HSK group compared to the control group, even in those with the mildest cases of HSK. Conclusions: DC density and morphological changes correlate with the degree of corneal edema in patients with HSK. Changes in DC density and morphology can be observed even in mild cases of HSK. IVCM may be a powerful tool for monitoring ocular surface immune responses in patients with HSK, aiding in the clinical diagnosis and management of this disease. Full article

Background: In an earlier murine model of myocardial infarction (MI), we showed that CD8 cells and myeloid dendritic cells (mDCs) infiltrate the infarcted myocardium within the first week. However, in humans, the spatial interplay between CD8⁺ T cells and dendritic cells in the spatial context of human myocardial infarction remains underexplored. Objective: In the present study, we applied spatial transcriptomics and functional assays to characterize immune–stromal dynamics in infarcted myocardium and peripheral blood. Methods & Results: Spatial transcriptomics analysis of infarcted human myocardium at days 2 and 6 post-MI, combined with peripheral blood flow cytometry and EPC colony-forming assays, was performed. Cell composition, pathway enrichment, and cell-to-cell communication analyses were conducted to map immune–stromal cells’ dynamics across time points. Spatial mapping identified dynamic shifts in immune, fibroblast, and endothelial populations, with fibroblasts and endothelial cells remaining abundant throughout. CD8⁺ T cells accumulated in ischemic regions while their circulating levels declined. Gene Ontology and pathway analyses of CD8A⁺ transcripts revealed enrichment of proinflammatory and NF-κB survival programs. ITGAX/CD33/THBD⁺ APCs progressively increased within infarct zones, activating antigen-presentation and leukocyte chemotaxis pathways. Early (day 2) APC–endothelial crosstalk showed the strongest predicted recruitment signals for CD8⁺ T cells, which diminished by day 6. Finally, EPC colony-forming capacity showed a tendency for reduction in MI patients and inversely correlated with coronary lesion burden, indicating impaired vascular repair potential. Conclusions: This integrative spatial and functional study demonstrates that APC-driven CD8⁺ recruitment and EPC dysfunction are key features of human MI. Immune–endothelial niches facilitate early cytotoxic T-cell infiltration, while progenitor depletion limits vascular regeneration. These findings provide mechanistic insight into immune–vascular imbalance during infarct healing and highlight potential therapeutic targets to modulate inflammation and restore vascular repair. Full article

Background: The combination of photodynamic therapy (PDT) and immunotherapy has been explored as an innovative approach to enhance efficacy against tumors. However, PDT shows limited effectiveness in treating deep-seated tumors, as light and lasers do not sufficiently penetrate tissue. Methods: Herein, we introduced a nanocarrier (NP_VR) via self-assembly, using an amphiphilic copolymer to co-deliver the hydrophobic photosensitizer verteporfin (VP) and the immunoadjuvant imiquimod (R837). Results: Our X-ray-induced photodynamic therapy (X-PDT) mechanism induced NP_VR to generate a large amount of cytotoxic reactive oxygen species (ROS), which directly killed cancer cells. Moreover, the released R837 facilitated immunogenic cell death following the X-PDT process and promoted the maturation of dendritic cells (DCs), thereby eliciting immune responses against malignant triple-negative breast cancer (TNBC). In animal experiments, the combined therapy using NP_VR showed a tumor growth inhibition rate of ~70%. Conclusions: This novel strategy opens new avenues to designing next-generation nanomedicines for use in immunotherapy and other combination therapies. Full article

Dendritic cells (DCs) are key sentinels in the lung mucosa that interpret environmental signals to either promote tolerance or trigger inflammation, influencing the development of chronic lung diseases. This review highlights recent mechanistic insights showing that metabolic checkpoints serve as upstream regulators of DC fate and activity: inflammatory stimuli activate HIF-1α/mTOR-linked glycolytic pathways that drive maturation, cytokine secretion, antigen presentation, and migration. In contrast, AMPK-related oxidative and lipid metabolism pathways support tolerogenic states that encourage regulatory T-cell responses and inhibit checkpoints like PD-1/PD-L1. We also present evidence that DC subset specialization (cDC1 vs. cDC2) and their tissue location interact with these metabolic pathways to regulate lymphoid tissue formation, including the development and persistence of tertiary lymphoid structures in chronically inflamed lungs. These ectopic lymphoid tissues enhance local immune responses through DC–stromal interactions and ongoing T follicular helper–B cell communication, contributing to persistent inflammation and tissue remodeling in conditions such as COPD, asthma, pulmonary hypertension, and fibrotic interstitial lung disease. Finally, we discuss the translational potential of targeting this immunometabolic–lymphoid pathway, suggesting that modulating metabolic regulators, migratory circuits, and tolerogenic programs could restore immune balance while maintaining host defense—a promising framework for developing advanced therapies for chronic lung inflammation. Full article

Background/Objectives: Osteoarthritis (OA) is a chronic inflammatory disease with limited disease-modifying therapies. This study explored a novel immunomodulatory approach using autologous, antigen-pulsed semi-mature dendritic cells (DCs) to modulate the inflammatory milieu in knee OA patients. Methods: In this open-label, quasi-experimental study, 29 subjects received a single subcutaneous injection of autologous DCs. Outcomes assessed at baseline and 4 weeks included the WOMAC index for symptoms and serum levels of IL-6 and TNF-α. Responses were analyzed in the overall cohort and by BMI subgroups. Results: The overall cohort showed a non-significant trend in WOMAC improvement (p = 0.080) and no change in IL-6 (p = 0.785) or TNF-α (p = 0.330). Subgroup analysis revealed differential patterns of response: WOMAC scores improved significantly only in normal-weight patients (p = 0.030), while serum TNF-α decreased significantly only in overweight patients (p = 0.025). IL-6 levels were unchanged across all groups. Conclusions: Autologous antigen-pulsed DC administration was associated with differential responses across BMI subgroups. Symptomatic benefit was observed in normal-weight individuals, while a reduction in systemic TNF-α occurred in overweight patients. These findings suggest that the host metabolic state may modulate the response to DC-based immunotherapy, and therefore warrant validation in a randomized, placebo-controlled trial. Full article

Background/Objective: Dietary polysaccharides are increasingly recognized as functional nutritional components that support human health through modulation of immune function. However, clinical evidence linking their intake to site-specific upper respiratory mucosal immune health in humans remains limited. This study investigated whether dietary β-1,3/1,6-glucan (SC-BG) from baker’s yeast may support upper respiratory mucosal immune health in healthy adults. Methods: Following in vitro assays on human dendritic cells (DCs), a randomized, double-blind, placebo-controlled parallel-group trial was performed in healthy adults (18–69 years) who consumed either SC-BG or placebo capsules for 12 weeks in Japan. The primary outcome was circulating DC activation. Secondary outcomes were mucosal immune markers including secretory immunoglobulin A (s-IgA) and lysozymes from site-specific mucosal swabs (posterior oropharyngeal wall/nasopharynx) and salivar, and self-perceived upper respiratory tract symptoms. Results: SC-BG increased CD80 expression in DCs in vitro. In the clinical trial, 40 participants were randomized (n = 20 per group), and 39 (SC-BG: n = 19, placebo: n = 20) were analyzed. At week 8, the SC-BG group showed higher cDC1 CD80 expression than placebo. SC-BG intake also attenuated declines in s-IgA levels in the posterior oropharyngeal wall and nasopharynx and increased salivary lysozyme concentrations. Participants receiving SC-BG reported fewer cumulative days with upper respiratory tract-related local and systemic symptoms. No test food-related adverse events were observed. Conclusions: These findings provide preliminary clinical and mechanistic observations suggesting that dietary SC-BG may enhance circulating cDC1 activation and may help support upper respiratory local mucosal immune health in healthy adults, highlighting the potential of dietary polysaccharides as functional nutritional strategies for maintaining immune resilience. Full article

Herpes simplex virus type 2 (HSV-2) is the primary pathogen responsible for genital herpes. Predominantly transmitted via sexual contact, HSV-2 not only poses significant physical and psychological burdens on infected individuals but also substantially elevates the risk of HIV acquisition and represents a potentially fatal threat to newborns. Following primary infection, HSV-2 establishes lifelong latent infection within the sacral ganglia. Currently, there are no vaccines or therapeutics capable of eradicating this latent virus reservoir or effectively preventing initial infection. The core impediment to developing such interventions lies in the incomplete elucidation of the protective immune mechanisms against HSV-2 and its precise molecular pathogenesis. The host immune response against HSV-2 hinges critically on the coordinated interplay between innate and adaptive immunity. The innate immune system, serving as the first line of defense, acts to curtail early viral replication and initiate adaptive responses. This is achieved through mechanisms, including the genital mucosal barrier, activation of Toll-like receptors (TLRs), the cGAS-STING signaling pathway, interferon (IFN)-mediated antiviral effector functions, and activation of innate immune cells such as natural killer (NK) cells and dendritic cells (DCs). Crucially, however, HSV-2 counteracts these host defenses by expressing immune modulatory proteins (e.g., ICP0, ICP27, ICP35) that target key host antiviral signaling pathways, thereby affecting immune evasion. Within the adaptive immune response, neutralizing antibodies generated by the humoral immunity can provide localized protection at mucosal sites, but their protective efficacy is limited due to sophisticated viral immune evasion mechanisms. Cellular immunity, particularly mediated by CD4+ T cells, constitutes the core mechanism for viral clearance and suppression of recurrent outbreaks. Notably, tissue-resident memory T cells (TRMs) play a pivotal role in controlling the reactivation of latent HSV-2 within the ganglia. This review integrates current research advances to delineate the innate and adaptive immune mechanisms engaged during HSV-2 infection from the perspective of the dynamic host–virus interplay, with an ultimate aim to provide a theoretical foundation informing the rational development of preventive vaccines and therapeutic agents against HSV-2. Full article