Search Results (110)

Ocular diseases, such as neovascular age-related macular degeneration (nAMD) and proliferative vitreoretinopathy (PVR), have a fibrotic component that negatively impacts vision. Unfortunately, few treatments are available to mitigate fibrosis in the eye. The clearance of inflammatory cells proceeds, at least in part, through the intrinsic cell death pathway in which Bcl-2 family members play integral roles. Here, we assessed the influence of Bcl-2 expression in mononuclear phagocytes (MP) on the engagement and clearance of inflammatory cells, choroidal neovascularization (CNV), and subsequent subretinal fibrosis in a mouse laser-induced CNV model. Lack of Bcl-2 expression in MP (Bcl-2^MP mice) decreased neutrophil (Gr1⁺) and microglia (Iba1⁺) presence without impacting M1 (CD80⁺) and M2 (CD206⁺) macrophage presence, CNV, or fibrosis during the first 2 weeks following laser photocoagulation. Later, after inflammation dampens, decreased later-stage fibrosis and CNV were noted in Bcl-2^MP mice, which were accompanied by increased presence of M2 macrophages (CD206⁺). However, how these increased levels of CD206⁺ M2 macrophages in the absence of Bcl-2 contribute to decreased CNV and fibrosis remains unknown. To address whether Bcl-2 expression affects other forms of ocular fibrosis, we utilized the dispase PVR model. Bcl-2^MP mice, or treatment of wild-type mice with Bcl-2 inhibitors, significantly decreased fibrosis in the PVR model. Furthermore, Bcl-2 inhibitors mitigated CNV and fibrosis (collagen I-defined) in wild-type mice during laser photocoagulation. Thus, inhibition of Bcl-2 activity prevents the late-stage clearance of CD206⁺ M2 macrophages during nAMD and PVR, mitigating ocular neovascularization and fibrosis. Full article

The omentum is an important immune surveillance organ located in the abdominal cavity, especially noteworthy in diseases displaying tropism for the mononuclear phagocyte system, such as canine leishmaniosis (CanL). In this context, this study aimed to evaluate the immune-inflammatory response of the omentum in dogs naturally infected with Leishmania infantum through systemic inflammatory biomarkers and anatomopathological alterations. A total of 40 dogs were investigated, comprising 10 seronegative animals and 30 symptomatic seropositive dogs with CanL. Following clinical and laboratory evaluations, median celiotomy was performed and omental samples sent to histopathological analyses. Infected dogs displayed normocytic normochromic anemia, dysproteinemia, hypoalbuminemia, hyperglobulinemia, significant reductions in albumin-to-globulin ratios (AGR), and increased neutrophil-to-albumin ratios (NAR), with these as the main inflammatory biomarkers. Microscopically, chronic inflammatory infiltrates presenting a predominant lymphoplasmacytic pattern were observed, associated with hyperemia, fibrosis, and granulomas, in addition to the presence of amastigote Leishmania spp. forms within the macrophage cytoplasm. A strong association was observed between histological inflammation grade and inflammatory pattern, whereas erythrogram parameters showed progressive reductions with increasing inflammatory grades. The omentum is, thus, noted as actively participating in CanL immunopathogenesis, acting as a potential niche for parasite persistence and a complementary indicator of systemic disease severity, while AGR and NAR demonstrate potential diagnostic and prognostic value for the clinical monitoring of canine leishmaniosis. Full article

This review offers an in-depth look at the diagnostic and therapeutic potential of MNPs as superparamagnetic and high-surface-area-to-volume entities, considering their applications in MRI, magnetic hyperthermia, and targeted drug delivery. Based on an integrative approach, which includes systematic searches in 3 main bibliographic databases, 870 articles, semantic network analysis, Retrieval-Augmented Generation (RAG), and gap classification (Miles’ taxonomy), our analysis identifies a constant gap between lab performances and in vivo applications, described through eight critical challenges. The development of MNP-based biotechnologies is largely hindered by open issues in terms of safety, standardization, and control of the nanobio interface, mainly incomplete physicochemical characterization and poor methodological harmonization, because the high sensitivity of MNPs to synthesis routes and scale is a major bottleneck for GMP-compatible translation. Moreover, the analysis of in vivo data suggests that, on average, less than 1% of the injected dose accumulates in solid tumors, whereas a substantial fraction is diverted to non-target organs, particularly those associated with the mononuclear phagocyte system, reinforcing concerns regarding off-target sequestration, incomplete clearance, and long-term safety. Other critical challenges include complex interactions with biofluids, lack of unifying conceptual frameworks, limited experimental validation, underexploited methodological integration, and geographical and biological biases. Consequently, successfully overcoming these challenges will require the early and deliberate integration of rigorous materials engineering, mechanistic biological insight, and application-oriented validation for robust, reproducible, and translatable magnetic nanoplatforms. Full article

The micro-immunotherapy medicine (MIM) 2LEID-N^® was developed to sustain immune response, notably in the framework of respiratory infections. This pilot study investigated the potential effects of one capsule of this MIM, referred to as 2LEID-N-9 throughout the manuscript, containing IL-12 (5 CH), IFN-γ (6 CH), and TNF-α (5 CH). Phagocytosis and surface marker expression were assessed using flow cytometry, and cytokine secretion was assessed by ELISA. Cellular models included human monocyte-derived macrophages, peripheral blood mononuclear cells (PBMCs) from healthy donors, and THP-1 cells. Liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS/MS) was used to detect the actives. Compared with vehicle control, 2LEID-N-9 showed a trend towards the enhanced phagocytic activity of macrophages. In PBMCs, 2LEID-N-9 upregulated the secretion of several cytokines, including IL-2, IL-4, IL-13, IFN-γ, and TNF-α in both basal and CD3/CD28-stimulated conditions. Notably, a tendency towards increased secretion of TNF-α was found in LPS-stimulated THP-1 cells. The presence of the three actives, as assessed by LC-HRMS/MS, combined with the functional data, provide promising exploratory evidence of immunomodulatory effects and tendencies towards the stimulation of innate and adaptive immune cells, warranting further investigation. Full article

Trained immunity refers to the enduring functional reprogramming of innate immune cells after particular stimuli, driven by epigenetic and metabolic alterations that augment non-specific responses upon subsequent exposure. Neutrophils and monocytes/macrophages, as essential innate effectors, are crucial for the induction and control of trained immunity, which is the primary emphasis of this review. Neutrophils, the predominant circulating leukocytes, were historically considered incapable of memory owing to their brief lifespan. Emerging evidence indicates that trained immunity functions at the bone marrow progenitor level, influencing granulopoiesis to produce neutrophils with lasting functional modifications. This research offers new insights into neutrophil functions in infection, cancer, and inflammation. Monocytes and macrophages, characterized by phenotypic plasticity and tissue residence, function as conventional models of trained immunity. They experience direct peripheral reprogramming or emerge as primed descendants of trained bone marrow precursors, performing pro-inflammatory or reparative roles in malignancies, infections, and ischemia lesions. This study comprehensively outlines the regulatory mechanisms of trained immunity in these cells, clarifies their functions in various clinical situations, and examines therapeutic applications. Comprehending these pathways is crucial for elucidating the cellular foundation of innate immunological memory, uncovering its multiple functions in disease, and guiding innovative therapeutics aimed at granulopoiesis and monocyte-macrophage polarization. Full article

Curcumin, a natural polyphenol derived from Curcuma longa, is widely recognized for its therapeutic properties. However, its clinical utility is limited because of poor solubility, rapid degradation and hence low bioavailability. To overcome these issues, nanoformulation approaches, especially PEGylated liposomes, have been explored as advanced delivery systems. PEGylation, which involves attaching polyethylene glycol (PEG) to the liposomal surface, enhances circulation time by creating a steric shield that reduces protein interactions and clearance by the mononuclear phagocyte system (MPS). However, PEG can alter lipid membrane properties, which may in turn affect curcumin’s solubility and distribution within the liposomal bilayer, ultimately reducing its loading efficiency. To ensure that PEG-modified liposomes can be effectively loaded with curcumin, we investigated curcumin–membrane interactions in saturated (DMPC) and unsaturated (POPC) liposomes, both in the presence and absence of PEG. Based on dissociation constants (K_d) obtained from fluorescence spectroscopy measurements, we found that PEGylated DMPC liposomes exhibit the strongest binding affinity for curcumin. Fluorescence quenching experiments showed that curcumin adopts a transbilayer orientation in all membranes examined. Curcumin’s location within PEGylated and non-PEGylated liposomal membranes was further confirmed by examining its effects on membrane properties, including fluidity, polarity, and oxygen transport. These effects were investigated using electron paramagnetic resonance (EPR) spectroscopy with spin labels. The results indicate that PEG does not impose major changes on membrane properties. Curcumin, however, was found to reinforce the liposomal membranes, increase their polarity, and reduce oxygen availability. Overall, the findings suggest that liposomes, particularly those composed of PEGylated DMPC, are effective vehicles for curcumin delivery. Full article

siRNA, as a precise, specific, and highly effective gene-silencing therapy, has been extensively studied. Before reaching tumor cell targets, siRNA formulations must overcome multiple extracellular barriers, including clearance from the bloodstream, membrane impermeability, capture by the mononuclear phagocyte system (MPS), rapid renal excretion, endosomal escape, and precise recognition of target cells. These challenges limit siRNA’s clinical application. Consequently, various modifications have been applied to siRNA to enhance transfection efficiency, while researchers continue to pursue improved siRNA-targeting delivery systems. Nanotechnology offers a rational technical approach to address siRNA delivery. Nanoparticles can increase transfection efficiency while exhibiting lower cytotoxicity and reduced off-target effects. Various matrices have been employed to construct nanoparticles for targeted therapeutic delivery. This review briefly discusses siRNA nanoparticle delivery strategies, illustrates examples of various siRNA nanodelivery systems, such as lipid nanoparticles, polymeric siRNA nanoparticles, inorganic nanoparticles, hybrid nanoparticles, and conjugate-siRNA delivery systems, and introduces clinical trials of siRNA-loaded nanoparticles for cancer treatment, which can provide valuable references for further research and clinical application of siRNA nanoparticle delivery systems. Full article

Chronic alcohol consumption increases the risk of osteoporosis and fracture by disrupting bone remodeling, in part by enhancing osteoclastogenesis. However, the cellular mechanisms underlying this process remain incompletely defined. We analyzed scRNA-seq data from osteoclasts differentiated in vitro from bone marrow mononuclear cells obtained from macaques following 12 months of chronic ethanol or isocaloric control solution consumption. Module scoring, trajectory inference with generalized additive modeling (tradeSeq), and CellChat-based analyses of intercellular communication were applied to uncover ethanol-induced changes in metabolic reprogramming, lineage progression, and signaling network dynamics. Module scoring indicated metabolic reprogramming toward oxidative phosphorylation, with reduced glycolytic, migratory, and phagocytic activities. Pseudotime analysis revealed accelerated osteoclast lineage commitment, broader intermediate differentiation states, and stabilization of mature osteoclasts. CellChat analysis showed globally amplified intercellular signaling, with mature osteoclasts functioning as dominant communication hubs sustained by autocrine feedback. Together, chronic alcohol consumption rewired osteoclastogenesis through early fate priming, metabolic adaptation, and hierarchical remodeling of intercellular communication, promoting enhanced osteoclastogenesis. These findings provide mechanistic insight into alcohol-induced bone pathology and highlight potential targets for therapeutic intervention. Full article

Neuroinflammation mediated by reactive microglia, the immune cells of the brain, contributes to numerous neuropathologies. Damage-associated molecular patterns (DAMPs), released from stressed or damaged cells, are implicated in neuroinflammation. Succinate, a tricarboxylic acid cycle intermediate, can accumulate intracellularly and be released into the extracellular space where it may function as a DAMP-like molecule. However, its specific roles in central nervous system (CNS) neuroimmune responses, particularly when acting extracellularly, remain largely unexplored. This study utilizes cell membrane-impermeable disodium succinate to model extracellular action and cell-permeable diethyl succinate to assess the intracellular activity of this metabolite in cell culture models. We demonstrate that extracellular disodium succinate significantly reduces the secretion of pro-inflammatory cytokines tumor necrosis factor-α (TNF) and interleukin (IL)-6, and lowers neurotoxic and phagocytic activities of immune-stimulated BV-2 murine microglia. It also rescues lipopolysaccharide (LPS)-induced decreases in mitochondrial respiration in human peripheral blood mononuclear cells (PBMCs) used as microglia models, which correlates with its actions on phagocytosis. In contrast, while intracellular diethyl succinate reduces TNF and IL-6 secretion, it does not reduce BV-2 microglia toxicity towards murine NSC-34 neuronal cells, indicating location-dependent effects. These results support extracellular succinate as a novel CNS DAMP with a predominantly anti-inflammatory action on microglia. Full article

Liposomes remain one of the most utilized drug delivery systems due to their numerous advantages. However, they face significant challenges primarily due to their low colloidal stability as well as their rapid clearance by the reticuloendothelial and mononuclear phagocyte systems. Surface modifications have been identified as a highly effective approach to address these challenges. Various molecules can be utilized as surface modifiers. However, polysaccharides are widely employed in this regard, due to their unique characteristics, such as biocompatibility, biodegradability, and non-toxicity, as well as their ability to interact with the liposomal surface through different mechanisms. The aim of the present review is to provide a thorough analysis of polysaccharide-modified liposomes, highlighting recent advancements in their design, synthesis, and therapeutic applications. The utilization of polysaccharides as surface modifiers has been demonstrated to have several notable effects on liposomes. These effects include the enhancement of liposome properties, the provision of “stealth” properties, and the augmentation of colloidal stability. This review provides a comprehensive, polysaccharide-oriented analysis of liposomal surface modification strategies, along with a novel focus on the correlation between polysaccharide structure, modification method, and the resulting physicochemical and biological performance of the designed hybrid liposomes across a wide range of applications. Full article

Background/Objectives: Advanced drug delivery systems (DDSs) are essential for targeted delivery, controlled release, and reduced systemic toxicity, but their clinical adoption is limited by biological barriers, manufacturing complexities, and cost. The aim of this systematic review is to critically evaluate the quantitative relationships between platform design, overcoming biological barriers, and clinical translation outcomes for DDS developed between 2016 and 2025. Methods: A comprehensive literature search was conducted in PubMed/MEDLINE, Scopus, and Web of Science (January 2016–April 2025) in accordance with the PRISMA 2020 guidelines. Included studies focused on experimental or clinical data for nanocarrier platforms (liposomes, lipid nanoparticles, polymer systems, biomimetic carriers, extracellular vesicles). Data on platform characteristics, interactions with barriers, pharmacokinetics, manufacturing, and clinical outcomes were extracted and synthesized in narrative form due to the significant methodological heterogeneity. Results: An analysis of 77 included studies confirms that successful clinical translation depends on matching the physicochemical properties of the carrier (size, surface chemistry, material) to specific biological barriers. Liposomes and lipid nanoparticles (LNPs) remain the most clinically validated platforms, exploiting the EPR effect and liver tropism, respectively. Key engineering solutions include stealth coatings, ligand-mediated targeting, and stimulus-responsive materials to overcome barriers such as mononuclear phagocyte system clearance, the blood–brain barrier, and mucosal barriers. Microfluidic and continuous manufacturing processes enable reproducibility, but scalability, cost, and immunogenicity (e.g., anti-PEG responses) remain key translational challenges. Engineered extracellular vesicles, biomimetic carriers, and 3D/4D-printed systems combined with AI-driven design demonstrate the potential for personalized, adaptive delivery. Conclusions: Cutting-edge DDSs have validated their clinical value, but realizing their full potential requires a holistic, patient-centered design approach integrating barrier-specific engineering, scalable manufacturing, and rigorous safety assessment from the earliest stages of development. Further progress will depend on standardizing methods for new platforms (e.g., extracellular vesicles), implementing digital and AI tools, and ensuring translational feasibility as a fundamental principle. Full article

Background: Microglial cells are the resident immune cells in the central nervous system (CNS) and constitute the brain’s innate immune system. They are the smallest of the glial cells and are derived from phagocytic white blood cells, fetal monocytes, which migrate from the blood into the brain during development. On the other hand, epilepsy is a chronic condition defined as recurrent unprovoked seizures, with at least two seizures occurring over 24 h apart. Methods: To determine the role of microglial activation in the pathogenesis of drug-resistant epilepsy, we systematically searched published data for biomarkers of microglial activation from main databases including PubMed, PubMed Central, Scopus, Embase, Google Scholar, and Medline. Two research registries were also searched: the Cochrane Registry and clinicaltrial.gov. Data was collected after applying inclusion and exclusion criteria and studies were appraised critically. Both Medical Subject Headings (MeSH) and regular keyword search strategies were employed. Results: Our systematic review shows significant elevation of biomarkers of microglial activation in patients with drug-resistant epilepsy, suggesting its role in the disease’s pathogenesis. Conclusions: Microglia cells are therefore considered as a special type of mononuclear phagocytes found in the CNS that plays important roles in both the brain’s immunity and homeostatic functions. The role of microglial activation in the pathogenesis of drug-resistant epilepsy is an active area of study, with potential therapies for drug-resistant epilepsy that target microglia currently being investigated. Full article

Biomimetic cell membrane-coated nanoparticles (BMCNPs) are an attractive drug delivery platform that combines the advantages of an inorganic core with the biological functionality of a natural cell membrane. This hybrid design merges the versatility of engineered nanomaterials with the complexity and specificity of biological systems, enabling prolonged circulation, immune evasion, enhanced tissue targeting, and improved therapeutic efficacy. In this review, we explore the in vivo behavior of BMCNPs, focusing on their interactions with biological barriers, including evasion of mononuclear phagocyte system clearance, biodistribution patterns, and circulation kinetics. We also examine how membrane source and surface properties influence targeting efficiency and delivery outcomes, while highlighting key considerations and emerging strategies to optimize therapeutic performance and translational potential. Full article

Background/Objectives: Resistin is an adipokine involved in obesity pathogenesis, but its effects on blood and colostrum immune cells from obese mothers remain unclear. This study evaluated the functional activity of phagocytes modulated by resistin in blood and colostrum from overweight and obese mothers. Methods: An observational study was conducted with 82 postpartum women divided according to pregestational BMI into control, overweight, and obese groups. Blood and colostrum samples were collected to determine resistin levels and assess the functional activity of mononuclear (MN) cells. Results: Plasma resistin levels were higher in overweight mothers, whereas colostrum levels were lower in obese mothers. Resistin treatment enhanced superoxide release in both colostrum and blood phagocytes, independent of maternal weight status. In the presence of enteropathogenic Escherichia coli (EPEC), resistin-treated phagocytes from both colostrum and maternal blood showed increased superoxide production. In blood cells from overweight mothers, resistin reduced superoxide dismutase (SOD) concentration, while in colostrum, the highest SOD levels were observed in cultures of resistin-treated cells from mothers with altered weight, regardless of weight status. Blood and colostrum cells treated with resistin increased phagocytosis rates. In colostrum, resistin-treated cells from eutrophic mothers showed high microbicidal indices, whereas cells from mothers with altered weight showed reduced microbicidal indices. In colostrum cells, adipokine levels were reduced in the obesity group. Conclusions: Resistin modulates oxidative metabolism and the functional activity of blood and colostrum phagocytes across all maternal weight statuses, suggesting a possible role for resistin in the maternal immune response associated with obesity. Full article

Multidrug resistance (MDR) remains a formidable barrier to successful cancer treatment, driven by mechanisms such as efflux pump overexpression, enhanced DNA repair, evasion of apoptosis and the protective characteristics of the tumour microenvironment. Nanoparticle-based delivery systems have emerged as promising platforms capable of addressing these challenges by enhancing intracellular drug accumulation, enabling targeted delivery and facilitating stimuli-responsive and controlled release. This review provides a comprehensive overview of the molecular and cellular mechanisms underlying MDR and critically examines recent advances in nanoparticle strategies developed to overcome it. Various nanoparticle designs are analysed in terms of their structural and functional features, including surface modifications, active targeting ligands and responsiveness to tumour-specific cues. Particular emphasis is placed on the co-delivery of chemotherapeutic agents with gene regulators, such as siRNA, and the use of nanoparticles to deliver CRISPR/Cas9 gene editing tools as a means of re-sensitising resistant cancer cells. While significant progress has been made in preclinical settings, challenges such as tumour heterogeneity, limited clinical translation and immune clearance remain. Future directions include the integration of precision nanomedicine, scalable manufacturing and non-viral genome editing platforms. Collectively, nanoparticle-based drug delivery systems offer a multifaceted approach to combat MDR and hold great promise for improving therapeutic outcomes in resistant cancers. Full article