Search Results (1,106)

In the human reproductive system, extracellular vesicles (EVs) have been recognized as playing a vital role in mediating cell–cell communication. They are considered critical for embryo development, implantation, gamete interaction, and fertilization. The various cargoes carried by EVs, depending on the physiological and pathological state of the cell, include proteins, lipids, nucleic acids, and mitochondrial components. EVs are recognized as critical carriers of redox-related signals and mitochondrial components, linking oxidative stress (OS) to reproductive failure and influencing gamete quality and embryo competence. Although considerable progress has been made, research remains poorly integrated, despite individual omics technologies providing valuable molecular insights. The use of multi-omics technologies, including transcriptomics, proteomics, metabolomics, and microbiome analysis, has been proposed as a global approach to understanding the complexities associated with EVs and discovering new biomarkers associated with infertility. ML and AI have been proposed to identify predictive signatures linked to ART effectiveness and reproductive outcomes, with a strong capacity to handle high-dimensional data. The review aims to provide an overview of current knowledge on EV-mediated redox–mitochondrial signaling in human reproduction, while highlighting the importance of emerging multi-omics and AI technologies for EV-mediated biomarker development. The review discusses the promise of EVs in the development of minimally invasive diagnostic approaches and therapeutic interventions, as well as the challenges in the standardization, integration, and clinical translation of EV-mediated research. In addition, the review proposes integrating computational approaches to better understand molecular pathways involved in the development of next-generation precision medicine in human reproduction. Full article

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disorder arising from the convergence of genetic susceptibility, epigenetic remodeling, environmental exposures, and dysregulated immune networks. Although traditionally characterized by autoantibody production and immune complex mediated tissue injury, advances in genomics, systems immunology, and multi-omics profiling have revealed that lupus represents a multilayered failure of immune homeostasis driven by interconnected molecular circuits. Genetic variants enriched in regulatory immune enhancers establish a permissive transcriptional landscape that sensitizes innate nucleic acid sensing pathways and interferon signaling. Epigenetic remodeling further amplifies inflammatory transcriptional programs, while environmental triggers such as ultraviolet radiation and viral infection initiate bursts of nucleic acid release and immune activation. Defective apoptotic cell clearance, mediated in part by scavenger receptor dysfunction and complement abnormalities, increases the availability of immunogenic nucleic acids that engage pattern recognition receptors and drive chronic type I interferon production. This interferon-dominated environment rewires immune cell metabolism, alters differentiation trajectories of T and B lymphocytes, and sustains autoreactive immune circuits. Emerging multi-omics studies reveal distinct molecular endotypes defined by interferon signatures, metabolic states, and immune cell composition, highlighting the heterogeneity of disease mechanisms across patients. In this review, we integrate genetic, epigenetic, metabolic, and immunological insights to propose a systems-level model of lupus pathogenesis in which defective debris clearance, nucleic acid sensing, interferon amplification, and metabolic reprograming form a self-reinforcing pathogenic network. Understanding this integrated molecular architecture provides a foundation for biomarker-guided therapeutic strategies and precision medicine approaches aimed at disrupting the key nodes that sustain chronic autoimmunity in SLE. Full article

Background: Neglected diseases caused by protozoan parasites remain a major public health burden, particularly in low- and middle-income countries. Among the chemical motifs explored in antiparasitic drug discovery, guanidine-containing compounds have attracted considerable attention due to their strong cationic character, high capacity for hydrogen bonding, and versatility in interacting with biological targets. Methodology: This review summarizes advances reported in the last decade regarding guanidine derivatives with activity against pathogens associated with Chagas disease, human African trypanosomiasis, Leishmaniasis, tuberculosis, toxoplasmosis, dengue and schistosomiasis. Results: Evidence gathered from synthetic, natural, and drug-repurposing studies indicates that the guanidine, guanidine-containing and guanidine-related compounds contribute to modulating biological activity by changing electrostatic interactions, hydrogen-bonding networks, and physicochemical properties, with enzymes, nucleic acids, and membrane-associated targets essential for parasite survival. Across the analyzed studies, several emerging structure–activity relationship trends were identified, including the contribution of polycationic or dicationic architectures, the influence of halogenated or lipophilic substituents, and the dependence of biological activity on the complete molecular framework, including heterocyclic systems, macrocycles, peptide conjugates, hybrid scaffolds, and repurposed drugs. In addition to direct antiparasitic effects, certain guanidine-containing and guanidine-related compounds demonstrate immunomodulatory or host-protective properties, expanding the therapeutic relevance of this class. Despite promising in vitro results, protonation trapping, efflux pump susceptibility, and pharmacokinetic limitations such as poor oral absorption, high polarity, plasma protein binding and limited membrane permeability remain significant challenges for clinical translation. Nonetheless, the integration of medicinal chemistry, computational modeling, and biological screening continues to accelerate the identification of optimized scaffolds. Conclusions: Overall, guanidine-based compounds constitute a promising scaffold for the development of new therapeutic strategies targeting neglected parasitic diseases, and further structural optimization may enable the emergence of candidates with improved efficacy, selectivity, and drug-like properties. Full article

Pancreatic cancer (PC) remains one of the most aggressive and lethal malignancies worldwide, largely due to late diagnosis, aggressive biology, limited therapeutic options and responsiveness. Conventional diagnostic and monitoring strategies, including imaging and serum biomarkers such as CA 19-9, provide limited sensitivity for early detection and suboptimal accuracy for the dynamic assessment of treatment response and disease evolution. These limitations highlight the urgent need for innovative, minimally invasive approaches capable of improving patient stratification and guiding personalized management. In this context, liquid biopsy has emerged as a promising, minimally invasive approach able to capture tumor-derived molecular information through the analysis of circulating cell-free nucleic acids, including circulating cell-free DNA (cfDNA) and circulating cell-free RNA (cfRNA). Released into the bloodstream by tumor cells, these analytes offer a real-time and comprehensive snapshot of tumor biology, capturing genetic, epigenetic, and transcriptional alterations through a simple blood draw. Liquid biopsy-based analyses hold significant potential for early detection, prognostic assessment, therapeutic decision-making, monitoring of minimal residual disease, and identification of resistance mechanisms. This review discusses the current state of research on circulating cell-free nucleic acids in PC, highlighting their biological basis, methodological approaches, clinical potential, and the challenges limiting their widespread implementation. By underscoring their translational relevance, we aim to outline how integrated liquid biopsy strategies, alongside the need for standardization and cross-study harmonization, may contribute to a more precise and dynamic approach to PC management. Full article

This review investigates biomaterial-based strategies for improved treatment of MPXV. We focus on emerging synthetic biomedical approaches to combating the virus. These include peptide nucleic acids, CRISPR-based systems, and small-molecule therapeutics. These methods work by targeting and blocking viral proteins and enzymes. Such synthetic platforms may help reduce viral transmission and minimize side effects. They also offer potential solutions to challenges such as viral resistance in humans. In addition, biomaterials contribute to the development of more stable and effective vaccines. Combining these biomaterials with mRNA technology provides a promising framework for future vaccine development. Overall, this review underscores biomaterial-driven antiviral systems as a major frontier in translational medicine with profound implications for global health and pandemic awareness. Full article

Cancer immunotherapy has transformed oncology by harnessing the immune system to recognize and eliminate malignant cells. However, many cancers exhibit limited or variable responses to this class of treatment due to insufficient antigen presentation and impaired interferon (IFN) signaling, creating an immunologically “cold” tumor microenvironment (TME) characterized by poor immune cell infiltration and treatment resistance. Viral mimicry has emerged as a therapeutic strategy to overcome these limitations by reactivating innate antiviral pathways within tumor cells. Viral mimicry occurs through the reactivation of endogenous retroviruses (ERVs) and other retrotransposons (e.g., LINE-1), which subsequently stimulate downstream nucleic acid sensing pathways. The resulting type I/III IFN responses restore antigen presentation and attract cytotoxic immune cells, sensitizing resistant tumors to immunotherapy. However, systemic stimulation of these pathways can trigger context-dependent inflammation and adaptive resistance, highlighting the need for temporal and spatial control. In this review, we examine the mechanistic foundation and clinical trajectory of viral mimicry, with an emphasis on its potential integration with established treatments and engineered immune cell platforms. By identifying the molecular and clinical gaps, viral mimicry can be harnessed to enhance tumor-specific immune activation and overcome treatment resistance in cancer immunotherapy. Full article

The CRISPR-Cas systems, identified initially as adaptive immune mechanisms in bacteria and archaea against viral threats, have rapidly evolved into transformative tools in genetic engineering and biotechnology. These RNA-guided systems are broadly classified into Class 1, comprising multi-subunit complexes, and Class 2, characterized by compact single-effector protein, such as Cas9, Cas12, and Cas13. Their remarkable structural and functional diversity enables microorganisms to adapt to diverse ecological niches, offering a vast repertoire of genome-editing strategies. Beyond their natural role in maintaining genome integrity and defense, CRISPR-Cas systems have been extensively repurposed for precise genome modification, transcriptional regulation, epigenetic editing, and nucleic acid detection. Recent advances in computational mining of microbial genomes and metagenomes have uncovered a broad range of novel CRISPR effectors with unique properties, distinct protospacer adjacent motif (PAM) requirements, RNA-targeting capabilities, miniature architectures, and promiscuous cleavage activities that significantly expand the molecular biology toolkit. The development of CRISPR-based technologies such as base editing, prime editing, gene knock-in/out, and live-cell DNA/RNA imaging exemplifies the versatility of these systems. Despite the challenges associated with delivering complex Class 1 systems, both classes are now being actively harnessed across diverse microbial platforms. Concurrently, the CRISPR-Cas research, particularly for guide RNA (gRNA) design and activity prediction, has revolutionized target specificity and editing efficiency. This review presents a comprehensive overview of CRISPR-Cas system diversity, their genomic landscape in microorganisms, and their cutting-edge biotechnological applications. It also emphasizes the transformative potential of CRISPR in synthetic biology, therapeutics, diagnostics, environmental remediation, and agriculture, while also addressing the ethical and biosafety considerations surrounding its deployment. As CRISPR-Cas systems continue to evolve, they stand at the forefront of innovations that bridge natural microbial immunity with engineered precision tools for next-generation biotechnology. Full article

The lung represents a promising yet underexploited target for RNA therapeutics due to its large surface area and accessibility via non-invasive inhalation delivery. Despite rapid advances in RNA-based modalities, including small interfering RNA (siRNA), microRNA (miRNA), messenger RNA (mRNA), and CRISPR-Cas systems, efficient pulmonary delivery remains a major challenge. Multiple biological barriers, such as mucus and surfactant layers, mucociliary clearance, immune surveillance, and limited cellular uptake of negatively charged nucleic acids, significantly restrict therapeutic efficacy. In addition, aerosolization processes may introduce mechanical stress, compromising RNA integrity. Nanoparticle-based delivery systems have emerged as a central strategy to address these limitations. By protecting RNA cargo, enhancing mucus penetration, and promoting cellular internalization, engineered nanoparticles enable more effective pulmonary delivery. In this review, we adopt a barrier-centered perspective to examine the key biological obstacles to lung-targeted RNA delivery and highlight recent advances in nanoparticle-mediated strategies, with a focus on lipid nanoparticles, polymeric systems, and inorganic nanomaterials. We further discuss design principles that govern RNA stability, transport, and intracellular release and critically compare the strengths, limitations, and translational potential of each platform, including considerations of toxicity, biodegradability, and clinical readiness. Finally, we outline emerging clinical applications of RNA-loaded nanoparticles, using lung cancer as a representative disease model, and discuss remaining challenges and future directions. Continued innovation in nanoparticle engineering and delivery strategies is expected to accelerate the clinical translation of RNA therapeutics for pulmonary diseases. Full article

Cancer remains one of the leading causes of mortality worldwide, with increasing recognition of the host microbiome as a modifiable contributor to tumour initiation and progression. Among microbial mediators, outer membrane vesicles (OMVs) derived from Gram-negative oral pathobionts have emerged as critical effectors of host–microbe interactions. These nanoscale vesicles function as delivery systems for a diverse range of bioactive cargo, including virulence factors, lipopolysaccharides, proteins, and nucleic acids, enabling both local and systemic modulation of host cellular processes. Emerging evidence suggests that OMVs produced by oral pathobionts, particularly Porphyromonas gingivalis and Fusobacterium nucleatum, are associated with tumour-promoting inflammation, immune dysregulation, epithelial transformation, and metastatic progression. Mechanistically, OMVs have been shown to activate key signalling pathways, disrupt mitochondrial function, induce oxidative stress, and reprogram the tumour microenvironment in ways that favour cancer cell survival and immune evasion. In addition, OMV-mediated modulation of host responses has been linked to resistance to anticancer therapies. In this review, we synthesize current evidence on the role of oral pathobionts’ OMVs in cancer biology, with a focus on their contributions to tumour initiation, progression, and metastasis. We further discuss emerging clinical associations, the potential of OMV-derived components as diagnostic biomarkers, and the growing interest in engineered OMVs as platforms for therapeutic intervention. Finally, we highlight key challenges and knowledge gaps that must be addressed to advance the translational application of OMV-based strategies in oncology. Overall, OMVs represent a promising but still evolving link between the oral microbiome and cancer, offering new insights into disease mechanisms and potential avenues for diagnosis and therapy. Full article

Background/Objectives: Molecular tumor profiling has recently transformed oncologic care delivery, establishing precision medicine as an essential approach for defining cancer biology and revealing intratumoral heterogeneity. The growing accessibility of advanced nucleic acid sequencing technologies has created a demand for specialized expertise in interpreting comprehensive genomic profiling results. Academic institutions currently employ a strategy of conducting initial broad-spectrum genomic testing, followed by matching patients to investigational therapies targeting their specific genomic alterations. Consequently, molecular tumor boards (MTBs) have emerged predominantly within major cancer centers and academic medical institutions, providing the specialized knowledge necessary to translate precision oncology into routine clinical care. However, despite the substantial benefits of collaborative case review within tumor boards, clinicians frequently encounter multiple barriers to effective MTB implementation. Methods: this report examines these challenges performing an exploratory quantitative synthesis approach and explores implementation strategies and best practices derived from collective institutional experiences, with the goal of establishing a functional MTB at the local level and thereby expanding oncology patient access to cutting-edge therapeutic options. Full article

Sepsis remains a leading cause of mortality worldwide and is increasingly recognized as a syndrome of dynamic immune dysregulation rather than a uniform inflammatory condition. The traditional paradigm of sequential hyperinflammation followed by immunosuppression has been replaced by a more complex view in which these processes coexist and evolve over time, contributing to marked interindividual variability in clinical outcomes. Despite advances in supportive care, current diagnostic and therapeutic approaches are still largely non-specific and fail to account for this biological heterogeneity. Extracellular vesicles (EVs) have emerged as key mediators of intercellular communication and potential integrators of immune activity in sepsis. These nanosized particles carry proteins, nucleic acids, lipids, and metabolites that reflect the functional state of their cells of origin and actively participate in immune regulation. Experimental and clinical evidence indicate that EVs exert context-dependent effects, contributing both to the propagation of inflammatory processes and the establishment of immunosuppressive states through the transfer of regulatory signals. Beyond their mechanistic role, EVs represent a promising platform for immune monitoring. Their cell-specific and dynamic molecular signatures have been associated with disease severity, organ dysfunction, and clinical trajectories, suggesting their role as biomarkers for patient stratification. In parallel, engineered and stem cell-derived EVs are being explored as therapeutic vectors capable of modulating immune responses and restoring immune homeostasis. In this review, we examine current concepts of immune dysregulation in sepsis and discuss how EVs may serve as both mediators and decoders of immune heterogeneity. We propose that EV-based approaches could bridge the gap between high-dimensional immunological profiling and precision immunotherapy, enabling more adaptive and individualized management of septic patients. Full article

Magnesium is an essential divalent cation required for adenosine triphosphate (ATP)-dependent reactions, nucleic acid metabolism, and ribosomal stability. Bacteria depend on specialized transport systems to maintain intracellular Mg²⁺ homeostasis as it cannot freely cross the phospholipid bilayer. During infection, host nutritional immunity restricts metal availability, and magnesium limitation within the phagosome compromises bacterial metabolism and stability. This review summarizes the major bacterial magnesium transport systems and their roles in survival and pathogenicity, with an emphasis on Salmonella and extension to clinically relevant ESKAPE pathogens. We focus on the PhoPQ-regulated MgtA, MgtB, and MgtC system, in which low magnesium, acidic pH, and other host-derived signals activate PhoPQ to induce mgt gene expression. MgtA and MgtB act as high-affinity P-type ATPases, whereas MgtC promotes bacterial survival within the intramacrophage environment by inhibiting bacterial F-type ATP synthase through specific interactions with subunit a. We also discuss CorA as a conserved channel for basal Mg²⁺ uptake and MgtE as a Mg²⁺-selective channel whose gating responds to intracellular Mg²⁺ and ATP. Finally, we consider the conservation and variation in these systems across pathogenic bacteria and their potential as therapeutic targets for antimicrobial development. Full article

Neurodegenerative diseases, characterized by progressive neuronal loss and functional decline, impose a substantial global health burden. Autophagy, the principal intracellular degradative pathway for clearing misfolded proteins and damaged organelles, is vital for neuronal homeostasis, whereas maladaptive neuroinflammation is increasingly being recognized as a central driver of disease progression. A growing body of evidence indicates a bidirectional, tightly coupled relationship between autophagy and neuroinflammation: impaired autophagic flux promotes accumulation of damage-associated molecules that activate innate immune responses, while sustained inflammatory signaling further disrupts autophagy, together forming a self-reinforcing cycle that accelerates neurodegeneration. This interplay is regulated by diverse genetic, molecular, cellular, and environmental factors and manifests in cell-type-specific ways across microglia, astrocytes. Therapeutic strategies emerging from these insights include modulation of autophagic pathways (e.g., mTOR, AMPK, TFEB), targeted inhibition of inflammasome and pro-inflammatory mediators (notably NLRP3-related signaling), and delivery platforms for small molecules or nucleic acids, with increasing interest in multi-target and stage-specific interventions. This review integrates mechanistic evidence and translational advances, highlights gaps in cell-type and stage-specific understanding, and outlines priorities for developing safe, effective therapies that target the autophagy–neuroinflammation axis in neurodegenerative disorders. Full article

Extracellular vesicles (EVs) are nanoscale membrane-bound particles that mediate intercellular communication by transferring proteins, nucleic acids, lipids, and metabolites. Increasing evidence implicates EVs in Alzheimer’s disease (AD) pathogenesis through the propagation of amyloid-β, tau, and neuroinflammatory signals across neural and glial networks. In parallel, EVs isolated from biofluids have emerged as promising sources of disease-associated biomarkers and potential therapeutic carriers. This review aims to synthesize current evidence on EV-mediated mechanisms in AD, evaluate the diagnostic value of EV-associated biomarkers, and discuss emerging EV-based and bioengineered therapeutic strategies. We summarize how EVs derived from neurons, astrocytes, microglia, and peripheral cells contribute to amyloid-β and tau spread, neuroinflammation, synaptic dysfunction, and metabolic stress in AD. Disease-associated alterations in EV cargo from blood, cerebrospinal fluid, and urine are critically assessed for biomarker applications. We further highlight advances in EV bioengineering, including cargo loading, surface modification, targeting strategies, and modulation of EV biogenesis. Finally, key translational challenges—such as EV heterogeneity, biodistribution, immune clearance, and standardization—are discussed to define future directions for leveraging EVs as diagnostic and therapeutic platforms in AD. Full article

Lipid nanoparticles (LNPs) have become the cornerstone of nucleic acid delivery platforms, particularly in RNA-based vaccines and therapeutics. However, the conventional methods of LNP production, which are primarily reliant on microfluidic mixing of aqueous and organic solvent phases, pose limitations in terms of mRNA stability, residual organic contamination, scalability, cost, and environmental impact. These limitations prompted a renewed search for non-conventional strategies with the promise of improving mRNA-LNP encapsulation approaches. These emerging approaches aim to address key bottlenecks, including mRNA hydrolysis-driven degradation, high production losses, and complex downstream purification. Moreover, the ability to decouple LNP synthesis from mRNA encapsulation could enable streamlined, modular manufacturing workflows and customizable payload delivery, including single- or multiple-mRNA payloads, thereby expanding the therapeutic scope of LNPs. This review offers an early insight into the design principles and scalability potential of emerging non-conventional LNP encapsulation approaches, including solvent-free and microfluidics-free methodologies, and pre-built LNP workflows. We also examine trends in emerging LNP encapsulation tools, including high-shear mixing, sonication, membrane contraction, and other approaches. Finally, we extrapolate the suitability of the methods for scale-up approaches and their economic implications based on the process information. Full article