Search Results (413)

Ischemic heart disease remains the leading cause of cardiovascular mortality worldwide. In myocardial infarction (MI), extracellular vesicles (EVs)—particularly small EVs (sEVs)—transport therapeutic cargo such as miR-21-5p, which suppresses apoptosis, and other proteins, lipids, and RNAs that can modulate cell death, inflammation, angiogenesis, and remodeling. This review synthesizes recent mechanistic and preclinical evidence on native and engineered EVs for post-MI repair, mapping therapeutic entry points across the MI timeline (acute injury, inflammation, and healing) and comparing EV sources (stem-cell and non-stem-cell), administration routes, and dosing strategies. We highlight engineering approaches—including surface ligands for cardiac homing, rational cargo loading to enhance potency, and biomaterial depots to prolong myocardial residence—that aim to improve tropism, durability, and efficacy. Manufacturing and analytical considerations are discussed in the context of contemporary guidance, with emphasis on identity, purity, and potency assays, as well as safety, immunogenicity, and pharmacology relevant to cardiac populations. Across small- and large-animal models, EV-based interventions have been associated with reduced infarct/scar burden, enhanced vascularization, and improved ventricular function, with representative preclinical studies reporting approximately 25–45% relative reductions in infarct size in rodent and porcine MI models, despite substantial heterogeneity in EV sources, formulations, and outcome reporting that limits cross-study comparability. We conclude that achieving clinical translation will require standardized cardiac-targeting strategies, validated good manufacturing practice (GMP)-compatible manufacturing platforms, and harmonized potency assays, alongside rigorous, head-to-head preclinical designs, to advance EV-based cardiorepair toward clinical testing. Full article

Background/Objectives: Extracellular vesicles (EVs) are nanosized carriers with high biocompatibility, low immunogenicity, and the ability to cross biological barriers, making them attractive for drug delivery. Despite growing interest, the clinical translation of drug-loaded EVs remains limited. This systematic review aimed to summarize current evidence on EV sources, loading strategies, therapeutic applications, and translational challenges. Methods: Following PRISMA 2020 guidelines, a systematic search was conducted in Embase, PubMed, Reaxys, and Scopus for the period 2020–2025. Eligible studies included original articles on drug-loaded EVs from human, animal, plant, or other sources. Data on EV source, drug type, particle size, loading method, administration route, and therapeutic application were extracted. Clinical trials were identified through ClinicalTrials.gov. Results: A total of 65 studies were included after screening 5316 records, along with two clinical trials. Human mesenchymal stem cell (MSC)-derived EVs were the most frequent source in oncology, while plant-derived EVs predominated in non-oncology applications. Anti-cancer drugs such as doxorubicin, gemcitabine, and docetaxel were most frequently loaded, alongside curcumin, berberine, and atorvastatin. EV sizes generally ranged from 50 to 200 nm, with larger vesicles reported for plant-derived EVs. Intravenous administration predominated, with most studies demonstrating sustained release and enhanced therapeutic efficacy. Passive loading was most common, especially for hydrophobic drugs, whereas active methods such as electroporation and sonication were preferred for hydrophilic cargo. Two clinical trials showed preliminary therapeutic benefits with favorable safety. Conclusions: Drug-loaded EVs represent a promising and versatile drug delivery platform, yet their clinical translation is hindered by variability in isolation and loading methods, production scalability, and safety evaluation. Further standardization and large-scale studies are needed to advance EV-based therapeutics toward clinical use. Full article

The intestinal microbiota, a diverse community of microorganisms residing in the human gut, recently attracted considerable attention as a contributing factor to various neurological disorders, including Alzheimer’s Disease (AD). Within the established framework of the gut–brain axis (GBA) concept, it is commonly suggested that dysbiosis, through microbial metabolites entering the brain, affect the cognitive functions in patients with AD. However, evidence for such a role of dysbiosis remains largely associative, and the complexity of the communication channels between the gut and the brain is not fully understood. Moreover, the new players of the GBA are emerging and the AD concept is constantly evolving. The objective of this narrative review is to synthesize the current evidence on the humoral, endocrine, immune, and neural communication mechanisms linking the gut and brain in AD and highlight newly discovered GBA messengers such as microRNAs, extracellular vesicles, T-cells, and the intestinal hormones, including emerging neuroprotective role for glucagon-like peptide-1 (GLP-1). Based on this knowledge, we aimed to develop a conceptual understanding of the GBA function in health and AD. We specify that, in AD, the GBA goes beyond a disrupted microbiome, but operates in conjunction with impaired intestinal secretion, motility, barrier permeability, and neuroinflammatory signaling. These factors are associated with the dysfunction of the hypothalamic–pituitary axis, altered somatic and autonomic neuronal gut regulation, and abnormal, due to memory problems, behavioral aspects of food intake. Identifying the individual profile of key molecular and cellular players contributing to an unbalanced GBA should optimize existing approaches or propose new approaches for the complex therapy of AD. Full article

Extracellular RNAs are released from cells and circulate stably in biofluids such as blood, cerebrospinal fluid, saliva, and urine via carriers including extracellular vesicles, RNA-binding proteins and lipoproteins. Because transcriptional and metabolic disturbances—notably mitochondrial dysfunction and oxidative stress—often precede protein aggregation, synaptic loss, and structural change in many brain diseases, exRNAs offer minimally invasive access to early disease biology. Mechanistic studies demonstrate selective RNA packaging and delivery: transferred mRNAs can be translated and miRNAs can modulate targets, indicating exRNAs both report intracellular programs and actively influence recipient cells. Clinical and preclinical data support a dual role for exRNAs as biomarkers and as mediators of pathology. Key technical hurdles—pre-analytical variability, isolation heterogeneity, and uncertain cellular origin—limit reproducibility; recommended solutions include standardized workflows, carrier- and cell type-specific enrichment, multimodal integration with proteomics/metabolomics and neuroimaging, and large, longitudinal validation studies. We synthesize mechanistic and clinical evidence for exRNA utility in early detection, prognosis, and therapeutic targeting and outline a roadmap to translate exRNA findings into robust clinical assays and interventions for neurodegenerative and brain disorders. Full article

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, continues to be a significant global health issue, especially in Latin America, with increasing international prevalence due to migration. Despite advancements in diagnosis and treatment, it remains a neglected tropical disease characterized by significant morbidity and mortality, mainly influenced by the complex interaction between parasite diversity and host immune responses. Importantly, the remarkable genetic diversity of T. cruzi lineages also contributes to clinical heterogeneity, influencing immune evasion, therapeutic responses, and vaccine feasibility. This review analyzes the impact of immunogenetics on host–parasite interactions in Chagas disease and explores its implications for personalized therapy approaches. Recent research, particularly over the last decade, has indicated that processes including antigenic variation, extracellular vesicle-mediated regulation, and disruption of host signaling pathways facilitate parasite persistence. Host genetic variables significantly influence susceptibility, disease development, and treatment outcomes, including changes in Human Leukocyte Antigen (HLA) genes, cytokine gene polymorphisms, and immunogenetic determinants of cardiac pathology. These findings underscore the potential of immunogenetic markers as tools for prognosis and as targets for personalized therapies. However, there are still considerable research deficiencies. Inadequate comprehension of gene–environment interactions, lack of representation of varied populations, and inconsistencies in study design limit the use of immunogenetic findings in therapeutic settings. At present, the concept of personalized medicine in Chagas disease remains largely aspirational, better understood as a framework for precision public health or stratified interventions guided by host immunogenetic and parasite lineage data. Addressing these issues necessitates comprehensive genomic research, mechanistic investigations of host–parasite interactions, and clinical validation of genetic markers. This study emphasizes the necessity of incorporating immunogenetics into personalized patient management strategies based on existing evidence. This integration has the potential to improve diagnosis, enhance treatment efficacy, and inform preventive interventions, thereby advancing personalized therapy for Chagas disease. Full article

Allogeneic blood transfusion is frequently performed in critically ill patients, but accumulating evidence demonstrates that it is not a biologically neutral intervention. Transfusion-associated immunomodulation (TRIM) encompasses the immunological effects of transfusion, ranging from immune suppression to proinflammatory activation and cancer recurrence, with potential impact on morbidity and mortality in the intensive care unit. We conducted a narrative review of recent experimental and clinical evidence on TRIM to describe the molecular pathways involved. We reviewed, randomized trials, metaanalyses, and large observational cohorts to evaluate the clinical relevance of TRIM in critically ill populations. TRIM arises from multiple converging mechanisms. These pathways alter innate and adaptive immunity, leading to increased risk of healthcare-associated infections, transfusion-related acute lung injury, acute kidney injury, multiorgan dysfunction, prolonged length of stay, and cancer recurrence in surgical patients. Blood-sparing strategies, including patient blood management (PBM), mitigate exposure. The impact of storage duration and novel processing technologies remains unclear. There is still a gap in research that needs to be addressed. Transfusion-associated immunomodulation (TRIM) is a phenomenon in which donor leukocytes, extracellular vesicles, microparticles, bioactive lipids, and cytokines interact with the host immune system to produce a spectrum of immunological effects. In critically ill patients, the immune system is already fragile, and these mechanisms predispose patients to infections, pulmonary complications, organ dysfunction, prolonged recovery, and even cancer recurrence. Although TRIM cannot currently be diagnosed through a single biomarker or clinical test, its existence is strongly supported by mechanistic studies and consistent clinical associations between transfusion exposure and adverse outcomes. Full article

Liver diseases, including fibrosis, viral hepatitis, hepatocellular carcinoma, and monogenic genetic disorders, represent a major global health burden with limited therapeutic options and frequent systemic toxicity from conventional treatments. Nanovesicle-based drug and gene delivery systems offer targeted approaches that may improve therapeutic precision and reduce off-target effects. This review aims to evaluate the promise and comparative potential of three key nanovesicle platforms—lipid nanoparticles (LNPs), extracellular vesicles (EVs) and liposomes—for drug and gene delivery in liver disease therapy. A systematic search of peer-reviewed studies published in electronic databases was performed, focusing on preclinical and clinical research investigating the use of LNPs, EVs and liposomes for hepatic drug or gene delivery. Studies were analyzed for vesicle composition, targeting efficiency, payload capacity, therapeutic outcomes, and reported limitations. The analysis indicates that LNPs demonstrate strong efficiency in nucleic acid encapsulation and delivery, supported by growing clinical translation. EVs show promising biocompatibility and innate targeting to hepatic cells but face challenges in large-scale production and standardization. Liposomes remain versatile and well-characterized platforms capable of carrying diverse therapeutic molecules, though rapid clearance can limit their efficacy. Together, these nanovesicle systems hold considerable potential for advancing targeted drug and gene therapies in liver disease. Future work should focus on improving stability, manufacturing scalability, and cell-specific targeting to support clinical translation. Full article

Background/Objectives: Cervical cancer remains a significant global health burden, underscoring the imperative for refined diagnostic and prognostic methodologies. This study aimed to evaluate the potential of extracellular vesicles (EVs) as non-invasive biomarkers for cervical cancer, focusing on diagnosis and prognosis. Methods: We conducted a systematic review and meta-analysis in accordance with PRISMA guidelines to assess the diagnostic and prognostic accuracy of EV-based biomarkers. We searched PubMed, EMBASE, and Web of Science for relevant studies. Twelve articles met the inclusion criteria: eight related to diagnostic accuracy, three to prognosis, and one to both outcomes. Six studies met the criteria for meta-analysis. We used a random-effects model to synthesise diagnostic data, while prognostic data were synthesised narratively. Results: The meta-analysis yielded a pooled area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI 0.80–0.92) for EVs in the diagnosis of cervical cancer, indicating high accuracy. The evaluated diagnostic biomarkers were primarily non-coding RNAs. For prognosis, data heterogeneity precluded quantitative synthesis; however, individual studies identified diverse EV-associated molecules correlated with recurrence and survival. GRADE assessment indicated a high risk of bias and heterogeneity across studies. Conclusions: Extracellular vesicles demonstrate robust promise as diagnostic biomarkers for cervical cancer; however, their prognostic utility remains inconclusive due to methodological and clinical heterogeneity. Future research must prioritise the standardisation of isolation protocols and the execution of large-scale, prospective studies to validate EV biomarkers for clinical application. Systematic Review Registration: PROSPERO, identifier: CRD420251014411. Full article

Smart vesicle therapeutics represent a transformative frontier in nanomedicine, offering precise, biocompatible, and adaptable platforms for drug delivery and theranostic applications. This review explores recent advances in the design and engineering of liposomes, niosomes, polymersomes, and extracellular vesicles (EVs), emphasizing their capacity to integrate therapeutic and diagnostic functions within a single nanoscale system. By tailoring vesicle size, composition, and surface chemistry, researchers have achieved improved pharmacokinetics, reduced immunogenicity, and fine-tuned control of drug release. Stimuli-responsive vesicles activated by pH, temperature, and redox gradients, or external fields enable spatiotemporal regulation of therapeutic action, while hybrid bio-inspired systems merge synthetic stability with natural targeting and biocompatibility. Theranostic vesicles further enhance precision medicine by allowing real-time imaging, monitoring, and adaptive control of treatment efficacy. Despite these advances, challenges in large-scale production, reproducibility, and regulatory standardization still limit clinical translation. Emerging solutions—such as microfluidic manufacturing, artificial intelligence-guided optimization, and multimodal imaging integration—are accelerating the development of personalized, high-performance vesicular therapeutics. Altogether, smart vesicle platforms exemplify the convergence of nanotechnology, biotechnology, and clinical science, driving the next generation of precision therapies that are safer, more effective, and tailored to individual patient needs. Full article

Brain tumors encompass a heterogeneous group of neoplasms, including primary and secondary metastatic lesions, with glioblastoma multiforme (GBM) representing the most aggressive primary malignancy. Despite advancements in surgical resection, radiotherapy, and chemotherapy, the prognosis for GBM remains poor due to its infiltrative nature, tumor heterogeneity and resistance mechanisms. Emerging diagnostic tools, such as liquid biopsies, and therapeutic strategies leveraging extracellular vesicles (EVs) are reshaping the field of neuro-oncology. EVs, lipid bilayer-enclosed particles secreted by cells, carry oncogenic cargo such as microRNAs and molecular chaperones, influencing tumor progression, immune evasion, and therapy resistance. Recent research highlights their potential as biomarkers for early diagnosis and vehicles for targeted drug delivery across the blood–brain barrier (BBB). EV-based nanotherapeutics show promise in improving treatment precision, reducing systemic toxicity, and advancing precision medicine in brain tumor management. However, challenges related to EV heterogeneity, cargo-loading efficiency, and large-scale production must be addressed to fully realize their therapeutic potential. This review explores the multifaceted roles of EVs in brain tumors, emphasizing their diagnostic, prognostic, and therapeutic applications. Full article

Mesenchymal stem cells are multipotent stromal cells with immunomodulatory, anti-inflammatory, and trophic properties that support tissue repair and regeneration. Increasing evidence suggests that their therapeutic effects are primarily mediated by paracrine signaling, especially through extracellular vesicles, which can cross the blood–brain barrier and act as cell-free therapeutic agents. Preclinical and clinical studies in stroke, multiple sclerosis, spinal cord injury, and neurodegenerative diseases report encouraging outcomes but also reveal major challenges, including limited engraftment, donor-related heterogeneity, incomplete understanding of mechanisms, and potential oncogenic risks. Recent advances in biotechnology—such as mesenchymal stem cell-derived extracellular vesicles, genetic engineering using CRISPR/Cas9 or viral vectors, 3D culture systems, and bioengineered delivery platforms—offer new opportunities to overcome these limitations. Early clinical trials demonstrate promising safety and functional improvements, yet results remain inconsistent, highlighting the need for standardized protocols and large-scale controlled studies. This review outlines current knowledge, key challenges, and emerging strategies aimed at optimizing mesenchymal stem cell-based approaches for regenerative neurology. Full article

The evaluation of the use of extracellular vesicles (derived from different cellular sources and mammalian fluids) in regenerative medicine has produced interesting results. This includes their great potential for the treatment of chronic skin ulcers, which is related to their effects on migration, proliferation, inflammation and angiogenesis, among other processes. However, large-scale production of mammalian extracellular vesicles may be limited by the need to maintain cell cultures continuously, without losing their ability to secrete extracellular vesicles with regenerative capacity. This may require complex and expensive infrastructures. It is therefore necessary to identify other possible, more efficient alternatives that can be easily transferred to clinical practice. Among these substitutes are plant-derived extracellular vesicles (PDEVs). Fortunately, they resemble those of mammals, playing a role in cell communications. As expected, their compositions depend on source tissues and the physiological conditions of the plants. They may carry numerous molecules with high biological activity. Interestingly, PDEVs are easy to obtain on a large scale, have good stability and are less immunogenic than mammalian-derived EVs. Numerous preclinical studies indicate that they can enhance chronic-wound healing through their immunomodulatory and angiogenic effects, among others. Thus, this review aims to describe the current state of knowledge on the potential therapeutic use of PDEVs in wound healing. It also describes the methods of obtaining and applying them, as well as regenerative processes in which they may intervene. The information provided shows the need to continue advancing knowledge about the production, isolation and mechanisms of action of PDEVs. This will allow new effective therapeutic strategies for the treatment of chronic cutaneous ulcers to be developed. Full article

Background/Objectives: The limited specificity of prostate-specific antigen (PSA) drives unnecessary biopsies in prostate cancer (PCa). Urinary extracellular vesicles (uEVs) provide a non-invasive reservoir of tumor-derived nucleic acids and proteins. Aptamers selected by SELEX enable highly specific capture, and artificial intelligence (AI) can accelerate their optimization. This systematic review evaluated AI-assisted SELEX for urine-derived and exosome-enriched aptamer panels in PCa detection. Methods: Systematic searches of PubMed, Scopus, and Web of Science (1 January 2010–24 August 2025; no language restrictions) followed PRISMA 2020 and PRISMA-S. The protocol is registered on OSF (osf.io/b2y7u). After deduplication, 1348 records were screened; 129 studies met the eligibility criteria, including 34 (26.4%) integrating AI within SELEX or downstream refinement. Inclusion required at least one quantitative metric (dissociation constant K_d, SELEX cycles, limit of detection [LoD], sensitivity, specificity, or AUC). Risk of bias was appraised with QUADAS-2 (diagnostic accuracy studies) and PROBAST (prediction/machine learning models). Results: AI-assisted SELEX workflows reduced laboratory enrichment cycles from conventional 12–15 to 5–7 (≈40–55% relative reduction) and reported K_d values spanning low picomolar to upper nanomolar ranges; heterogeneity and inconsistent comparators precluded pooled estimates. Multiplex urinary panels (e.g., PCA3, TMPRSS2:ERG, miR-21, miR-375, EN2) yielded single-study AUCs between 0.70 and 0.92 with sensitivities up to 95% and specificities up to 88%; incomplete 2 × 2 contingency reporting prevented bivariate meta-analysis. LoD reporting was sparse and non-standardized despite several ultralow claims (attomolar to low femtomolar) on nanomaterial-enhanced platforms. Pre-analytical variability and absent threshold prespecification contributed to high or unclear risk (QUADAS-2). PROBAST frequently indicated high risk in participants and analysis domains. Across the included studies, lower K_d and reduced LoD improved analytical detectability; however, clinical specificity and AUC were predominantly shaped by pre-analytical control (matrix; post-DRE vs. spontaneous urine) and prespecified thresholds, so engineering gains did not consistently translate into higher diagnostic accuracy. Conclusions: AI-assisted SELEX is a promising strategy for accelerating high-affinity aptamer discovery and assembling multiplex urinary panels for PCa, but current evidence is early phase, heterogeneous, and largely single-center. Priorities include standardized uEV processing, complete 2 × 2 diagnostic reporting, multicenter external validation, calibration and decision impact analyses, and harmonized LoD and K_d reporting frameworks. Full article

Chronic pain is a pervasive global health issue that significantly impairs quality of life and remains inadequately managed by current therapeutic options. Traditional pharmacological treatments often offer limited relief and are associated with significant side effects, highlighting the urgent need for safer and more effective alternatives. Among emerging strategies, mesenchymal stem cell (MSC)-derived secretome, an acellular product composed of bioactive molecules such as cytokines, growth factors and extracellular vesicles, has gained increasing attention for its potent anti-inflammatory, neuroprotective and immunomodulatory properties. Unlike whole-cell therapies, secretome-based interventions offer advantages, including lower immunogenicity, higher safety and easier standardization and storage. Preclinical studies demonstrated that MSC secretome effectively alleviates pain-like behavior across various models of neuropathic, inflammatory and degenerative pain, primarily through neuroimmune modulation and glial cell reprogramming. In vitro experiments confirm its role in promoting neuronal survival, regulating opioid receptor expression and modulating (neuro)inflammatory responses. Preliminary clinical evidence supports its analgesic efficacy in conditions such as osteoarthritis, chronic low back pain and post-surgical pain, with a favorable safety profile and promising therapeutic outcomes. However, challenges remain, including variabilities in secretome composition, lack of standardized production protocols and absence of large-scale clinical trials. Despite these limitations, MSC secretome therapy represents a transformative approach in pain medicine. Continued research efforts are essential to optimize formulation, dosing and delivery strategies, as well as to clarify the regulatory landscape. With further validation, the MSC secretome could emerge as a novel, scalable and clinically viable solution for the management of chronic pain, bridging critical gaps in current treatment paradigms. Full article

The mango (Mangifera indica L.) is a commonly cultivated tropical fruit across the globe. It is known to be rich in carotenoids, polyphenols, and vitamins, compounds that largely account for its nutritional and medicinal properties. Although the beneficial effects of mango phytochemicals have been widely documented, virtually no studies have investigated extracellular vesicles (EVs) originating from mango fruit. In the presented work, we developed a workflow combining differential centrifugation, filtration, and size-exclusion chromatography for the isolation of EVs from mango pulp. The isolates were characterized in accordance with the guidelines of the International Society of Extracellular Vesicles recommendations. The optimized size-exclusion chromatography column, packed with Sepharose CL-6B beads, enabled the recovery of a high-quality EV fraction, which was characterized in terms of physicochemical properties. Additionally, proteomic analysis identified 1084 proteins, many of which are associated with antioxidant, antimicrobial, and anti-inflammatory functions. These findings provide the first comprehensive characterization of mango-derived EVs and suggest that they may contribute to the biological activity traditionally attributed to mango consumption. Full article