Therapeutic potential of plant-derived exosome-like nanovesicles as a phytomedicine in age-related diseases.

Cancer therapy is increasingly shaped by delivery platforms designed to overcome the limitations of conventional chemotherapy and radiotherapy. Among these, bacterial outer membrane vesicles (OMVs) have emerged as versatile nanocarriers with intrinsic tumor-interacting properties, immunomodulatory capacity, and amenability to bioengineering. Their lipid bilayer composition not only enhances stability and cellular uptake but also intersects with tumor lipid metabolism-an axis increasingly recognized as central to oncogenesis, immune evasion, and therapeutic resistance. Here, we review mechanistic links between OMV lipid composition and autophagy regulation and discuss how engineered OMVs can be used to modulate tumor metabolism, immune responses, and therapy sensitivity. By influencing lipid-autophagy crosstalk, OMVs function as more than passive delivery vehicles; they can actively engage intracellular stress pathways and metabolic dependencies. Autophagy, a context-dependent regulator of cancer survival and suppression, is particularly relevant, as OMVs can deliver bioactive lipids, proteins, or nucleic acids that either promote immunogenic stress responses or attenuate tumor-protective autophagy. Preclinical examples-including doxorubicin-loaded OMVs and PD-1-engineered OMVs-illustrate how these principles translate into enhanced anti-tumor efficacy and immune activation. We further discuss how integration with lipidomics, systems biology, and artificial intelligence-guided design may improve OMV engineering and therapeutic predictability. Collectively, these advances position OMVs as a promising, though still emerging, platform for precision oncology.

7-ketocholesterol as a theranostic target: Potential applications and future perspectives.

Bioactive lipid nanoparticles as active rehabilitative regulators for fibrotic microenvironment remodeling

Oxylipin profile data analysis: Current methodologies, challenges, and future directions.

Dual targeting of NCF1 and NLRP3 by roburic acid orchestrates redox homeostasis and inhibits macrophage death in septic lung injury.

Ceramide is a central bioactive lipid that acts as both a membrane structural component and a crucial signaling molecule in the cells. In order to maintain cellular homeostasis, ceramide metabolism is tightly regulated by enzymes in the endolysosomal system such as acid ceramidase (AC) and acid sphingomyelinase (ASM). We investigate the biochemical consequence of ceramide accumulation within the endolysosomes of living animal cells by optical nanoprobing, using surface-enhanced Raman scattering (SERS) with gold nanoparticles. The ceramide level in 3T3 fibroblast cells was systematically increased by interfering with two key enzymatic pathways in sphingolipid metabolism as well as by adding exogenous ceramide. The modulation of enzyme activity occurred by the inhibition of AC using the inhibitor N-[(2S,3R)-1,3-dihydroxyoctadecan-2-yl]2-chloroacetamide (SACLAC) in different incubation schemes and supplementation of the cells with additional ASM, respectively, both were added through the culture medium. The analysis of SERS data from the endolysosomal compartment reveals changes in the structure and interaction of proteins alongside variations in membrane composition and organization that correspond to ceramide stress. Combined cryo soft-X-ray nanotomography data of the intact cells show that the biomolecular alterations transform the cellular ultrastructure to varying degrees depending on the specific route and extent of ceramide increase. The ultrastructural changes include severe membrane deformation and changed vesicular organization as a consequence of a high ceramide content. The results demonstrate the label-free optical monitoring of metabolic processes at the subcellular level, before their complex biochemical background, and refine the description of molecular and nanostructure changes associated with distorted sphingolipid metabolism.

FAHFAs are detected in postprandial chylomicron and VLDL fractions and can be released from TG estolides by LPL in vitro.

Exosomes are nanoscale extracellular vesicles secreted by cells via endosomal pathways. They mediate intercellular communication by transporting bioactive molecules, including proteins, lipids, and nucleic acids. During tumorigenesis, exosomes critically participate in multiple oncogenic processes, including metastatic dissemination, immune evasion, tumor microenvironment remodeling, angiogenesis, and the development of chemoresistance. Comprehensive characterization and molecular profiling of vesicular surface epitopes are essential for tracing their origins. These membrane-bound biomarkers not only facilitate precise vesicle classification but also enable the selective enrichment of tissue-specific molecular signatures that are crucial for targeted therapeutic applications. Accumulating evidence indicates that tumor-derived exosomes have emerged as promising diagnostic biomarkers with exceptional specificity, while their intrinsic biocompatibility and cargo-loading capacity confer transformative potential for next-generation drug delivery platforms. This review critically examines exosome roles in tumor biology. It highlights clinical applications in oncology. We focus on exosome biomarkers in liquid biopsy, engineered exosomes for drug delivery, and pharmacological or genetic strategies targeting exosome biogenesis.

Cachexia is a metabolic wasting syndrome affecting many patients with cancer, with poor survival outcomes. Disturbed lipid metabolism is a hallmark of cachexia, and our previous work has identified increased levels of circulating ceramides, which are bioactive lipids with adverse effects in metabolic diseases, as biomarkers for cachexia in mouse models and patients. Here, we investigated the role of ceramides on cachexia development using the well-established C26 colon carcinoma model. We demonstrated that elevated ceramides in cachexia arose from increased liver synthesis. We showed that ceramides directly contributed to impaired mitochondrial function and energy homeostasis in cachexia target tissues. Targeting ceramide synthesis using miRNA interference, or myriocin, an approved compound targeting the key synthesis enzyme serine palmitoyltransferase (SPT), improved markers of muscle atrophy in cachectic male mice. Importantly, we demonstrated that key enzymes involved in ceramide production were also elevated in livers, but not in other organs, of patients with cancer cachexia, correlating with disease severity. Our data place ceramides as contributors to metabolic dysfunction in cachexia and highlight the suitability of the ceramide synthesis pathway for therapeutic targeting.

Extracellular Vesicles as Paradigm Shifters: Transformative Roles in Diagnosis and Therapy for Brain Disorders.

Dengue virus (DENV) appears to manipulate several cellular metabolic pathways to permit its replication and immune evasion in the host. Here, we employed high-resolution mass spectrometry (HR-MS) to investigate the serum metabolomic landscape of clinical DENV infection. Serum specimens from primary dengue (n = 11), secondary dengue (n = 9) samples, and healthy controls (n = 10) were used for untargeted and targeted metabolomic quantification on a Waters Xevo G2-XS QTof Mass Spectrometer. The binding potential of selected ligands against DENV NS1, NS3, and NS5 was evaluated. Crystal structures were retrieved from Protein Data Bank and prepared using the Schrodinger's protein preparation wizard. Based on findings from untargeted metabolomics, we validated certain bioactive lipid metabolites using commercial enzyme immunoassays. Serum metabolomic profiling revealed multiple distinct patterns for primary and secondary dengue versus controls. A consistent peak was observed at 2.06 mins across all samples. Certain bioactive lipid metabolites, such as, lysophospholipids, phosphatidylcholines, phosphatidylserines, and phosphatidylinositols, were detected alongside carnitine fragments, ceramides, diacylglycerols (DAGs), and bile acid conjugates in dengue. Molecular docking showed that DAG consistently exhibited strong binding to all the DENV proteins. Notably, LPC 22:6 showed a selectively strong affinity for NS5. Enzyme validation showed that in the secondary dengue cohort, LPC was significantly elevated than primary and healthy controls (p < 0.05). Our investigations of the metabolomic landscaping, unveiled certain characteristic anabolic shift revealing metabolic vulnerabilities in clinical DENV infection, warranting investigations for use as potential biomarkers of inflammation in disease diagnosis and prognosis.

Post-acute sequelae of severe acute respiratory syndrome coronavirus 2 infection (PASC) is a heterogeneous multisystemic condition with unclear pathogenesis. Emerging evidence suggests that the disruption in metabolism, including lipid metabolism, can be involved in the pathogenesis of coronavirus disease 2019 (COVID-19). We previously measured the bioactive lipids in acute COVID-19, and we hypothesized that bioactive lipid dysregulation play a role in PASC pathogenesis. We conducted targeted LC-MS/MS analysis of sphingolipids and glycerophospholipids in serum samples from individuals with acute-phase COVID-19, including those who developed PASC, alongside healthy controls. We systematically examined lipidomic changes in serum samples, including analyses using linear mixed model, and found that no sphingolipid or glycerophospholipid species differed between the COVID-19 and PASC groups. Although these results are exploratory, the group x time interaction in the linear mixed model suggested that phosphatidylglycerol (PG) may represent a bioactive lipid distinguishing the COVID-19 and PASC groups. Given the small PASC sample size and that the signal was detected only at specific time points, these findings are hypothesis generating and should be confirmed in larger, adequately powered, and independently validated cohorts.

Sciadonic acid (SCA), Δ5-unsaturated fatty acid with anti-inflammatory and lipid-regulatory properties, is predominantly derived from seeds of gymnosperms. This study established a systematic engineered Yarrowia lipolytica platform for efficient SCA production and assessing the anti-colitis efficacy of SCA as a novel therapeutic lipid. First, production of eicosadienoic acid (EDA) was biosynthesized by iterative expression of endogenous polyunsaturated fatty acid desaturase and Δ9 elongase. Different Δ5 desaturases were screened to identify high-activity enzymes capable of catalyzing EDA-CoA substrates, bypassing the rate-limiting step of phosphatidylcholine (PC)-bound substrate catalysis. Further, combined with the deletion of the β-oxidation pathway, enhancement of triglyceride assembly and malonyl-CoA supply, the resulting strain overproduced 195.5 mg/L SCA in shake flasks. Under optimized bioreactor fermentation, SCA yield reached 1.2 g/L with glucose, representing the high level of SCA production reported in Y. lipolytica. Finally, SCA significantly ameliorated dextran sulfate sodium salt (DSS) -induced colitis in mice, demonstrating dose-dependent improvements in disease activity index, colon histopathology, and pro-inflammatory cytokine suppression. Overall, this work establishes an efficient microbial production platform for SCA and provides in vivo evidence supporting the anti-colitis potential of this bioactive lipid.

Oxylipins are bioactive lipid mediators that play key roles in biological and pathological processes. Their remarkable chemical diversity makes their identification by untargeted LC-MS/MS analyses challenging. To date, effective solutions for their comprehensive characterization remain unavailable. Here, we present the first implementation of the recently refined Ion Identity Molecular Networking (IIMN) strategy to map the chemical space of oxylipins, together with a systematic evaluation of factors that hinder accurate annotation in MS/MS datasets. Building on recent mzmine software developments, we implemented a fully local strategy to perform the IIMN analysis without requiring web platforms or external tools. We established a high-quality MS/MS spectral library from 67 commercially available oxylipin standards using LC-MS data obtained in data-dependent acquisition mode. Integrating the detailed characterization of ion species generated during electrospray ionization into IIMN reduced network complexity. Across configurations, the modified cosine algorithm proved most effective for separating full-length from cyclized forms and for clustering oxylipins through structurally coherent relationships. Application of the IIMN workflow to mouse spleen extracts, in combination with our in-house and publicly available experimental MS/MS libraries, enabled the organization of oxylipins into molecular families, facilitating their structural characterization and the discovery of novel species. Although manual curation remained necessary for certain coeluting isomers and ambiguous fragments, the IIMN-based approach significantly improved network interpretability and understanding. Overall, this study establishes IIMN as a robust bioinformatic tool for decoding oxylipin diversity and provides a successful strategy for mapping their chemical space, characterizing them within samples, and discovering novel mediators in biological matrices. The new combined reference spectral library has been made publicly available and will serve as a valuable resource for future redox lipidomics research.

The Fontan procedure enhances systemic oxygenation and survival in patients with complex congenital heart defects not amenable to biventricular repair. Despite these improvements, individuals with Fontan circulation often develop progressive multisystem dysfunction, the biochemical underpinnings of which remain poorly understood. Oxylipins are bioactive lipid mediators implicated in cardiovascular disease and represent targetable pathways that may contribute to the pathophysiology of the Fontan state. The study aims to quantify plasma oxylipins in individuals with Fontan circulation, compared with matched controls, and assess correlations with hemodynamic function and exercise capacity. A total of 20 adult patients with Fontan circulationand 20 matched controls underwent assessment of body composition, frailty, cardiopulmonary exercise testing, and noninvasive hemodynamic evaluation. Absolute plasma oxylipin concentrations were measured using triple quadrupole HPLC-MS/MS. Compared with controls, Fontan participants exhibited significantly increased (34%) total plasma oxylipin concentrations, with a 42% elevation in ω-6 fatty acid-derived oxylipins. Among these, metabolites generated via the 15-lipoxygenase (15-LOX) pathway were elevated by 52%. In addition, product-to-substrate ratios reflecting putative soluble epoxide hydrolase (sEH) activity for ω-6 fatty acids were nearly threefold higher in the Fontan group. Several oxylipins derived from ω-3 and ω-6 fatty acids, including those generated by 15-LOX and sEH pathways, demonstrated significant correlations with key clinical parameters, including resting and exercise hemodynamics, ventilatory efficiency, and peak oxygen consumption (V̇o2). Individuals with Fontan circulation exhibit marked alterations in circulating oxylipins, particularly those involving ω-6 fatty acid metabolism via 15-LOX and sEH. These findings offer mechanistic insights and identify potentially modifiable targets.NEW & NOTEWORTHY Fontan patients exhibit a distinct oxylipin signature characterized by markedly elevated total and ω-6-derived oxylipins, including increased 15-LOX activity and higher sEH product-to-substrate ratios, alongside reduced ω-3 species such as 20-hydroxydocosahexanoic acid (20-HDoHE) and 17,18-dihydroxyeicosatetraenoic acid (DiHETE). Elevated ω-6 oxylipins correlated with poorer exercise capacity, greater frailty, and impaired hemodynamics, whereas ω-3 oxylipins showed the opposite trend. These findings identify oxylipin dysregulation as a central metabolic hallmark and potential therapeutic target in Fontan circulation.

Extracellular vesicles (EVs) have emerged as versatile carriers of therapeutic cargo, including nucleic acids, proteins, and small molecules. However, their potential to deliver bioactive lipid mediators remains largely unexplored. Here, we present a novel synthetic biology-based strategy to selectively load EVs with proresolving lipid mediators of the resolvin D- and E-series by coexpressing the resolvin biosynthetic enzymes cyclooxygenase 2, 5-lipoxygenase, and 15-lipoxygenase using a custom-designed multigene expression vector. Human embryonic kidney 293 T cells transfected with the multigene expression vector and cultured in the presence of fatty acid free bovine serum albumen-complexed docosahexaenoic acid, eicosapentaenoic acid, and aspirin produced multiple members of the resolvin D, aspirin-triggered resolvin D-series, and resolvin E1 and E2, along with their biosynthetic precursors, which were subsequently packaged into EVs (referred to as resolvin EVs). Resolvin EVs attenuated neutrophil adhesion to endothelial cells both under static and flow conditions and preserved endothelial barrier integrity by upregulating VE-cadherin. In macrophages, resolvin EVs suppressed nuclear factor κB reporter activity and the release of IL6 and TNFα. Effects of resolvin EVs on endothelial permeability and macrophage activation were abrogated by pharmacologic inhibition of EV uptake using nystatin and cytochalasin D. Furthermore, resolvin EVs enhanced efferocytosis in THP-1-derived macrophages compared to control EVs. Notably, postinjury administration of resolvin EVs attenuated pulmonary inflammation in lipopolysaccharide-treated mice without inducing systemic or pulmonary toxicity. Together, these findings establish a novel, scalable platform for generating resolvin-loaded EVs and highlight their therapeutic potential for acute lung injury and other chronic inflammatory disorders.

Osteoarthritis (OA) is a common degenerative joint disease. Current therapeutic strategies mainly focus on symptom relief and are still unable to effectively halt disease progression. Mesenchymal stem cells (MSCs) possess immunomodulatory, anti-inflammatory, and tissue-repair capacities; however, direct cell transplantation remains limited by insufficient stability during in vitro expansion, potential safety risks, and difficulties in quality control. Recent studies have shown that MSC-derived extracellular vesicles (MSC-EVs) can carry bioactive components, including proteins, lipids, mRNA, and miRNA, participate in intercellular communication, and exhibit promising therapeutic potential in OA. Compared with MSCs, MSC-EVs have advantages such as lower immunogenicity, easier storage, and greater suitability for engineering modification. This review summarizes the major mechanisms by which MSC-EVs may contribute to OA treatment, including regulation of inflammation and the synovial microenvironment, promotion of cartilage repair, modulation of immune responses, delay of chondrocyte senescence, and alleviation of pain. In addition, strategies such as surface-targeting modification, miRNA overexpression, hypoxic preconditioning, and low-intensity pulsed ultrasound are discussed for their potential to enhance the therapeutic efficacy of MSC-EVs. Although MSC-EVs show favorable prospects in OA treatment, their key bioactive components, quality standards, large-scale production, and clinical safety require further clarification.

Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory myopathy characterized by muscle weakness and distinctive skin rashes. Despite advancements in the clinical understanding of JDM, metabolic disturbances underlying the disease remain poorly understood. This study aimed to investigate serum metabolite differences in JDM compared to age- and sex-matched unaffected siblings (US) and unrelated healthy controls (HC), and to identify metabolite abundance differences associated with disease severity. Serum samples from JDM (n = 16) and adult dermatomyositis (DM; n = 15) patients and corresponding US and HC underwent untargeted metabolomics profiling. Multivariate, univariate, and correlation analyses were employed to identify metabolites differentiating groups and correlating with Physician Global Damage (PGD) scores. JDM patients exhibited modest but discernible alterations in serum metabolites compared to controls, many of which also correlated with PGD. Several bioactive lipids and pyroglutamic acid were upregulated in JDM and positively correlated with PGD. Changes in xanthine, methionine and N-acetylneuraminic acid also indicated increased oxidative stress and inflammation. Markers of increased energy demand and muscle damage, including acylcarnitines, creatine, 4-guanidinobutyric acid, glutamine, and phenylacetylglutamine, were differential and correlated with PGD in some cases. A metabolite abundance gradient from JDM to US to HC groups suggests that siblings help account for genetic and environmental influences on the metabolome. DM patients did not show significant serum changes compared to US. Untargeted metabolomics revealed distinct serum metabolite alterations in JDM, providing insights into disease-related metabolic perturbations. These findings enhance understanding of JDM pathophysiology and inform future large-scale, targeted studies.

Exosomes are increasingly recognized as critical mediators of intercellular communication within the central nervous system and along the brain-periphery axis, with emerging relevance to the pathophysiology of depression. These nanoscale extracellular vesicles transport bioactive cargo-including microRNAs (miRNAs), proteins, lipids, and metabolites-that can modulate neuroinflammatory signaling, synaptic remodeling, hypothalamic-pituitary-adrenal (HPA) axis dynamics, and gut-brain communication. Converging evidence from human and preclinical studies suggests that alterations in circulating and brain-derived exosomal cargo are associated with major depressive disorder (MDD) and secondary depression following neurological insults such as traumatic brain injury (TBI), implicating shared inflammatory and synaptic pathways alongside distinct etiological drivers. Circulating neuron-enriched exosomes carrying miRNAs such as miR-16 and miR-124 have been proposed as minimally invasive biomarkers reflecting brain-relevant molecular alterations. However, most human data remain cross-sectional and associative, with limited longitudinal replication and incomplete validation of cellular origin. Therapeutically, mesenchymal stem cell (MSC)-derived exosomes demonstrate antidepressant-like effects in rodent models through modulation of microglial activation, enhancement of synaptic plasticity, and attenuation of neuroinflammatory cascades. Engineered exosomes further offer a potential platform for targeted delivery of anti-inflammatory or neuroplasticity-enhancing cargo. Induced pluripotent stem cell (iPSC)-derived exosomes represent a potentially scalable and standardizable therapeutic platform. Despite this promise, substantial barriers impede clinical translation. Isolation workflows-including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture-vary in yield, purity, and reproducibility, complicating cross-cohort comparability. Moreover, definitive attribution of vesicle origin in peripheral biofluids remains technically constrained, and standardized reporting frameworks are inconsistently applied. Advances in multi-omics profiling, high-throughput sequencing, mass spectrometry, and spatially resolved molecular analyses may improve mechanistic resolution and biomarker robustness. Collectively, exosome research in depression resides at an early but rapidly evolving translational stage. Rigorous methodological standardization, longitudinal cohort validation, and mechanistic dissection across primary and injury-related depression will be essential to determine whether exosome-based diagnostics and therapeutics can fulfill their potential within precision psychiatry.