BACKGROUND Diabetic osteoporosis(DOP),a serious complication of type 2 diabetes mellitus(T2DM),involves ferroptosis-mediated disruption of bone metabolism.While endothelial cell-derived exosomes(EC-Exos)demonstrate in...BACKGROUND Diabetic osteoporosis(DOP),a serious complication of type 2 diabetes mellitus(T2DM),involves ferroptosis-mediated disruption of bone metabolism.While endothelial cell-derived exosomes(EC-Exos)demonstrate inherent bone-targeting properties,their role in counteracting high glucose(HG)-induced osteoblast ferroptosis remains unexplored.AIM To investigate whether EC-Exos protect against HG-induced osteoblast ferroptosis through microRNA(miR)-335-3p-mediated regulation of prostaglandin endoperoxide synthase 2(PTGS2)and evaluate clinical relevance in DOP.METHODS Mouse vascular endothelial cells(bEND.3)and osteoblasts(MC3T3E1)were used.Exosomes were isolated and subsequently characterized by transmission electron microscopy,nanoparticle tracking analysis,and western blotting for CD63 and CD81.miR expression profiles were compared between HG-treated osteoblasts and exosome-cocultured groups using high-throughput sequencing and quantitative reverse transcription polymerase chain reaction.Targeting of PTGS2 mRNA by miR-335-3p was validated by dual-luciferase reporter assay.Ferroptosis markers,reactive oxygen species,malondialdehyde,glutathione(GSH),PTGS2,GSH peroxidase 4,solute carrier family 7 member 11,and solute carrier family 3 member 2,were quantified following miR-335-3p inhibition.Serum samples from 30 T2DM patients and 32 DOP patients were analyzed.miR-335-3p levels were measured by quantitative reverse transcription polymerase chain reaction,and PTGS2 concentrations were determined via enzyme-linked immunosorbent assay.Diagnostic performance was assessed using receiver operating characteristic curves and logistic regression.RESULTS EC-Exos significantly reduced reactive oxygen species levels and malondialdehyde,while increasing GSH in HG-treated osteoblasts.miR-335-3p expression increased 3.7-fold in exosome-treated cells vs HG controls.miR-335-3p directly bound the PTGS23’untranslated region.Inhibition of miR-335-3p abolished exosomal protection against ferroptosis,as demonstrated by increased PTGS2 expression and reduced levels of GSH peroxidase 4,solute carrier family 7 member 11,and solute carrier family 3 member 2.DOP patients exhibited lower serum miR-335-3p and higher PTGS2 compared with T2DM controls,showing a strong inverse correlation.miR-335-3p demonstrated diagnostic potential for DOP.CONCLUSION EC-Exos affect ferroptosis in osteoblasts induced by HG by activating miR-335-3p/PTGS2.Serum miR-335-3p may be a novel diagnostic biomarker.展开更多
Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues...Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.展开更多
Objective:Osimertinib can selectively inhibit both epidermal growth factor receptor(EGFR)sensitizing and T790M gatekeeper mutations,and has shown remarkable therapeutic effects in patients with lung adenocarcinoma.How...Objective:Osimertinib can selectively inhibit both epidermal growth factor receptor(EGFR)sensitizing and T790M gatekeeper mutations,and has shown remarkable therapeutic effects in patients with lung adenocarcinoma.However,almost all patients inevitably develop drug resistance.Herein,we sought to clarify the roles of exosomal lncRNA H19 in modulating osimertinib resistance,focusing on the PI3K-PTEN-Akt signaling axis.Methods:Functional assays,including cell viability assay,colony formation,cell apoptosis and xenograft mouse,employed in evaluate the effects of exosomal lncRNA H19 on cell growth and apoptosis.RNA quantitation and western blot were adopted to demonstrate the regulatory roles of exosomal lncRNA H19 in PI3K-PTEN-Akt signaling pathway.Immunofluorescence was applied to obverse the function and distribution of exosomes.Furthermore,dual-luciferase reporter analysis combined with RNA immunoprecipitation(RIP)was applied to verify the molecular interaction between lncRNA H19 and phosphatase and tensin homolog(PTEN).Results:LncRNA H19 exhibited obviously decreased expression in H1975R cells and their secreted exosomes.Overexpression of H19 enhances the cytotoxicity of osimertinib,inhibits the growth of H1975R cells,and promotes apoptosis.Conversely,H19 silencing promotes osimertinib resistance in H1975 cells and enhances the cell-resistant phenotype.Furthermore,exosome-transferred lncRNA H19 sponged miR-148-3p to augment PTEN expression,which in turn inactivated the PI3K-Akt signaling pathway and ultimately induced cell apoptosis.Conclusion:Exosome-encapsulated lncRNA H19 can be delivered to osimertinib-resistant H1975R cells,thereby reversing resistance through the miR-148-3p/PTEN/PI3K-Akt axis.Our results uncover a potential therapeutic approach to surmount osimertinib resistance in lung cancer.展开更多
Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondri...Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondrial quality control as central drivers of chondrocyte failure,extracellular matrix breakdown,and inflammation amplification.Mitophagy—particularly the phosphatase and tensin homolog-induced kinase 1(PINK1)/Parkin axis—has therefore emerged as an attractive,mechanistically grounded intervention point.In this context,synovial mesenchymal stem cell-derived exosomes(SMSC-Exos)represent a compelling cell-free platform capable of delivering functional biomolecules into inflamed cartilage microenvironments.Recent experimental work demonstrates that engineering SMSC-Exos to deliver the mitochondrial co-chaperone GrpE-like 1(GRPEL1)restores chondrocyte proliferative and migratory capacity under interleukin-1βstress,preserves anabolic extracellular matrix markers(collagen type II alpha 1/aggrecan),suppresses catabolic mediators(matrix metalloproteinase 13/A disintegrin and metalloproteinase with thrombospondin motifs 5),and mitigates oxidative damage while enhancing mitophagy signatures.Mechanistically,GRPEL1 directly associates with PINK1,and PINK1 knockdown attenuates the protective phenotype,supporting a GRPEL1-PINK1 coupling model.In vivo,intra-articular administration of GRPEL1-enriched SMSC-Exos improves histological cartilage integrity and mitophagy-related readouts in a rat OA model.Here,we synthesize mechanistic implications,highlight interpretive nuances(e.g.,mitophagy activation concurrent with membrane potential recovery),and outline translational priorities,including cargo quantification,mitophagy flux validation,dosingetention kinetics,manufacturing standardization,and biomarker-driven patient stratification.展开更多
Neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis represent a significant global health challenge with limited therapeutic options.In recent years,stem cel...Neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis represent a significant global health challenge with limited therapeutic options.In recent years,stem cell-based therapies have shown promise in promoting neural repair and modulating disease progression.However,concerns related to immune rejection,tumorigenicity,and ethical considerations have limited their clinical application.As an alternative,exosomes derived from stem cells have emerged as a novel,acellular therapeutic strategy.These nanoscale extracellular vesicles carry a rich cargo of proteins,lipids,and nucleic acids,capable of modulating neuroinflammation,promoting neuroprotection,and enhancing tissue repair.Their ability to cross the blood-brain barrier and their low immunogenicity make them especially attractive for treating central nervous system disorders.This review highlights the therapeutic potential of stem cell-derived exosomes in the management of neurodegenerative diseases,discussing their mechanisms of action,current research progress,and future clinical applications.The development of exosome-based therapies marks a significant step toward safe,effective,and cell-free neurodegeneration.展开更多
Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases.It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibr...Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases.It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction,which collectively contribute to the progressive loss of synapses and neurons.As a result,individuals with Alzheimer's disease experience gradual memory loss and cognitive decline.Currently,the global patient population is nearing 50 million,a number expected to increase dramatically over the coming decades.Conventional treatments focus on symptom management through acetylcholinesterase inhibitors,such as donepezil,galantamine,and rivastigmine,and the N-methyl-D-aspartate receptor antagonist memantine.However,the past few years have seen the approval of newer agents such as sodium oligomannate,aducanumab,and lecanemab,which show some promise in slowing disease progression.Unfortunately,most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred.This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease.This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer's disease involving micro RNAs.In the in vivo animal studies of Alzheimer's disease reviewed,extracellular vesicles and exosomes from various sources improved memory and cognitive decline,lowered inflammation and amyloid deposition,and increased neuron survival in the brain.Loading extracellular vesicles and exosomes with micro RNA mimics(e.g.,miR-22,-29b,-124,-132,-138-5p,-342-5p,-711,and-7670-3p)or antagomirs(e.g.,miR-206-antagomir)improved outcomes in animal models of Alzheimer's disease.Supporting results were found in the in vitro cell studies reviewed.展开更多
Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms o...Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.展开更多
In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,...In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.展开更多
Background:Excessive extracellular matrix accumulation,primarily as a result of hepatic stellate cell activation,is a hallmark of hepatic fibrosis,a progressive outcome of chronic liver injuries.Recent research studie...Background:Excessive extracellular matrix accumulation,primarily as a result of hepatic stellate cell activation,is a hallmark of hepatic fibrosis,a progressive outcome of chronic liver injuries.Recent research studies suggest that stem cells,hepatocytes,and extracellular vesicles may provide therapeutic advantages due to their anti-inflammatory,antioxidative,and regenerative activities.This study aimed to comparatively evaluate the therapeutic efficacy of these agents in a rat model of carbon tetrachloride(CCl4)-induced hepatic fibrosis.Methods:Liver fibrosis was induced in male Wistar rats via intraperitoneal CCl4 injections for 8 weeks.Then the animals were intravenously administrated stem cells,hepatocytes,hepatocyte-derived exosomes,or stem cell-derived exosomes.Also,a fibrosis,a sham,a intact,and a PBS-treated group were consider the controls.After treatment,protein expression(alpha-smooth muscle actin(α-SMA),desmin),oxidative stress markers(superoxide dismutase,glutathione peroxidase,malondialdehyde),serum biochemical parameters(aspartate aminotransferase,alanine aminotransferase,glucose,uric acid,cholesterol,triglycerides),and fibrosis-related gene expression(matrix metalloproteinase 2(MMP2),platelete-derived growth factor receptor beta(PDGFRB),transforming growth factor-beta(TGF-β),thymosin beta-10(TMSB10)and transmembrane protein 176B(TMEM176B))were assessed.Results:Significant liver damage,changed metabolic parameters,increased oxidative stress,and upregulated fibrosis markers were all observed in the fibrosis group.On the contrary,all treatments caused considerable improvements,though exosomes derived from stem cells demonstrated the most significant effects.Along with improved histopathological features,this group exhibited significant decreases in oxidative damage,liver enzymes,and profibrotic marker expression.Conclusion:Liver fibrosis was considerably reduced by stem cells,hepatocytes,and particularly their exosomes.Exosomes made from stem cells demonstrated the strongest therapeutic effect,confirming their potential as a viable noncellular hepatic fibrosis treatment approach.展开更多
Knee osteoarthritis is recognised as a whole-joint disorder involving cartilage,synovium,subchondral bone and nociceptive pathways.Conventional therapies provide symptomatic relief but rarely alter structural progress...Knee osteoarthritis is recognised as a whole-joint disorder involving cartilage,synovium,subchondral bone and nociceptive pathways.Conventional therapies provide symptomatic relief but rarely alter structural progression.Mesenchymal stromal cell(MSC)injections improve pain and function,yet structural benefits remain modest and variable.Increasing evidence indicates that much of the MSC effect is mediated by secreted extracellular vesicles(EVs),particularly those derived from bone marrow MSCs.These vesicles deliver proteins,lipids,microRNAs and long noncoding RNAs that regulate catabolic enzymes,inflammatory mediators and survival pathways,thereby influencing chondrocyte apoptosis,matrix turnover,macrophage polarisation,osteoclast activity and nociceptive signalling.This review uniquely synthesises mechanistic insights into extracellular vesicles derived from bone marrow MSCs cargo,compares their performance with other MSC sources,and highlights translational priorities including Minimal Information for Studies of EVs 2023-compliant characterisation,dose-finding,and adequately powered trials with structural and biomarker endpoints.展开更多
BACKGROUND The global prevalence of type 2 diabetes mellitus(T2DM)is increasing.Although globular adiponectin(gAd)shows potential in improving islet function,its clinical application is limited by rapid clearance.Give...BACKGROUND The global prevalence of type 2 diabetes mellitus(T2DM)is increasing.Although globular adiponectin(gAd)shows potential in improving islet function,its clinical application is limited by rapid clearance.Given the promising prospects of adipose-derived mesenchymal stem cell exosomes(Exos)in targeted therapy,whether this nanocarrier can enhance gAd’s efficacy in improving islet function warrants significant research attention.AIM To develop a new synergistic therapeutic strategy based on adipose-derived mesenchymal stem cells Exos loaded with gAd(gAd-Exo).METHODS A T2DM rat model was established using a high-fat diet and streptozotocin.Rats were randomized into control,T2DM,T2DM+gAd,T2DM+Exo,and T2DM+gAd-Exo groups,receiving respective treatments via tail vein injection for four weeks.Pancreatic tissues were subjected to histological,immunohistochemical,and biochemical analyses.Meanwhile in vitro experiments assessed the protective effects of gAd-Exo on palmitic acid-injured INS-1 cells.RESULTS gAd-Exo treatment significantly ameliorated hyperglycemia,improved pancreatic islet morphology,and reducedβ-cell apoptosis compared to other groups.It enhanced insulin sensitivity and down-regulated glucagon expression.Mechanistically,gAd-Exo activated the AMP-activated protein kinase/acetyl-CoA carboxylase signaling pathway.In vitro,gAd-Exo superiorly mitigated palmitic acid-induced oxidative stress and apoptosis in INS-1 cells.CONCLUSION This study shows that the combination of gAd and Exo produced a significant synergistic effect.gAd-Exo can relieve type 2 diabetes by reducing blood glucose,improving hyperinsulinaemia and islet function,and at the same time reducing isletβcells apoptosis.It may be achieved by activating the AMP-activated protein kinase/acetyl-CoA carboxylase pathway.The discovery provides a new strategy with synergistic regenerative potential for diabetes treatment.展开更多
The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal conten...The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal content opens the possibility for guiding treatment strategies for cancer diseases.Exosomal microRNA are considered one of the prime candidates for exosomal biomarkers.Exosomal circular RNAs represent excellent biomarkers for liquid biopsy because of their stability in many types of cancer.Exosomal proteins remain reliable biomarkers also.Exosomes have emerged as promising therapeutic candidates.Their biological properties render them ideal vectors for drug delivery.Genetic modification of exosomes is an effective way to deliver material capable of modulating cellular pathways involved in drug resistance.Furthermore,exosomes have been explored as carriers for metal-chelating agents.Integrating exosome-based therapies with traditional anticancer agents aims to exploit the natural targeting abilities of exosomes to enhance drug delivery.Despite the dynamic development of this field,many mechanisms of exosome action remain incompletely understood.Therefore,it is necessary to conduct further studies that will allow for a better understanding of their role in the process of resistance and will enable the development of effective therapeutic strategies.展开更多
Radiolabeled exosomes have emerged as a transformative platform at the intersection of nanomedicine,molecular imaging,and precision theranostics.These nanoscale extracellular vesicles exhibit intrinsic biocompatibilit...Radiolabeled exosomes have emerged as a transformative platform at the intersection of nanomedicine,molecular imaging,and precision theranostics.These nanoscale extracellular vesicles exhibit intrinsic biocompatibility,low immunogenicity,and inherent targeting capabilities,making them highly attractive for both diagnostic and therapeutic applications.The integration of radiochemistry with exosome biology enables noninvasive,real-time tracking of biodistribution,pharmacokinetics,and target engagement using advanced imaging modalities such as positron emission tomography and single-photon emission computed tomography.This minireview comprehensively summarizes current radiolabeling strategies for exosomes,including direct and indirect approaches,highlighting their advantages,limitations,and impact on vesicle integrity and imaging accuracy.Furthermore,we discuss key imaging platforms,in vivo biodistribution patterns,and pharmacokinetic profiles that influence therapeutic efficacy.Critical challenges such as rapid clearance by the mononuclear phagocyte system,labeling instability,and the lack of standardized protocols are also addressed.Finally,we outline future perspectives focusing on advanced bioengineering,multimodal imaging integration,and clinical translation frameworks.Radiolabeled exosomes represent a promising next-generation theranostic system with the potential to enable personalized,image-guided therapies across oncology and regenerative medicine.展开更多
Acupuncture,as a significant component of Traditional Chinese Medicine(TCM),has attracted increased attention for its mechanism of controlling the physiological functions of the human body and promoting the recovery o...Acupuncture,as a significant component of Traditional Chinese Medicine(TCM),has attracted increased attention for its mechanism of controlling the physiological functions of the human body and promoting the recovery of diseases by stimulating specific acupoints.Despite its long history and wide clinical application,the mechanism of action of acupuncture is still not fully understood.More research needs to be done on how acupuncture affects molecular communication and cellular function.Exosomes are nanoscale vesicles that rely on cellular multivesicular bodies(MVBs)fused with cell membranes to be released into the extracellular matrix.They are crucial for information transfer between cells and are currently a hot research topic in the world's cutting-edge life sciences.Previous research has demonstrated that the therapeutic effect of acupuncture may be related to stimulating certain cells to secrete exosomes,that exosomes released may contain“acupuncture information”,and that manipulating the back-injection of exosomes to produces“acupuncture-like”effects.These findings suggest that exosomes could serve as a bridge between conventional acupuncture therapy and modern precision medicine.They also offer fresh prospects and difficulties for acupuncture translational medicine research.To better define the relationship between exosomes and acupuncture,we reviewed and systematized the literature on past studies related to exosomes and acupuncture.This paper provides a significant theoretical and experimental foundation for applying exosomes in precision medicine by summarizing and analyzing the relationship between acupuncture stimulation and exosome function.This is expected to promote the combination of traditional acupuncture therapy and modern biotechnology and bring innovation and progress to future medical practice.展开更多
Gut microbiota-derived exosomes(MDEs)have emerged as a novel class of drug delivery and are secreted by bacteria,fungi,and archaea in the human microbiota within the human intestinal ecosystem and possess inherent bio...Gut microbiota-derived exosomes(MDEs)have emerged as a novel class of drug delivery and are secreted by bacteria,fungi,and archaea in the human microbiota within the human intestinal ecosystem and possess inherent biocompatibility and lower immunogenicity,enabling seamless integration within host intestinal and systemic bioenvironments.This review elucidates the cellular and molecular mechanisms governing MDE function,explaining how their unique lipid bilayer composition facilitates cellular entry via receptor-mediated endocytosis and membrane fusion.This review discusses how gut MDEs traverse biological barriers,such as the blood-brain barrier and intestinal mucosa,by modulating tight junction proteins and accurately transporting cargoes to desired tissues.Upon internalization,MDE cargoes actively modulate intracellular signaling cascades.Various drugs,including RNA,proteins,and small molecules,can be loaded into MDEs via physical or biological methods.Furthermore,bioengineering strategies to functionalize MDE surfaces with specific ligands for precise molecular targeting are evaluated.While obstacles regarding standardized production and quality control remain,gut MDEs have great promise in achieving personalized and precision medicine by targeting diseases such as cancer,inflammatory diseases,and male infertility.Future clinical translation relies on exploring these molecular interactions to generate highly efficient,engineered nanocarriers.展开更多
Heart failure results in impaired cardiac systolic and/or diastolic functions.Traditional pharmacological and non-pharmacological approaches provide,at best,only short-term symptomatic relief,and the long-term prognos...Heart failure results in impaired cardiac systolic and/or diastolic functions.Traditional pharmacological and non-pharmacological approaches provide,at best,only short-term symptomatic relief,and the long-term prognosis remains poor.Regenerative medicine,particularly mesenchymal stem cells(MSCs),presents a promising alternative for cardiac repair.Ye and Liu published a study in the recent issue of World Journal of Stem Cell highlights the cell-free therapy approach,focusing on the therapeutic potential of MSC-derived paracrine secretions,which exert crucial pleiotropic effects on cardiac repair and regeneration.Their mechanisms involve the seven primary modules that promote angiogenesis,inhibit apoptosis,reduce oxidative stress,modulate inflammatory responses,facilitate cardiomyogenesis,and reduce myocardial fibrosis.Furthermore,their complex repair mechanisms,regenerative pathways,and emerging strategies,which bring us a step closer to their clinical translation,have been discussed as part of the future perspective.While MSC-derived secretomes and exosomes show immense promise for myocardial reparability and improving cardiac function,further research is warranted to fully understand their roles,optimize techniques,and establish their safety and effectiveness for clinical use.展开更多
BACKGROUND Preeclampsia(PE)is a serious complication in pregnancy.It is one of the primary causes of maternal and perinatal mortality.Human amniotic epithelial cells(hAECs)and mesenchymal stem cells(MSCs)derived from ...BACKGROUND Preeclampsia(PE)is a serious complication in pregnancy.It is one of the primary causes of maternal and perinatal mortality.Human amniotic epithelial cells(hAECs)and mesenchymal stem cells(MSCs)derived from human umbilical cord blood(hucbMSCs)are both perinatal stem cells,capable of expressing characteristic stem cell surface markers.MSC-derived exosomes(MSCs-exos)exhibit functional properties comparable to those of MSCs,while offering advantages such as greater biological stability and the ability to circumvent potential complications associated with MSC-based therapy.This study utilized hAEC-derived exosomes(hAECs-exos)and hucbMSC-derived exosomes(hucbMSCs-exos)to treat preeclamptic rats and investigate their therapeutic effects.AIM To investigate the therapeutic effects of hAECs-exos and hucbMSCs-exos on PE in rats.METHODS Thirty-two pregnant rats were divided into four groups(normal pregnancy,PE,and two exosome-treated groups;n=8).The PE model was induced by L-arginine methyl ester.From gestation day 12,the treatment groups received hAECs-exos or hucbMSCs-exos for 7 days,while controls received normal saline.Blood pressure,urinary protein,fetal/placental weight,and tissue analyses were performed.Quantitative data are expressed as the mean±SD.Differences among multiple groups were analyzed by one-way analysis of variance(ANOVA),followed by the LSD-t test for pairwise comparisons.A P value<0.05 was considered statistically significant.RESULTS Compared to the normal pregnancy group,rats in the PE group exhibited significantly elevated blood pressure and 24-hour urinary protein levels,indicating successful model establishment.Furthermore,the PE group showed significantly increased levels of interleukin-6,tumor necrosis factor-α,soluble fms-like tyrosine kinase-1,and malondialdehyde,along with decreased fetal/placental weight,levels of interleukin-10,placental growth factor,vascular endothelial growth factor,superoxide dismutase,and placental CD31 expression(P<0.05).Treatment with both exosomes significantly reversed all these alterations compared to the PE group(P<0.05).Histological analysis further confirmed that the treatments markedly alleviated renal and placental pathological damage induced by PE.CONCLUSION This study demonstrates that both hAECs-exos and hucbMSCs-exos have therapeutic effects in rats with PE,potentially through mechanisms involving the inhibition of oxidative stress and inflammatory responses.展开更多
BACKGROUND Exosomes(Exos)derived from mesenchymal stem cells(MSCs)have emerged as a promising therapeutic option for diabetic wound healing owing to their strong pro-angiogenic potential.Nevertheless,their relatively ...BACKGROUND Exosomes(Exos)derived from mesenchymal stem cells(MSCs)have emerged as a promising therapeutic option for diabetic wound healing owing to their strong pro-angiogenic potential.Nevertheless,their relatively low bioactivity remains a major barrier to successful clinical application.Fractional CO2laser therapy offers a precise and controllable form of photothermal stimulation that may potentiate exosome activity without the need for additional exogenous agents,possibly promoting more effective diabetic wound repair.AIM To investigate the mechanisms through which low-energy fractional Exos derived from CO2laser-preconditioned adipose-derived MSCs(Ad-MSCs)(CO2laser-Exos)promote the healing of diabetic wounds.METHODS Ad-MSCs were subjected to a single exposure of fractional CO2laser at energy densities of 30 mJ/cm2,40 mJ/cm2,or 50 mJ/cm2.Infrared thermography was employed to monitor temperature fluctuations in the culture medium.To determine the optimal energy level,western blotting was performed to assess heat shock protein 90 expression,while apoptosis was analyzed by flow cytometry.Exos were subsequently isolated through ultracentrifugation,and sphingosine-1-phosphate(S1P)concentrations within the Exos were measured using enzymelinked immunosorbent assay.The therapeutic efficacy and underlying mechanisms of CO2laser-Exos were further investigated through a series of in vitro and in vivo experiments.RESULTS Following a single exposure to fractional CO2laser,the culture medium temperature increased rapidly and then gradually declined.Among the tested groups,Ad-MSCs treated with 40 mJ/cm2demonstrated the highest heat shock protein 90 expression and exhibited reduced apoptosis.in vitro,CO2laser-Exos markedly promoted the proliferation,migration,and tube formation of human umbilical vein endothelial cells,while their S1P content was higher than that of unconditioned Exos.Under high-glucose conditions,human umbilical vein endothelial cells showed increased expression of S1P receptor 1(S1PR1).Silencing S1PR1 significantly impaired the pro-angiogenic activity of CO2laser-Exos and suppressed the expression of phosphorylated protein kinase B,hypoxia-inducible factor 1 alpha,and vascular endothelial growth factor-A.In vivo,compared with Exos,CO2laser-Exos substantially accelerated diabetic wound healing by promoting neovascularization within the wound bed.CONCLUSION Low-energy fractional CO2laser irradiation augments the biological activity of MSC-derived Exos through photothermal stimulation.These Exos,in turn,enhance endothelial cell functions by activating the S1PR1/protein kinase B/hypoxia-inducible factor 1 alpha signaling pathway,ultimately accelerating the repair of diabetic wounds.展开更多
Background Exosomes are crucial mediators of intercellular communication.As a key component of milk,milkderived exosomes are abundant in genetic cargo,particularly micro RNAs(mi RNAs),indicating their potential role i...Background Exosomes are crucial mediators of intercellular communication.As a key component of milk,milkderived exosomes are abundant in genetic cargo,particularly micro RNAs(mi RNAs),indicating their potential role in regulating mammary gland physiology.Therefore,this study aimed to investigate the specificity of mi RNAs in milkderived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells(BMECs).Results Based on 17,838 DHI records showing a significantly higher milk fat percentage(MFP)in late lactation(4.24%±1.07%),10 high-(5.96%±0.26%,HMF)and 10 low-MFP(1.68%±0.23%,LMF)cows were selected during this stage for milk-derived exosome isolation and mi RNA profiling.Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9,CD81,and TSG101.mi RNA sequencing identified 1,320 differentially expressed mi RNAs(496 upregulated and 824 downregulated)between the HMF_EXO and LMF_EXO groups.Uptake assays confirmed that BMECs internalized these exosomes,and q RT-PCR validation showed that mi R-423-5p and mi R-125b were significantly upregulated and downregulated in HMF_EXO-and LMF_EXO-treated BMECs,respectively.Functionally,exosomal mi R-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5,whereas mi R-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1.Conclusions This study demonstrates that milk-derived exosomal mi RNAs represent a novel mechanism for regulating milk fat synthesis.Specifically,mi R-423-5p and mi R-125b directly modulated lipid metabolism in BMECs via the mi R-423-5p/APOA5 and mi R-125b/SLC27A1 pathways.These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland.展开更多
●Ocular graft-versus-host disease(oGVHD)is an immune disease that occurs in the eye after allogeneic hematopoietic stem cell transplantation and seriously affects the vision and quality of life of patients.Current tr...●Ocular graft-versus-host disease(oGVHD)is an immune disease that occurs in the eye after allogeneic hematopoietic stem cell transplantation and seriously affects the vision and quality of life of patients.Current treatment modalities are inadequate,and new treatment options and targets are required to improve the therapeutic efficacy of oGVHD.In recent years,a large number of studies have shown that exosomes,as important mediators of cell-to-cell communication,have important research value in the pathogenesis,diagnosis,and treatment of oGVHD.This article reviews the research progress on exosomes from different sources of oGVHD.展开更多
基金Supported by Natural Science Projects of Bengbu Medical College,No.2022byzd088Anhui Province Higher Education Scientific Research Project,No.2024AH051285+1 种基金Anhui Provincial Department of Education Humanities and Social Science Key Project,No.2023AH051900the Key Research and Development Program Projects of Anhui Province,No.202204295107020049.
摘要BACKGROUND Diabetic osteoporosis(DOP),a serious complication of type 2 diabetes mellitus(T2DM),involves ferroptosis-mediated disruption of bone metabolism.While endothelial cell-derived exosomes(EC-Exos)demonstrate inherent bone-targeting properties,their role in counteracting high glucose(HG)-induced osteoblast ferroptosis remains unexplored.AIM To investigate whether EC-Exos protect against HG-induced osteoblast ferroptosis through microRNA(miR)-335-3p-mediated regulation of prostaglandin endoperoxide synthase 2(PTGS2)and evaluate clinical relevance in DOP.METHODS Mouse vascular endothelial cells(bEND.3)and osteoblasts(MC3T3E1)were used.Exosomes were isolated and subsequently characterized by transmission electron microscopy,nanoparticle tracking analysis,and western blotting for CD63 and CD81.miR expression profiles were compared between HG-treated osteoblasts and exosome-cocultured groups using high-throughput sequencing and quantitative reverse transcription polymerase chain reaction.Targeting of PTGS2 mRNA by miR-335-3p was validated by dual-luciferase reporter assay.Ferroptosis markers,reactive oxygen species,malondialdehyde,glutathione(GSH),PTGS2,GSH peroxidase 4,solute carrier family 7 member 11,and solute carrier family 3 member 2,were quantified following miR-335-3p inhibition.Serum samples from 30 T2DM patients and 32 DOP patients were analyzed.miR-335-3p levels were measured by quantitative reverse transcription polymerase chain reaction,and PTGS2 concentrations were determined via enzyme-linked immunosorbent assay.Diagnostic performance was assessed using receiver operating characteristic curves and logistic regression.RESULTS EC-Exos significantly reduced reactive oxygen species levels and malondialdehyde,while increasing GSH in HG-treated osteoblasts.miR-335-3p expression increased 3.7-fold in exosome-treated cells vs HG controls.miR-335-3p directly bound the PTGS23’untranslated region.Inhibition of miR-335-3p abolished exosomal protection against ferroptosis,as demonstrated by increased PTGS2 expression and reduced levels of GSH peroxidase 4,solute carrier family 7 member 11,and solute carrier family 3 member 2.DOP patients exhibited lower serum miR-335-3p and higher PTGS2 compared with T2DM controls,showing a strong inverse correlation.miR-335-3p demonstrated diagnostic potential for DOP.CONCLUSION EC-Exos affect ferroptosis in osteoblasts induced by HG by activating miR-335-3p/PTGS2.Serum miR-335-3p may be a novel diagnostic biomarker.
基金supported by the Joint Funds for the Innovation of Science and Technology,Fujian Province,No.2023Y9233(to HH)the QuanzhouScience and Technology Project,No.2022C036R(to HH)+1 种基金the Science and Technology Bureau of Quanzhou,No.2020CT003(to SL)the Quanzhou MunicipalMedical and Health Guiding Science and Technology Project,No.2023N066S(to YZhou).
摘要Spinal cord injury is a critical event characterized by intricate pathogenic mechanisms.Although recent studies have highlighted tissue exosomes as key mediators of inflammatory responses in diverse organs and tissues,their role in spinal cord injury has yet to be determined.In this study,we investigated the role and mechanisms of spinal cord tissue exosomes in the inflammatory response following spinal cord injury.We found morphological,concentration,and functional differences between exosomes extracted from injured and normal spinal cord tissues,and identified proinflammatory effects associated with spinal cord injury-generated tissue exosomes but not with exosomes derived from normal spinal cord tissue.Our in vivo and in vitro analyses showed that spinal cord injury-generated tissue exosomes promoted microglial M1 polarization and inflammatory cytokine expression,thereby exacerbating tissue and neuronal injury in the spinal cord.In addition,the combination of exosomal miRNA sequencing and experimental verification showed that the miR-155-5p level was higher in spinal cord injury-generated tissue exosomes than in spinal cord tissue.We further found that spinal cord injury-generated tissue exosomes-derived miR-155-5p induced a significant inhibition of forkhead box O3a phosphorylation and activated the nuclear factor-kappa B pathway,thereby promoting microglial M1 polarization and inflammatory cytokine expression.These findings suggest that injury-induced miR-155-5p-containing exosomes exacerbate spinal cord injury via the promotion of microglial M1 polarization and inflammatory responses.Thus,targeting miR-155-5p expression or exosome secretion could be a novel strategy for attenuating inflammation and reducing secondary injury post-spinal cord injury.
基金the National Natural Science Foundation of China(8220142161 to Rui Chen).
摘要Objective:Osimertinib can selectively inhibit both epidermal growth factor receptor(EGFR)sensitizing and T790M gatekeeper mutations,and has shown remarkable therapeutic effects in patients with lung adenocarcinoma.However,almost all patients inevitably develop drug resistance.Herein,we sought to clarify the roles of exosomal lncRNA H19 in modulating osimertinib resistance,focusing on the PI3K-PTEN-Akt signaling axis.Methods:Functional assays,including cell viability assay,colony formation,cell apoptosis and xenograft mouse,employed in evaluate the effects of exosomal lncRNA H19 on cell growth and apoptosis.RNA quantitation and western blot were adopted to demonstrate the regulatory roles of exosomal lncRNA H19 in PI3K-PTEN-Akt signaling pathway.Immunofluorescence was applied to obverse the function and distribution of exosomes.Furthermore,dual-luciferase reporter analysis combined with RNA immunoprecipitation(RIP)was applied to verify the molecular interaction between lncRNA H19 and phosphatase and tensin homolog(PTEN).Results:LncRNA H19 exhibited obviously decreased expression in H1975R cells and their secreted exosomes.Overexpression of H19 enhances the cytotoxicity of osimertinib,inhibits the growth of H1975R cells,and promotes apoptosis.Conversely,H19 silencing promotes osimertinib resistance in H1975 cells and enhances the cell-resistant phenotype.Furthermore,exosome-transferred lncRNA H19 sponged miR-148-3p to augment PTEN expression,which in turn inactivated the PI3K-Akt signaling pathway and ultimately induced cell apoptosis.Conclusion:Exosome-encapsulated lncRNA H19 can be delivered to osimertinib-resistant H1975R cells,thereby reversing resistance through the miR-148-3p/PTEN/PI3K-Akt axis.Our results uncover a potential therapeutic approach to surmount osimertinib resistance in lung cancer.
基金Supported by Key Scientific Research Projects of Colleges and Universities in Henan Province,No.26A320038Henan Province Medical Science and Technology Research Plan Project(Joint Construction),No.LHGJ20250403,No.LHGJ20220566,and No.LHGJ20240365+1 种基金Key Research and Development Program of Henan Province,No.231111311000the Medical Education Research Project in Henan Province,No.WJLX2023079.
摘要Osteoarthritis(OA)remains a highly prevalent degenerative joint disorder for which truly disease-modifying therapies are still lacking.Accumulating evidence positions mitochondrial dysfunction and impaired mitochondrial quality control as central drivers of chondrocyte failure,extracellular matrix breakdown,and inflammation amplification.Mitophagy—particularly the phosphatase and tensin homolog-induced kinase 1(PINK1)/Parkin axis—has therefore emerged as an attractive,mechanistically grounded intervention point.In this context,synovial mesenchymal stem cell-derived exosomes(SMSC-Exos)represent a compelling cell-free platform capable of delivering functional biomolecules into inflamed cartilage microenvironments.Recent experimental work demonstrates that engineering SMSC-Exos to deliver the mitochondrial co-chaperone GrpE-like 1(GRPEL1)restores chondrocyte proliferative and migratory capacity under interleukin-1βstress,preserves anabolic extracellular matrix markers(collagen type II alpha 1/aggrecan),suppresses catabolic mediators(matrix metalloproteinase 13/A disintegrin and metalloproteinase with thrombospondin motifs 5),and mitigates oxidative damage while enhancing mitophagy signatures.Mechanistically,GRPEL1 directly associates with PINK1,and PINK1 knockdown attenuates the protective phenotype,supporting a GRPEL1-PINK1 coupling model.In vivo,intra-articular administration of GRPEL1-enriched SMSC-Exos improves histological cartilage integrity and mitophagy-related readouts in a rat OA model.Here,we synthesize mechanistic implications,highlight interpretive nuances(e.g.,mitophagy activation concurrent with membrane potential recovery),and outline translational priorities,including cargo quantification,mitophagy flux validation,dosingetention kinetics,manufacturing standardization,and biomarker-driven patient stratification.
摘要Neurodegenerative disorders such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis represent a significant global health challenge with limited therapeutic options.In recent years,stem cell-based therapies have shown promise in promoting neural repair and modulating disease progression.However,concerns related to immune rejection,tumorigenicity,and ethical considerations have limited their clinical application.As an alternative,exosomes derived from stem cells have emerged as a novel,acellular therapeutic strategy.These nanoscale extracellular vesicles carry a rich cargo of proteins,lipids,and nucleic acids,capable of modulating neuroinflammation,promoting neuroprotection,and enhancing tissue repair.Their ability to cross the blood-brain barrier and their low immunogenicity make them especially attractive for treating central nervous system disorders.This review highlights the therapeutic potential of stem cell-derived exosomes in the management of neurodegenerative diseases,discussing their mechanisms of action,current research progress,and future clinical applications.The development of exosome-based therapies marks a significant step toward safe,effective,and cell-free neurodegeneration.
摘要Alzheimer's disease is a complex and devastating neurodegenerative disorder that accounts for roughly 80% of all dementia cases.It is primarily marked by the accumulation of senile amyloid-β plaques and neurofibrillary tangles composed of hyperphosphorylated tau protein.These pathological features are accompanied by chronic neuroinflammation and glial cell dysfunction,which collectively contribute to the progressive loss of synapses and neurons.As a result,individuals with Alzheimer's disease experience gradual memory loss and cognitive decline.Currently,the global patient population is nearing 50 million,a number expected to increase dramatically over the coming decades.Conventional treatments focus on symptom management through acetylcholinesterase inhibitors,such as donepezil,galantamine,and rivastigmine,and the N-methyl-D-aspartate receptor antagonist memantine.However,the past few years have seen the approval of newer agents such as sodium oligomannate,aducanumab,and lecanemab,which show some promise in slowing disease progression.Unfortunately,most patients are not diagnosed until moderate or advanced stages when irreversible brain damage has occurred.This highlights an urgent need for early diagnosis and biomarkers together with therapeutic strategies aimed at early-stage intervention and identifying novel drug targets that address prodromal and established forms of the disease.This article is a literature review of extracellular vesicles/exosomes treatment in animal models of Alzheimer's disease involving micro RNAs.In the in vivo animal studies of Alzheimer's disease reviewed,extracellular vesicles and exosomes from various sources improved memory and cognitive decline,lowered inflammation and amyloid deposition,and increased neuron survival in the brain.Loading extracellular vesicles and exosomes with micro RNA mimics(e.g.,miR-22,-29b,-124,-132,-138-5p,-342-5p,-711,and-7670-3p)or antagomirs(e.g.,miR-206-antagomir)improved outcomes in animal models of Alzheimer's disease.Supporting results were found in the in vitro cell studies reviewed.
基金supported by the National Key R&D Program of China,Nos.2021YFA1101703/2021YFA1101700(to YD).
摘要Ischemic stroke remains a leading cause of disability and death,with mesenchymal stem cell-derived exosomes emerging as a promising therapeutic avenue.However,the optimal timing and underlying therapeutic mechanisms of exosome treatment require further elucidation.In this study,we used a murine model of middle cerebral artery occlusion to investigate the therapeutic efficacy of human umbilical cord mesenchymal stem cell-derived exosomes administered intravenously at an early(6 hours)or delayed(3 days)time point post-ischemia.Compared with delayed treatment,early administration of exosomes resulted in significantly superior efficacy,as evidenced by improved neurological function scores and reduced infarct volumes.Transcriptomic analysis of brain tissues from mice receiving early exosome treatment revealed marked downregulation of inflammation-related genes,including Ccl2,Ccl5,Cxcl10,Il-1β,Il-6,Itgam,Itgax,and Tnf-α.Metabolomic profiling of these brain tissues further identified modulation of key metabolites,including trimethylamine N-oxide,glutathione,1-stearoyl-rac-glycerol,and phosphatidylcholine,suggesting that alteration of metabolic pathways contributes to the therapeutic effect.Integrated transcriptomic and metabolomic analysis pinpointed significant modulation of pathways involving metabolism of eicosapentaenoic acid,lysine,propanoate,and tyrosine.These findings suggest that umbilical cord mesenchymal stem cell-derived exosomes,particularly when administered early post-ischemia,exert their neuroprotective effects by broadly suppressing inflammatory pathways and modulating key metabolic processes in the ischemic brain,highlighting their potential as a therapeutic intervention for ischemic stroke.
基金supported by the National Natural Science Foundation of China,No.22103055(to JG)the Natural Science Foundation of Hebei Province,No.F2024110001(to HC)Open Project of Tianjin Key Laboratory of Optoelectronic Detection Technology and System,Nos.2024LODTS215(to NL),2024LODTS216(to XS).
摘要In recent years,exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research.Exosomes are small and can effectively cross the blood-brain barrier,allowing them to target deep brain lesions.Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines,mRNAs,and disease-related proteins,thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects.However,exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells.This limitation can lead to side effects and toxicity when they interact with non-specific cells.Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases.In this review,we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases.Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases.We introduce the strategies being used to enhance exosome targeting,including genetic engineering,chemical modifications(both covalent,such as click chemistry and metabolic engineering,and non-covalent,such as polyvalent electrostatic and hydrophobic interactions,ligand-receptor binding,aptamer-based modifications,and the incorporation of CP05-anchored peptides),and nanomaterial modifications.Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases.However,several challenges remain in the clinical application of exosomes.Improvements are needed in preparation,characterization,and optimization methods,as well as in reducing the adverse reactions associated with their use.Additionally,the range of applications and the safety of exosomes require further research and evaluation.
基金Physiology Research Center and the Department of Physiology,Afzalipour School of Medicine,Kerman University of Medical Sciences,Kerman,Iran,Grant/Award Number:402000873。
摘要Background:Excessive extracellular matrix accumulation,primarily as a result of hepatic stellate cell activation,is a hallmark of hepatic fibrosis,a progressive outcome of chronic liver injuries.Recent research studies suggest that stem cells,hepatocytes,and extracellular vesicles may provide therapeutic advantages due to their anti-inflammatory,antioxidative,and regenerative activities.This study aimed to comparatively evaluate the therapeutic efficacy of these agents in a rat model of carbon tetrachloride(CCl4)-induced hepatic fibrosis.Methods:Liver fibrosis was induced in male Wistar rats via intraperitoneal CCl4 injections for 8 weeks.Then the animals were intravenously administrated stem cells,hepatocytes,hepatocyte-derived exosomes,or stem cell-derived exosomes.Also,a fibrosis,a sham,a intact,and a PBS-treated group were consider the controls.After treatment,protein expression(alpha-smooth muscle actin(α-SMA),desmin),oxidative stress markers(superoxide dismutase,glutathione peroxidase,malondialdehyde),serum biochemical parameters(aspartate aminotransferase,alanine aminotransferase,glucose,uric acid,cholesterol,triglycerides),and fibrosis-related gene expression(matrix metalloproteinase 2(MMP2),platelete-derived growth factor receptor beta(PDGFRB),transforming growth factor-beta(TGF-β),thymosin beta-10(TMSB10)and transmembrane protein 176B(TMEM176B))were assessed.Results:Significant liver damage,changed metabolic parameters,increased oxidative stress,and upregulated fibrosis markers were all observed in the fibrosis group.On the contrary,all treatments caused considerable improvements,though exosomes derived from stem cells demonstrated the most significant effects.Along with improved histopathological features,this group exhibited significant decreases in oxidative damage,liver enzymes,and profibrotic marker expression.Conclusion:Liver fibrosis was considerably reduced by stem cells,hepatocytes,and particularly their exosomes.Exosomes made from stem cells demonstrated the strongest therapeutic effect,confirming their potential as a viable noncellular hepatic fibrosis treatment approach.
摘要Knee osteoarthritis is recognised as a whole-joint disorder involving cartilage,synovium,subchondral bone and nociceptive pathways.Conventional therapies provide symptomatic relief but rarely alter structural progression.Mesenchymal stromal cell(MSC)injections improve pain and function,yet structural benefits remain modest and variable.Increasing evidence indicates that much of the MSC effect is mediated by secreted extracellular vesicles(EVs),particularly those derived from bone marrow MSCs.These vesicles deliver proteins,lipids,microRNAs and long noncoding RNAs that regulate catabolic enzymes,inflammatory mediators and survival pathways,thereby influencing chondrocyte apoptosis,matrix turnover,macrophage polarisation,osteoclast activity and nociceptive signalling.This review uniquely synthesises mechanistic insights into extracellular vesicles derived from bone marrow MSCs cargo,compares their performance with other MSC sources,and highlights translational priorities including Minimal Information for Studies of EVs 2023-compliant characterisation,dose-finding,and adequately powered trials with structural and biomarker endpoints.
基金Supported by Basic Research Program of Shanxi Province,No.20210302123241.
摘要BACKGROUND The global prevalence of type 2 diabetes mellitus(T2DM)is increasing.Although globular adiponectin(gAd)shows potential in improving islet function,its clinical application is limited by rapid clearance.Given the promising prospects of adipose-derived mesenchymal stem cell exosomes(Exos)in targeted therapy,whether this nanocarrier can enhance gAd’s efficacy in improving islet function warrants significant research attention.AIM To develop a new synergistic therapeutic strategy based on adipose-derived mesenchymal stem cells Exos loaded with gAd(gAd-Exo).METHODS A T2DM rat model was established using a high-fat diet and streptozotocin.Rats were randomized into control,T2DM,T2DM+gAd,T2DM+Exo,and T2DM+gAd-Exo groups,receiving respective treatments via tail vein injection for four weeks.Pancreatic tissues were subjected to histological,immunohistochemical,and biochemical analyses.Meanwhile in vitro experiments assessed the protective effects of gAd-Exo on palmitic acid-injured INS-1 cells.RESULTS gAd-Exo treatment significantly ameliorated hyperglycemia,improved pancreatic islet morphology,and reducedβ-cell apoptosis compared to other groups.It enhanced insulin sensitivity and down-regulated glucagon expression.Mechanistically,gAd-Exo activated the AMP-activated protein kinase/acetyl-CoA carboxylase signaling pathway.In vitro,gAd-Exo superiorly mitigated palmitic acid-induced oxidative stress and apoptosis in INS-1 cells.CONCLUSION This study shows that the combination of gAd and Exo produced a significant synergistic effect.gAd-Exo can relieve type 2 diabetes by reducing blood glucose,improving hyperinsulinaemia and islet function,and at the same time reducing isletβcells apoptosis.It may be achieved by activating the AMP-activated protein kinase/acetyl-CoA carboxylase pathway.The discovery provides a new strategy with synergistic regenerative potential for diabetes treatment.
摘要The last research focuses on the role of exosomes in cancer treatment.Exosomes are extracellular vesicles.They can be secreted by cancer cells,and they can modulate chemotherapy sensitivity.Determining exosomal content opens the possibility for guiding treatment strategies for cancer diseases.Exosomal microRNA are considered one of the prime candidates for exosomal biomarkers.Exosomal circular RNAs represent excellent biomarkers for liquid biopsy because of their stability in many types of cancer.Exosomal proteins remain reliable biomarkers also.Exosomes have emerged as promising therapeutic candidates.Their biological properties render them ideal vectors for drug delivery.Genetic modification of exosomes is an effective way to deliver material capable of modulating cellular pathways involved in drug resistance.Furthermore,exosomes have been explored as carriers for metal-chelating agents.Integrating exosome-based therapies with traditional anticancer agents aims to exploit the natural targeting abilities of exosomes to enhance drug delivery.Despite the dynamic development of this field,many mechanisms of exosome action remain incompletely understood.Therefore,it is necessary to conduct further studies that will allow for a better understanding of their role in the process of resistance and will enable the development of effective therapeutic strategies.
摘要Radiolabeled exosomes have emerged as a transformative platform at the intersection of nanomedicine,molecular imaging,and precision theranostics.These nanoscale extracellular vesicles exhibit intrinsic biocompatibility,low immunogenicity,and inherent targeting capabilities,making them highly attractive for both diagnostic and therapeutic applications.The integration of radiochemistry with exosome biology enables noninvasive,real-time tracking of biodistribution,pharmacokinetics,and target engagement using advanced imaging modalities such as positron emission tomography and single-photon emission computed tomography.This minireview comprehensively summarizes current radiolabeling strategies for exosomes,including direct and indirect approaches,highlighting their advantages,limitations,and impact on vesicle integrity and imaging accuracy.Furthermore,we discuss key imaging platforms,in vivo biodistribution patterns,and pharmacokinetic profiles that influence therapeutic efficacy.Critical challenges such as rapid clearance by the mononuclear phagocyte system,labeling instability,and the lack of standardized protocols are also addressed.Finally,we outline future perspectives focusing on advanced bioengineering,multimodal imaging integration,and clinical translation frameworks.Radiolabeled exosomes represent a promising next-generation theranostic system with the potential to enable personalized,image-guided therapies across oncology and regenerative medicine.
基金Fujian Outstanding Youth Science Foundation Project:Research on Electroacupuncture-mediated Regulation of Time-pattern-dependent Synaptic Plasticity in the Hippocampus of Rats with Vascular Cognitive Impairment and Its Mechanisms(No.2021J06028)。
摘要Acupuncture,as a significant component of Traditional Chinese Medicine(TCM),has attracted increased attention for its mechanism of controlling the physiological functions of the human body and promoting the recovery of diseases by stimulating specific acupoints.Despite its long history and wide clinical application,the mechanism of action of acupuncture is still not fully understood.More research needs to be done on how acupuncture affects molecular communication and cellular function.Exosomes are nanoscale vesicles that rely on cellular multivesicular bodies(MVBs)fused with cell membranes to be released into the extracellular matrix.They are crucial for information transfer between cells and are currently a hot research topic in the world's cutting-edge life sciences.Previous research has demonstrated that the therapeutic effect of acupuncture may be related to stimulating certain cells to secrete exosomes,that exosomes released may contain“acupuncture information”,and that manipulating the back-injection of exosomes to produces“acupuncture-like”effects.These findings suggest that exosomes could serve as a bridge between conventional acupuncture therapy and modern precision medicine.They also offer fresh prospects and difficulties for acupuncture translational medicine research.To better define the relationship between exosomes and acupuncture,we reviewed and systematized the literature on past studies related to exosomes and acupuncture.This paper provides a significant theoretical and experimental foundation for applying exosomes in precision medicine by summarizing and analyzing the relationship between acupuncture stimulation and exosome function.This is expected to promote the combination of traditional acupuncture therapy and modern biotechnology and bring innovation and progress to future medical practice.
基金The Deanship of Scientific Research(DSR)at King Abdulaziz University(KAU),Jeddah,Saudi Arabia,has funded this project under grant No.(RG-20-166-43).
摘要Gut microbiota-derived exosomes(MDEs)have emerged as a novel class of drug delivery and are secreted by bacteria,fungi,and archaea in the human microbiota within the human intestinal ecosystem and possess inherent biocompatibility and lower immunogenicity,enabling seamless integration within host intestinal and systemic bioenvironments.This review elucidates the cellular and molecular mechanisms governing MDE function,explaining how their unique lipid bilayer composition facilitates cellular entry via receptor-mediated endocytosis and membrane fusion.This review discusses how gut MDEs traverse biological barriers,such as the blood-brain barrier and intestinal mucosa,by modulating tight junction proteins and accurately transporting cargoes to desired tissues.Upon internalization,MDE cargoes actively modulate intracellular signaling cascades.Various drugs,including RNA,proteins,and small molecules,can be loaded into MDEs via physical or biological methods.Furthermore,bioengineering strategies to functionalize MDE surfaces with specific ligands for precise molecular targeting are evaluated.While obstacles regarding standardized production and quality control remain,gut MDEs have great promise in achieving personalized and precision medicine by targeting diseases such as cancer,inflammatory diseases,and male infertility.Future clinical translation relies on exploring these molecular interactions to generate highly efficient,engineered nanocarriers.
摘要Heart failure results in impaired cardiac systolic and/or diastolic functions.Traditional pharmacological and non-pharmacological approaches provide,at best,only short-term symptomatic relief,and the long-term prognosis remains poor.Regenerative medicine,particularly mesenchymal stem cells(MSCs),presents a promising alternative for cardiac repair.Ye and Liu published a study in the recent issue of World Journal of Stem Cell highlights the cell-free therapy approach,focusing on the therapeutic potential of MSC-derived paracrine secretions,which exert crucial pleiotropic effects on cardiac repair and regeneration.Their mechanisms involve the seven primary modules that promote angiogenesis,inhibit apoptosis,reduce oxidative stress,modulate inflammatory responses,facilitate cardiomyogenesis,and reduce myocardial fibrosis.Furthermore,their complex repair mechanisms,regenerative pathways,and emerging strategies,which bring us a step closer to their clinical translation,have been discussed as part of the future perspective.While MSC-derived secretomes and exosomes show immense promise for myocardial reparability and improving cardiac function,further research is warranted to fully understand their roles,optimize techniques,and establish their safety and effectiveness for clinical use.
基金Supported by Shenyang Science and Technology Plan in 2022,No.22-321-32-16.
摘要BACKGROUND Preeclampsia(PE)is a serious complication in pregnancy.It is one of the primary causes of maternal and perinatal mortality.Human amniotic epithelial cells(hAECs)and mesenchymal stem cells(MSCs)derived from human umbilical cord blood(hucbMSCs)are both perinatal stem cells,capable of expressing characteristic stem cell surface markers.MSC-derived exosomes(MSCs-exos)exhibit functional properties comparable to those of MSCs,while offering advantages such as greater biological stability and the ability to circumvent potential complications associated with MSC-based therapy.This study utilized hAEC-derived exosomes(hAECs-exos)and hucbMSC-derived exosomes(hucbMSCs-exos)to treat preeclamptic rats and investigate their therapeutic effects.AIM To investigate the therapeutic effects of hAECs-exos and hucbMSCs-exos on PE in rats.METHODS Thirty-two pregnant rats were divided into four groups(normal pregnancy,PE,and two exosome-treated groups;n=8).The PE model was induced by L-arginine methyl ester.From gestation day 12,the treatment groups received hAECs-exos or hucbMSCs-exos for 7 days,while controls received normal saline.Blood pressure,urinary protein,fetal/placental weight,and tissue analyses were performed.Quantitative data are expressed as the mean±SD.Differences among multiple groups were analyzed by one-way analysis of variance(ANOVA),followed by the LSD-t test for pairwise comparisons.A P value<0.05 was considered statistically significant.RESULTS Compared to the normal pregnancy group,rats in the PE group exhibited significantly elevated blood pressure and 24-hour urinary protein levels,indicating successful model establishment.Furthermore,the PE group showed significantly increased levels of interleukin-6,tumor necrosis factor-α,soluble fms-like tyrosine kinase-1,and malondialdehyde,along with decreased fetal/placental weight,levels of interleukin-10,placental growth factor,vascular endothelial growth factor,superoxide dismutase,and placental CD31 expression(P<0.05).Treatment with both exosomes significantly reversed all these alterations compared to the PE group(P<0.05).Histological analysis further confirmed that the treatments markedly alleviated renal and placental pathological damage induced by PE.CONCLUSION This study demonstrates that both hAECs-exos and hucbMSCs-exos have therapeutic effects in rats with PE,potentially through mechanisms involving the inhibition of oxidative stress and inflammatory responses.
基金Supported by the National Natural Science Foundation of China,No.82172224Xuzhou Health Commission Science and Technology Project,No.XWKYHT20220136Xuzhou Health Commission Youth Project,No.XWKYHT20220145。
摘要BACKGROUND Exosomes(Exos)derived from mesenchymal stem cells(MSCs)have emerged as a promising therapeutic option for diabetic wound healing owing to their strong pro-angiogenic potential.Nevertheless,their relatively low bioactivity remains a major barrier to successful clinical application.Fractional CO2laser therapy offers a precise and controllable form of photothermal stimulation that may potentiate exosome activity without the need for additional exogenous agents,possibly promoting more effective diabetic wound repair.AIM To investigate the mechanisms through which low-energy fractional Exos derived from CO2laser-preconditioned adipose-derived MSCs(Ad-MSCs)(CO2laser-Exos)promote the healing of diabetic wounds.METHODS Ad-MSCs were subjected to a single exposure of fractional CO2laser at energy densities of 30 mJ/cm2,40 mJ/cm2,or 50 mJ/cm2.Infrared thermography was employed to monitor temperature fluctuations in the culture medium.To determine the optimal energy level,western blotting was performed to assess heat shock protein 90 expression,while apoptosis was analyzed by flow cytometry.Exos were subsequently isolated through ultracentrifugation,and sphingosine-1-phosphate(S1P)concentrations within the Exos were measured using enzymelinked immunosorbent assay.The therapeutic efficacy and underlying mechanisms of CO2laser-Exos were further investigated through a series of in vitro and in vivo experiments.RESULTS Following a single exposure to fractional CO2laser,the culture medium temperature increased rapidly and then gradually declined.Among the tested groups,Ad-MSCs treated with 40 mJ/cm2demonstrated the highest heat shock protein 90 expression and exhibited reduced apoptosis.in vitro,CO2laser-Exos markedly promoted the proliferation,migration,and tube formation of human umbilical vein endothelial cells,while their S1P content was higher than that of unconditioned Exos.Under high-glucose conditions,human umbilical vein endothelial cells showed increased expression of S1P receptor 1(S1PR1).Silencing S1PR1 significantly impaired the pro-angiogenic activity of CO2laser-Exos and suppressed the expression of phosphorylated protein kinase B,hypoxia-inducible factor 1 alpha,and vascular endothelial growth factor-A.In vivo,compared with Exos,CO2laser-Exos substantially accelerated diabetic wound healing by promoting neovascularization within the wound bed.CONCLUSION Low-energy fractional CO2laser irradiation augments the biological activity of MSC-derived Exos through photothermal stimulation.These Exos,in turn,enhance endothelial cell functions by activating the S1PR1/protein kinase B/hypoxia-inducible factor 1 alpha signaling pathway,ultimately accelerating the repair of diabetic wounds.
基金supported by the National Natural Science Foundation of China(no.32372838,U22A20506)the National Key Research and Development Program of China(no.2024YFD1300104)+1 种基金the scientific and technological development program of Jilin province(YDZJ202203CGZH037)the earmarked fund for JLARS-2025-070203。
摘要Background Exosomes are crucial mediators of intercellular communication.As a key component of milk,milkderived exosomes are abundant in genetic cargo,particularly micro RNAs(mi RNAs),indicating their potential role in regulating mammary gland physiology.Therefore,this study aimed to investigate the specificity of mi RNAs in milkderived exosomes and their regulatory roles in lipid synthesis in bovine mammary epithelial cells(BMECs).Results Based on 17,838 DHI records showing a significantly higher milk fat percentage(MFP)in late lactation(4.24%±1.07%),10 high-(5.96%±0.26%,HMF)and 10 low-MFP(1.68%±0.23%,LMF)cows were selected during this stage for milk-derived exosome isolation and mi RNA profiling.Exosomes isolated via differential ultracentrifugation were verified as 50-150 nm vesicles expressing CD9,CD81,and TSG101.mi RNA sequencing identified 1,320 differentially expressed mi RNAs(496 upregulated and 824 downregulated)between the HMF_EXO and LMF_EXO groups.Uptake assays confirmed that BMECs internalized these exosomes,and q RT-PCR validation showed that mi R-423-5p and mi R-125b were significantly upregulated and downregulated in HMF_EXO-and LMF_EXO-treated BMECs,respectively.Functionally,exosomal mi R-423-5p promoted intracellular lipid accumulation and TG synthesis in BMECs by targeting APOA5,whereas mi R-125b inhibited lipolysis and fatty acid oxidation by repressing SLC27A1.Conclusions This study demonstrates that milk-derived exosomal mi RNAs represent a novel mechanism for regulating milk fat synthesis.Specifically,mi R-423-5p and mi R-125b directly modulated lipid metabolism in BMECs via the mi R-423-5p/APOA5 and mi R-125b/SLC27A1 pathways.These findings provide new insights into the molecular regulation of milk fat synthesis and highlight the importance of exosome-mediated intercellular communication in the lactating mammary gland.
摘要●Ocular graft-versus-host disease(oGVHD)is an immune disease that occurs in the eye after allogeneic hematopoietic stem cell transplantation and seriously affects the vision and quality of life of patients.Current treatment modalities are inadequate,and new treatment options and targets are required to improve the therapeutic efficacy of oGVHD.In recent years,a large number of studies have shown that exosomes,as important mediators of cell-to-cell communication,have important research value in the pathogenesis,diagnosis,and treatment of oGVHD.This article reviews the research progress on exosomes from different sources of oGVHD.