Page 2 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477they have considerable latent drug delivery systems forthe treatment of chronic inflammatory disorders [6]. Fur-thermore, exosomes generated from mesenchymal stemcells (MSCs), astrocytes, and dendritic cells (DCs) frominflammatory sites with immunomodulatory capabilitiesare commonly employed as transport vehicles to delivercargo to inflammatory areas for improved anti-inflam-matory effects [7–9]. Exosomes released by inflammatorycells have strong inflammatory affinity and targeting, thusthey can transport cargo to inflammatory cells via theinteraction of surface-antibody and cell surface recep-tors, resulting in a more potent anti-inflammatory impact[9].Exosome biogenesis, composition and targetmodificationExosomes are double-membraned vesicles with diam-eters ranging from 30 to 200 nm that cells secrete intotheir environment. Exosomes transport lipids, proteins,messenger RNA (mRNA), microRNA (miRNA), longnon-coding RNA (lncRNA), and DNA, allowing themto maintain cellular homeostasis, remove cellular trash,and facilitate intercellular and interorgan communication(Fig. 1). Exosomes circulate across all body fluids andcarry molecular messages in an autocrine, paracrine, andendocrine way [10].A variety of essential components for cell communi-cation are included in exosomes, including about 4,563proteins, particularly tetraspanins (Alix, TSG101, CD9,Fig. 1 Exosome biogenesis, their molecular composition, and protective effect on different inflammatory diseases. The figure is generated using Bioren-der scientific image and illustration software (h t t p s : / / www. b i o re n d e r. c o m /)
Page 3 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477CD63, CD81, and CD82), which control cell adhesionand fusion [11]. Additional proteins include differentGTPases involved in intracellular transport and fusion,Rab proteins (Rab11, Rab27a, Rab27b), and heat shockproteins (HSP70, HSP90) [12]. Additionally, they have194 known lipids that are essential to the exosomal struc-ture, such as phosphatidylcholines, phosphatidylserines,and sphingolipids [13]. Exosomes contain DNA, includ-ing mitochondrial DNA, 1,639 mRNAs, and 764 miRNAs[14–16]. Certain miRNAs, such as miR-1 and miR-21, areassociated with hematopoiesis and carcinogenesis [15].Membrane proteins like CD55 and CD59 help to stabi-lize exosomes outside of cells by inhibiting the comple-ment system [17]. There are two ways that exosomes aresecreted: constitutive release through the Trans-Golginetwork and pathogen-inducible release [18], which iscontrolled by Rab proteins (Rab27a, Rab27b, Rab35 &Rab11) [19] and impacted by variables like as pH andpotassium levels [17, 20]. Through processes like phago-cytosis and endocytosis, exosomes can fuse with destina-tion cells after being released, delivering their cargo andproducing biological consequences [21–23].Exosomes’ inherent characteristics offer them cer-tain advantages in target cell absorption as compared toconventional nanomedicine delivery methods. However,additional changes are required to enhance exosomes’capacity to target disease sites [24]. It is commonly recog-nized that the most advanced targeted modification tech-nique is genetic engineering, which aims to fuse ligandswith distinctive functionalities to a wide variety of trans-membrane proteins on the surface of exosomes, includ-ing CD9, CD63, and Lamp2b. Plasmids or viruses thatencode fusion ligands for transmembrane proteins canbe used to genetically modify parental cells [25]. HSTP1and the membrane protein Lamp2b efficiently increasedHSC-T6 cells’ absorption of exosomes [26]. Exosomedirect engineering provides a regulated and effectivemethod of alteration [27]. Small peptides, proteins, andother specific molecules can be attached to the surface ofexosomes via physical and chemical techniques, improv-ing their usefulness without compromising their integ-rity [28]. By employing physical surface modification tomomentarily break the lipid structure, physical altera-tions enable exosomes to subsequently revert to theiroriginal state [29]. Mild reactions are used in chemicalmodifications to bind suitable molecules covalently ornon-covalently without changing size [25, 30]. Targetcells absorb exosomes by membrane fusion, receptor-ligand interactions, and mostly endocytosis [31]. Fluores-cent probes and laser confocal microscopy can be usedto visualize exosome uptake and flow cytometry can beused to analyze the results [32]. Exosomes in living cellsmay be tracked in detail thanks to sophisticated methodslike single-molecule localization microscopy (SMLM)[33]. Exosome distribution can also be tracked in vivousing other imaging techniques such as bioluminescence,nuclear imaging, CT, and MRI [34–36].Exosome therapy has more benefits than stem cell-based therapy, such as preventing immunological reac-tions, preventing tumorigenicity, being stable and suitedfor long-term preservation, and promoting better signal-ing in intercellular communication, among other benefits[3, 37, 38].Different cell-derived exosomes and their functionSeveral studies demonstrated that therapeutic agentsknown as mesenchymal stem cells (MSCs) are beingused to target the pro-inflammatory cytokines [39, 40].In any case, the utilization of MSCs as therapeutics hasa few downsides including potential cancer develop-ment, non-specific differentiation, unwanted immuneresponses, difficulty of quality control, and short half-lifebefore administration [41]. MSCs are intriguing alterna-tive agents for the treatment of inflammatory diseasesdue to their immunomodulatory function. Several clini-cal trials on MSC-based products are currently beingconducted [42]. Exosomes released by macrophages cantransmit miRNA from the host cell to a particular targetcell, facilitating tumor invasion [43] proving exosomes apromise nanocarriers for chemotherapeutic medicines,neuroprotective proteins, and imaging agents, efficientlydelivering therapies for drug-resistant malignancies, Par-kinson’s disease, and gliomas [44].Dendric cells-derived exosomes (Dex) are involvedin antigen-specific immunity and tolerance [45]. Dexhas demonstrated immunostimulatory properties andpotential as a cancer immunotherapy vaccine, effectivelyeliciting antigen-specific immune responses, enhancingcytotoxic T lymphocyte activity, and inhibiting tumorgrowth, particularly in hepatocellular carcinoma (HCC)[46, 47]. Exosome-mediated signaling is a novel way forfetal and maternal communication. It can send birth sig-nals by increasing maternal pregnancy cell inflammation.Amniotic epithelial-derived exosomes cause inflamma-tion in uterine cells and restore ovarian function by deliv-ering miRNAs that resist apoptosis [48, 49]. Exosomesderived from endothelial progenitor can inhibit micro-vascular dysfunction and sepsis by delivering miR-126and inhibiting neointimal hyperplasia following carotiddamage in rats [50, 51]. Exosomes from cardiac fibro-blasts have a vital function in activating the renin-angio-tensin system in cardiomyocytes [52]. Exosomes fromnephron cell origin can transmit pro-inflammatory orpro-fibrotic signals from tubular epithelial and intersti-tial cells, including fibroblasts and immune cells. This cancontribute to kidney fibrosis [53].Anti-inflammatory medications, especially biologicdisease-modifying antirheumatic drugs (bDMARDs),
Page 4 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477which stop and slow the disease process in inflamma-tory diseases, such as TNF inhibitors and rituximab,raise the risk of severe infections including bacterial,mycobacterial, and HBV reactivation [54]. Non-steroidalanti-inflammatory drugs (NSAIDs) have significant con-cerns for individuals with treatment-resistant hyperten-sion, high cardiovascular risk, and severe chronic kidneydisease (CKD), and need rigorous pre-treatment evalu-ation and monitoring [55]. Furthermore, combinationmedications for inflammatory bowel disease (IBD) thatinclude TNF antagonists and corticosteroids dramati-cally increase infection risks, although monotherapy withimmunosuppressive drugs is rather safe [56]. Steroidsused to treat IBD might worsen risk factors for athero-sclerotic cardiovascular disease (ASCVD), increasing thechance of sudden myocardial infarction and stroke, espe-cially in women and younger patients [57].A recent study questions the effectiveness of using exo-somes from adipose-derived stem cells (ADSC-Exos) inregenerative medicine. Exosome donors with metabolicproblems had reduced adipose stem cell number andtherapeutic potential [58]. Despite possible challenges,the utilization of exosomes derived from multiple celltypes continues to show promise in the treatment ofinflammatory diseases. Their distinct features and capac-ity to target specific cells make them a feasible alterna-tive to existing immunosuppressive medicines, which arefrequently associated with considerable risks and adverseeffects. As research advances, better knowledge anddevelopment of exosome-derived therapies may lead tosafer and more effective therapeutic choices for control-ling chronic inflammatory disorders, ultimately enhanc-ing patient outcomes and quality of life.Characterization techniques for exosomes inbiomedical therapiesExosomes are characterized by their physical, chemi-cal, functional, structural, and biological properties, forcritical biomedical therapies such as enzyme replacementtherapy (ERT). Robust characterization methods areessential to ensure consistency in composition, structure,and functionality (Fig. 2). Previously, the morphology ofexosomes was often described as cup-shaped but nowthe gold standards for morphological characterizationFig. 2 Different techniques for characterization of exosomes before therapeutic applications. The figure was generated using Biorender scientific imageand illustration software (https://www.biorender.com/)
Page 5 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477are Electron Microscopic Technologies [59]. Visualizingexosome structure is crucial using transmission electronmicroscopy (TEM) and Cryo-TEM, although samplepreparation can influence results [60, 61]. Scanning elec-tron microscopy (SEM) aided backscattered electrondetection and revealed surface morphology and features[62]. Nanoparticle tracking analysis (NTA) and FlowCytometry measure particle diameter through light scat-tering and Brownian motion, while dynamic light scat-tering (DLS) assesses particle size distribution, despitechallenges with heterogeneous particle size [63–65].Atomic force microscopy (AFM) provides high-resolu-tion three-dimensional imaging and biophysical insight[66].The characterization of exosomes using western blotand qPCR is critical for understanding their molecularcomposition and functional roles [67, 68]. Western blotprovides insight into exosomal protein content, whileqPCR allows for the sensitive and specific quantificationof RNA species, especially miRNAs. A positive signal fortetraspanins (CD63, CD9, CD81) and ESCRT compo-nents (TSG101, Alix) confirms the presence of exosomes[69, 70]. The absence of negative markers such as cal-nexin indicates that the exosome preparation is free fromcellular contaminants. Quantitative PCR (qPCR) is a piv-otal method for characterizing exosomes, particularly inanalyzing their RNA content, such as microRNAs (miR-NAs) [71]. Analyzing the proteome content of exosomesis as challenging as determining RNA content. Exosomeshave yielded a variety of RNA types, including mRNA,miRNA, and others. For RNA extraction, commercialkits are frequently utilized, and the main technique forprofiling is reverse-transcription quantitative polymerasechain reaction (RT-qPCR) [16, 72]. In order to amplifyDNA and analyze its length and nucleotide sequences,this procedure transforms extracted RNA into cDNA[73]. RNA sequencing (RNA-seq) is an effective tool forcharacterizing exosomes, providing insights into theirRNA content, including mRNA, miRNA, and non-cod-ing RNAs. This approach enhances our understandingof exosome biogenesis, their role in disease mechanisms,and their potential as diagnostic or therapeutic agents invarious conditions [74].The main methods for determining the protein compo-sition of exosomes are two-dimensional gel electropho-resis (2DGE) and liquid chromatography combined withtandem mass spectrometry (LC-MS/MS) [75, 76]. Pro-teins are removed and produced as peptide fragments,which are more suited for LC-MS analysis, following thepurification of extracellular vesicles (EVs). High-pressureliquid chromatography is then used to isolate these pep-tides before they are subjected to tandem mass spec-trometry (MS/MS) [77]. Ions are created and segregatedbased on the mass-to-charge ratio in the first stage, andthe chosen ions are broken up for additional examinationin the second stage [77]. This allows the identificationand quantification of thousands of proteins from complexsamples by comparing the resultant data to a database.Fluorescence correlation microscopy (FCM) and colo-rimetric enable specific identification and quantificationof exosomes [78], while enzyme-linked immunosorbentassay (ELISA) measures exosomal proteins [79]. Surfaceplasmon resonance (SPR) and nuclear magnetic reso-nance (NMR) techniques further enhance characteriza-tion by analyzing biochemical and structural data [80,81],. The SIMOA approach allows for the direct detec-tion of plasma EVs [82], miR-141, cortisol, and IL-6, a3-plex created by combining direct nucleic acid hybrid-ization with competitive and sandwich immunoassays[83]. Using Glypican-1 (GPC-1) [84] for detection over adynamic range of 5 orders of magnitude, with limits aslow as 10 exosomes per microliter.Therapeutic impacts of exosomes in inflammatorydiseases and biomedical therapiesExosome-based therapies in inflammatory bowel disease(IBD)IBD, encompassing Crohn’s disease (CD) and ulcer-ative colitis (UC), is a chronic immunological conditionaffecting the gastrointestinal tract caused by a dysregu-lated response to intestinal microbiota in genetically sus-ceptible individuals [85]. The deregulation of mucosalimmunity plays a pivotal role in the development andprogression of IBD. Diagnosis is based on clinical symp-toms, biochemical indicators, as well as imaging and his-tological investigations [86, 87]. This section examinesthe possibility of exosome-based therapeutics with anemphasis on therapeutic efficacy and biomarker identifi-cation in the management of IBD.Biomarker identification using exosomeThere is no specific biomarker that distinguishes betweenUC and CD individuals in IBD. Notable biomarkerssuch as ASCA, pANCA, CRP, lactoferrin, and calpro-tectin [88]. Alongside the saliva exosome biomarkerPSMA7, the biomarkers α-amylase and calprotectinare also present in patients with IBD [89, 90]. Addition-ally, IBD patients exhibit elevated levels of endogenousANXA1-containing EVs, which might act as a biomarkerfor intestinal mucosa inflammation [91]. Exosomes fromintestinal luminal aspirates in IBD patients could alsoshow promise as fecal biomarkers for detecting mucosalinflammation [92]. Exosomal RNA NEAT1 has been pro-posed as another potential biomarker for IBD pathogen-esis [93]. Identifying precise and sensitive biomarkers forIBD could significantly enhance diagnosis, treatment, andprognosis, and pave the way for innovative medicines.
Page 6 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477Therefore, continued research into these markers andtheir pathways is essential [94].Therapeutic efficacy of exosome-derived treatmentsExosomes derived from murine colon cancer cells CT26(CT26-Exos) were isolated by using ultracentrifugation,characterized via proteome analysis, and evaluated inDSS induced IBD mouse model. Compared to the controland 293 T exosome therapies, CT26-Exos treatment sig-nificantly reduced disease activity index (DAI) and colonshortening rate while histological examination showeddecreased inflammatory infiltration and increased epi-thelial goblet cells. Mechanistically, CT26-Exos specifi-cally suppressed Th17 cell differentiation in the colon andinhibited pro-inflammatory cytokine release by colonicDCs [95]. Intravenous administering human adiposemesenchymal stem cell-derived exosomes (hADSC-Exos)to DSS-induced IBD animals improves functional recov-ery, reduces inflammation, decreases intestinal cell apop-tosis, promotes epithelial regeneration, and preservesintestinal barrier integrity. Furthermore, co-culturedinjured colon organoids with hADSC-Exos and TNF-αdemonstrate anti-inflammatory effects and enhancedproliferation of Lgr5+ ISCs and epithelial cells. Thesefindings suggested hADSC-Exos as a potential treatmentfor IBD and highlighted a cell-free therapeutic strategyfor the disease [96].Similar to human umbilical cord mesenchymal stemcells (hucMSCs), exosomes labeled with indocyaninegreen (ICG) were injected into IBD animals, and within12 h, they targeted colon tissues. By upregulating IL-10expression and downregulating TNF-α, IL-1β, IL-6,iNOS, and IL-7 gene expressions in spleen and colon tis-sues, the exosomes considerably reduced the severity ofIBD. Exosome therapy also reduced macrophage infiltra-tion in colon tissues of IBD animals. In vitro coculture ofmouse enterocele macrophages with exosomes decreasediNOS and IL-7 expression, suggesting a potential mech-anism for exosome-mediated inflammation control inIBD. Moreover, elevated IL-7 expression in colon tissuesof colitis patients highlights a promising target for exo-some-based IBD therapies [97]. Oral administration ofcolostrum-derived exosomes (Col-Exos) alleviates colitissymptoms such as weight loss, gastrointestinal bleeding,and persistent diarrhea by regulating intestinal inflamma-tion. Bovine colostrum-derived exosomes exhibit excep-tional stability and show significant potential as naturaltherapies for colitis recovery [98]. Exosomes derived frommurine bone marrow-derived macrophages (BMDMs),cultured in the presence or absence of lipopolysaccha-ride (LPS) were analyzed via miRNA sequencing in aDSS-induced IBD animal model. MiR-223 emerged as akey miRNA deteriorating intestinal barrier dysfunction;target prediction and time-dependent mRNA analysisidentified Tmigd1 as a critical barrier-related factor [99](Fig. 3).Current limitation and future directionHowever, the use of exosomes in therapeutic applicationshas been limited due to the hazards of aggressive behav-ior and ambiguity regarding their biological function inother organs [100]. One notable limitation is the prob-lem of purifying and characterizing exosomes, which iscritical for their therapeutic value [101]. Infected cellscan produce exosomes, which contain biomolecules thatinfluence the innate immune responses of surroundingcells [102]. Overcoming these constraints necessitates acomprehensive research effort to develop reliable meth-ods for isolating and characterizing exosomes, as well asa complete investigation of their biological activity andsafety profile to ensure their safe and effective therapeu-tic application.Exosome-based therapies in acute liver injury and fibrosisHepatic fibrosis, caused by chronic liver damage, resultsin excessive collagen and extracellular matrix (ECM)buildup. Hepatitis B and C, alcoholic liver disease, andnonalcoholic steatohepatitis (NASH) all contribute tofibrosis [103]. Hepatic fibrosis was once believed to beirreversible [104]. TGF-β has a crucial role in chronicliver disease, influencing its development from injury tofibrosis [105]. TGF-β activates growth factors and cyto-kines implicated in fibrogenesis, including PDGF, CCN2,ILs (IL-1α, IL-β, IL-6), and TNF-α [106, 107]. The acti-vation of myofibroblasts from fibroblasts, which includehepatic stellate cells (HSCs), portal fibroblasts (PFs), andfibrocytes, is an important event in liver fibrosis. Fibro-blasts either stay dormant or activate into myofibroblastsdepending on the ECM composition [108].Biomarker identification by using exosomeAccurately determining the degree and progression ofliver fibrosis is critical for guiding clinical decisions onpatient care. The “gold standard” in liver biopsy thougheffective, is expensive, invasive, and carries risk. Exo-some components offer a promising alternative novelbiomarker for the identification and evaluation ofmolecular markers associated with liver fibrosis, actingas a dynamic reflection of the core pathologic diseasein patients. Moreover, exosomal components can bedetected in circulating plasma and serum with stabilityowing to their resistance to proteinase-dependent deg-radation, which makes them ideal biomarkers for varioustherapeutic applications [109, 110]. Studies have linkedelevated amounts of CD10 protein in the urine exosomesof glycine N-methyltransferase mutant mice to steatosis,fibrosis, and hepatocellular injury [111]. Furthermore, thedegree of fibrosis and inflammation has been correlated
Page 7 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477with CD81-enriched serum exosomes in patients withchronic HCV infection [112]. Decreased levels of miR-NAs (miR-34c, miR-151-3p, miR-483-5p, or miR-532-5p)in serum exosomes from CCl4-induced mice or humanpatients with F3/4 fibrosis suggest their potential as anindicator of disease severity [113].Therapeutic efficacy of exosome-derived treatmentsHuman umbilical cord-derived MSC-Exos have beenshown to modify macrophage phenotypes, regulatingthe inflammatory milieu in the liver and facilitating tis-sue repair. Delivery of miR-148a, which inhibits theSTAT3 pathway and targets Kruppel-like factor 6 (KLF6),resulted in this modulation, which suppresses pro-inflammatory macrophages and promotes anti-inflam-matory macrophages. These effects demonstrate thepotential of MSC-Exos in treating liver fibrosis by con-trolling inflammatory responses within the liver andorchestrating macrophage functions [114]. Adipose tis-sue stem cells (ADSCs) derived exosomes inhibited pro-fibrogenic indicators and the activation of hepatic stellatecells (HSCs). Glutamine synthetase (Glul) was upregu-lated in hepatocytes during ADSC-Exos therapy, and themetabolic pathways for glutamine and ammonia werealtered, according to an RNA-seq study. Glul inhibitionreduced the therapeutic effects of ADSC-Exos, empha-sizing the function of this compound in metabolic repro-gramming to relieve hepatic fibrosis. According to Wu etal. results, targeting HSC activation and metabolic path-ways with ADSC-Exos is a potentially effective therapeu-tic approach for treating hepatic fibrosis [115].TNF-α pretreatment of umbilical cord mesenchy-mal stem cell-derived exosomes showed strong anti-inflammatory effects in an acute liver failure (ALF)animal model brought on by LPS and D-GalN after itwas enriched and examined for size and surface mark-ers. Inhibiting the activation of NLRP3 and otherinflammation-associated proteins, T-Exos therapy sub-stantially decreased serum levels of ALT, AST, and pro-inflammatory cytokines [116]. Through the reduction ofcollagen buildup, enhancement of liver function, sup-pression of inflammation, and promotion of hepatocyteFig. 3 (1) Therapeutic efficacy of exosomes derived from different cells. (2) Exosome biogenesis extracted from donor cells (3) Delivery of exosomes tothe diseased area according to their therapeutic efficacy. The figure was generated using Biorender scientific image and illustration software (https://www.biorender.com/)
Page 8 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477regeneration, hBM-MSCs-Exos therapy considerablyreduced hepatic fibrosis. Mechanistically, in both hepaticstellate cells (HSCs) and liver fibrosis tissue, hBM-MSCs-Exos suppressed the production of important elementsof the Wnt/β-catenin signaling pathway (PPARγ, Wnt3a,Wnt10b, β-catenin, WISP1, Cyclin D1), as well as α-SMAand Collagen I [117]. Exosomes derived from NK-92MIcells (NK-Exo) were extracted and identified usingtransmission electron microscopy, nanoparticle track-ing analysis, and western blotting. After that, mice withliver fibrosis produced by CCl4 and LX-2 cells treatedwith TGF-β1 were given NK-Exo. NK-Exo reduced CCl4-induced liver fibrosis and decreased TGF-β1-inducedHSC activation and proliferation. The exosome inhibitorGW4869 reversed this HSC-inhibitory action. Conse-quently, NK-Exo efficiently prevents liver fibrosis broughton by CCl4 and HSC activation produced by TGF-β1[118] (Fig. 3).Rat bone-marrow-derived.Current limitation and future directionMany studies on chronic liver illnesses have made prog-ress, but exosomes continue to present significantobstacles. The majority of present research on exosome-based therapeutics is focused on cell and animal models,with clinical trials yet to be completed. Exosomes andmicrovesicles in human fluids are difficult to distinguishdue to their similar sizes, necessitating the developmentof particular biomarkers. Further investigation into themolecular processes of exosome synthesis, release, andinteraction with target cells is required for therapeuticuse. As more researchers enter the field, the practical useof exosomes may soon benefit patients [119].Exosome-based therapies in lung injury and inflammationAcute lung inflammation is caused by an innate immunedefense against invading microorganisms; chronicinflammation occurs when the response fails to eliminatethe inflammatory trigger [120]. Acute lung injury (ALI)is a common clinical lung condition that can be fatal. Insurvivors, fibrotic lung healing may result in acute respi-ratory distress syndrome (ARDS). Respiratory distress,hypoxemia, and non-cardiogenic pulmonary edema arethe hallmarks of the debilitating clinical condition knownas ARDS [121].Therapeutic efficacy of exosome-derived treatmentsExosomes derived from macrophages, neutrophils, andepithelial cells in bronchoalveolar lavage fluid (BALF)throughout time after ALI was induced in mice usingLPS. The main early secretors of pro-inflammatory cyto-kines in BALF-exosomes stimulated neutrophils to gen-erate cytokines and IL-10. Post-ALI fibrosis may havebeen exacerbated by neutrophil-derived IL-10 in BALF-exosomes, which polarized macrophages to M2c [122].Alveolar epithelial cells (AECs)-derived Exosome play arole in alveolar macrophage (AM) activation and sepsis-induced ALI. By using a rat model of septic lung injury,Liu et al. discovered that GW4869 inhibited exosomes,which decreased lung harm. LPS-treated cells producedAEC-derived exosomes (LPS-Exos), which activatedAMs and increased alveolar permeability and pulmo-nary inflammation. By inducing the NF-κB pathway anddownregulating PTEN, miR-92a-3p, which is abundantin LPS-Exos, stimulated AMs. These proinflammatoryeffects were lessened by inhibiting miR-92a-3p. Thus,exosomes produced from AECs activate AMs and causeinflammation through miR-92a-3p, indicating an ALItherapeutic target [123].Rat bone-marrow-derived MSC exosomes outper-formed the phosgene group in terms of respiratory per-formance, wet-to-dry lung weight ratio, and total proteincontent in BALF. They reduced inflammatory markersTNF-α, IL-1β, and IL-6 while boosting IL-10. Further-more, exosomes reduced MMP-9 and increased SP-Clevels. Thus, MSC-derived exosomes reduce phosgene-induced ALI by regulating inflammation, decreasingMMP-9, and increasing SP-C levels [124]. BMSC-derivedexosomes suppress glycolysis in macrophages, mak-ing them effective in treating sepsis-induced lung dam-age. They decreased M1 polarization while promotingM2 polarization in MH-S cells (murine alveolar mac-rophages) by reducing cellular glycolysis. Inhibitinghypoxia-inducible factor 1 (HIF-1) α resulted in thedown-regulation of critical glycolysis proteins. In anLPS-induced ARDS mouse model, BMSC-derived exo-somes decreased inflammation and lung damage whileinhibiting LPS-induced glycolysis in lung tissue [125].Macrophages absorbed ADMSC-derived exosomes,which reduced IL-27 release in vitro. In vivo, IL-27 dele-tion reduced CLP-induced ALI, while ADMSC-derivedexosomes blocked macrophage aggregation in lung tis-sues, decreased IL-27 secretion, and decreased levelsof IL-6, TNF-α, and IL-1β. Furthermore, ADMSC-exo-somes reduced pulmonary edema, tissue damage, andvascular leakage, hence increasing survival rates. Inject-ing recombinant IL-27 abolished the protective benefitsof ADMSC-derived exosomes. Thus, ADMSC-derivedexosomes reduce sepsis-induced ALI by reducing IL-27secretion in macrophages [126] (Fig. 3).Current limitations and future directionCell-free treatment, notably with exosomes, has receiveda lot of attention for treating lung diseases. Despiteadvances, the actual mechanism of action of exosomesis still unknown, with recent studies focused on theirRNA cargos but not fully comprehending other compo-nents. Limitations include the high costs and technicalproblems of isolating and purifying exosomes, as well as
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Stem Cell Research & Therapy (2024) 15:477the requirement to immortalize stem cells for large-scaleproduction, which entails hazards and complications[127].Exosome-based therapies in neuroinflammation andtraumatic brain injuryTherapies for neuroinflammatory diseases like mul-tiple sclerosis, acute disseminated encephalomyeli-tis, viral encephalitis, and bacterial meningitis, as wellas other conditions of the central nervous system thathave an inflammatory component (such as schizophre-nia, migraine headaches, and neurodegenerative disor-ders like Parkinson’s and Alzheimer’s disease), are beingdeveloped through extensive translational research [128].Exosomes released by several neural cell types performcrucial roles in both CNS development and adult brainmaintenance, such as synaptic activity control and regen-eration after damage [129].Exosomal biomarker in neuroinflammatory disordersNeuroinflammatory disorders are frequently misdi-agnosed due to unknown pathophysiology and a lackof early diagnostic markers [38, 130]. Exosome identi-fication in Parkinson’s and Alzheimer’s disorders canhelp with early diagnosis and tracking [131]. Exosomesfrom cerebrospinal fluid (CSF) can be analyzed to helpresearchers understand illness development [132, 133].Exosomes from neuroinflammatory disease samplesare analyzed for protein markers α-syn and tau via massspectrometry and immunoassay, as well as dysregulatedexosomal RNAs such as miR-132 using RT-PCR. MiR-132, miR-125b-5p and miR-132-3p were increased anddownregulated in AD brain tissues and EVs, respectively,which delivers neuroprotection in tauopathies (disorderscharacterized by deposition of abnormal tau protein inthe brain) [134–136], is downregulated in plasma-derivedexosomes from Alzheimer’s patients [137] CSF vol-ume has limitations, and nanoparticles identical to exo-somes contaminate samples and are unrecognizable bynanoparticle tracking analysis (NTA) [138, 139]. A studypublished in the European Journal of Neurology suggeststhat the proportion of α-synuclein in brain-derived exo-somes in the blood can serve as a biomarker for early-stage Parkinson’s disease (PD) [140].Stuendl et al. created a high-sensitivity ELISA utilizing0.5 mL of CSF to detect exosomal α-syn via electroche-miluminescence [141]. Vandendriessche et al. employedthe ExoView R100 platform to discriminate exosomesfrom other CSF particles in an Alzheimer’s animal model,detecting CD9+/CD81 + extracellular vesicles and cho-roid plexus-specific CSF EVs using an anti-transthyretinantibody [142]. ExoView syndicates immunodetectionand imaging in a small sample volume, and it showspotential for characterizing CSF-derived exosomes [139].Therapeutic efficacy of exosome-derived treatmentshWJ-MSC (Human Wharton’s jelly mesenchymal stemcells)-derived Exosome inhibited LPS-induced inflam-mation-related gene expression and pro-inflammatorycytokine production in BV-2 microglia and primarymixed glial cells. They influenced Toll-like receptor 4signaling in BV-2 microglia, preventing NFκB inhibi-tor degradation and mitogen-activated protein kinaseactivation after LPS stimulation. hWJ-MSC-derivedexosome delivered intranasal stretch to the brain andconcentrated microglia-mediated neuroinflammationin rat pups which caused brain damage, indicating theirpromise as a treatment for perinatal brain injury [143,144]. Astrocyte-derived exosomes isolated from culturedastrocytes after exposure to brain extracts, facilitated thetransition of microglia from the M1 to M2 phenotype,with miR-148a-3p playing critical role. Exosomes con-taining miR-873a-5p reduced LPS-induced microglialM1 transition and inflammation by lowering ERK andNF-κB p65 activation, as confirmed in vitro and in vivostudies [145]. Similarly, miR-148a-3p controlled the phe-notypic shift and suppressed the inflammatory responsein microglia. In animal models of TBI, both miRNAsinhibited the nuclear factor κB pathway, improving neu-rological results and reducing brain injury [146]. In sum-mary, these findings highlight the therapeutic potentialof astrocyte-derived exosomal miR-873a-5p and miR-148a-3p in modulating the microglial phenotype andtreating traumatic brain injury (TBI). Both miRNAs havebeen shown to reduce inflammation and improve neuro-logical outcomes by inhibiting key pathways involved inmicroglial activation and brain injury.Bone marrow MSCs-derived exosomes (BMSC-Exos) decrease proinflammatory cytokines and enhanceanti-inflammatory cytokines while also promoting thepolarization of activated BV2 microglia to an anti-inflam-matory phenotype. In mice models of traumatic braininjury (TBI), BMSC-Exos reduced cell death in corti-cal tissue, suppressed neuroinflammation, and inducedmicroglial anti-inflammatory phenotypes. MicroRNAsequencing identified miR-181b as an important role inthis process. Overexpression of miR-181b in TBI micemodels through lentiviral transfection reduced apoptosisand neuroinflammation while fostering an anti-inflam-matory microglial phenotype through the interleukin10/STAT3 pathway [147]. The hADSC-Exos had similareffects to hADSC treatment in terms of functional recov-ery, neuroinflammation suppression, neuronal apoptosisreduction, and neurogenesis enhancement. In vivo, imag-ing revealed the accumulation of DiR-labeled hADSC-Exos in the lesion area, and immunofluorescent stainingconfirmed microglia/macrophage uptake in brain slicesand primary mixed neural cell cultures. In a lipopoly-saccharide-induced inflammatory model, hADSC-Exos
Page 10 of 19Saleem et al. Stem Cell Research & Therapy (2024) 15:477suppressed microglia/macrophage activation by regulat-ing P38 MAPK and NF-κB signaling pathways. hADSC-Exo’s ability to target and enter microglia/macrophages,decreases their activity, thereby reducing inflammationand enhancing neurological recovery [148].Neural stem cell- and mesenchymal stem cell-derivedexosomes can promote axonal outgrowth and neuralrepair in PC12 cells, influence inflammatory responses,and cause microglial polarization towards the M2 phe-notype. Furthermore, a nanofibrous scaffold loaded withthese dual stem cell-derived exosomes (Duo-Exo@NF)enhanced functional recovery in a mouse traumatic braininjury model by lowering microglia and reactive astro-cytes and increasing levels of growth-related protein-43and doublecortin [149] (Fig. 3).Current limitation and future directionMore study is needed to improve their separation andcharacterization procedures, as well as to clarify theirmechanisms of action, although exosomes have greatpromise as a novel therapy option for TBI and PCS[150]. Until now, Exosomal miRNA delivery has receivedminimal attention for its therapeutic potential in neuro-logical illnesses [151, 152]. However, before conductinglarge-scale clinical research, isolation techniques must bedeveloped and enhanced, along with a complete under-standing of the extracellular vesicle biology aspects linkedwith the neurological system, to improve their sensitivityand specificity in the field of TBI application [153].Exosome-based therapies in myocardial infarctionMyocardial infarction (MI), one of the major causesof death globally, occurs when the coronary arteryis stopped by rupture or erosion of an atheroscle-rotic plaque, resulting in cell death in the ischemia andhypoxic region [154]. Even though prompt interventionsimprove MI patients’ survival rates, permanent cardio-myocyte loss and unfavorable left ventricular remodelingcontinue to cause heart failure or sudden cardiac death inmany survivors [155, 156]. Therefore, additional effectivetherapeutic strategies are needed to improve the progno-sis of patients with MI.Exosomal biomarkersResearchers have discovered particular exosomal pro-teins and miRNAs linked to particular acute myocardialInfection (AMI) by examining the molecular pathwaysof MI progression [157]. For instance, patients with AMIhad greater plasma levels of miRNA-1, miRNA-133a,miRNA-208a and miRNA-499 than do people withoutAMI demonstrated to be a more accurate and precisebiomarker for AMI than traditional cardiac troponin test(cTn) [158]. Exosomes generated from platelets that carrymiRNA-21, miRNA-191, miRNA-223, miRNA-320, andmiRNA-339 have been connected to platelet aggregation,which results in the development of atherosclerosis [159].Cheng et al. created a microfluidic device that detectsproangiogenic and cardioprotective miR-21 and miR-126from serum samples. This system combines exosome iso-lation and microRNA extraction, with antibody-coatedmagnetic beads and field effect transistors (FETs) fordetection. By targeting PTEN and FoxO1 and activatingthe AKT/mTOR pathway, miR-486 protects against car-diac I/R injury and myocardial apoptosis and mediatesthe positive effect of exercise on myocardial protection[160]. The FET sensors are highly sensitive, detectingmiRNAs at femtomolar concentrations using a 5-hourprocedure. Although still in development, these deviceshave potential for exosomal investigations and CVDdiagnosis [158, 161].Therapeutic efficacy of exosome-derived treatmentsM2 macrophage-derived exosomes (M2-Exos) dramati-cally improved heart function, increased angiogenesis,and decreased infarct size both in vivo and in vitro. Theincreased abundance of miR-132-3p in M2-Exos wascritical to these effects, as it reduced THBS1 expres-sion by binding to its 3’UTR. M2-exos’ proangiogenicand cardioprotective activities were dependent on miR-132-3p regulation. M2-Exos promotes heart healingby delivering miR-132-3p to endothelial cells, offeringfresh insights into the mechanics of intercellular com-munication in post-infarction angiogenesis [162] ADSC-Exos dramatically increased left ventricular ejectionfraction while decreasing MI-induced cardiac fibrosisand it reduced cardiomyocyte apoptosis while increas-ing angiogenesis. ADSC-Exos stimulates microvascularendothelial cell proliferation and migration via miRNA-205, which enhances angiogenesis and decreases cardio-myocyte death. These findings indicate that ADSC-Exoscan reduce cardiac injury and improve cardiac functionrecovery [163].Induced pluripotent stem cell-derived cardiomyo-cytes-derived Exosome (iCM-Exos), like cell transplanta-tion, enhances cardiomyocyte survival under hypoxia aswell as cardiac function in a mouse myocardial infarc-tion model. They cause transcriptional alterations inthe peri-infarct area, namely altering mTOR signaling,and increasing autophagy and autophagic flux. Thus,iCM-Ex might be a viable bioactive alternative to livecell injections for ischemic myocardial healing [164].Mouse embryonic stem cell-derived exosomes (mES Ex)improved the survival, proliferation, and cardiac dif-ferentiation of cardiac progenitor cells (CPCs), result-ing in an increase in c-kit + CPCs and the production ofnew cardiomyocytes in the infarcted heart. Analysis ofmiRNA content in these exosomes indicated a consid-erable presence of the miR-290-295 cluster, particularly
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