Cardiovascular disease (CVD) and its complications are expected to account for a significant proportion of morbidity and death cases worldwide, with an estimated 23.6 million cases anticipated by the year 2030 (Clark, 2013; WHO, 2017). CVD encompasses a range of conditions, including coronary heart disease, deep vein thrombosis, pulmonary embolism, and myocardial infarction (MI). These conditions are characterized by the occurrence of ischemia and subsequent tissue death. MI and heart failure are the primary conditions that might result in mortality (Chandarana et al., 2018). Morphogenesis, cardiac rhythm, and muscle function and repair are all abnormalities associated with cardiac disease (Ouyang and Wei, 2021). Hypertension, atherosclerosis, and dyslipidemia are the principal etiological factors contributing to the prevalence of CVD. MI can result in a loss of approximately 25% of cardiomyocytes within the heart (Weinberger and Riley, 2023). Due to the inability of adult cardiomyocytes to proliferate, the heart is incapable of generating new cardiomyocytes to replace those that have been lost. It therefore self-heals through the formation of unbeatable fibrotic scar tissue. The gradual process of ventricular remodeling, commonly referred to as the healing process, leads to the weakening of the cardiac muscles. This weakening subsequently leads to a decline in contractility and muscular strength, ultimately resulting in the development of congestive heart failure and eventual death (Prajnamitra et al., 2019). One potential strategy for addressing heart disorders involves the targeted administration of cardioprotective medications directly to the infarcted myocardial and cardiovascular systems. Hence, the need for improved therapeutic interventions and the utilization of numerous drugs within the cardiac domain led to the emergence of targeted drug delivery. The knowledge, application, and implementation of nanoscience in medicine are novel methods for treating CVD and have the potential to enhance CVD treatment (Hu et al., 2020).

In numerous human tissues, mesenchymal stem cells (MSCs) are found and perform a variety of functions. They are present in a variety of tissues, including the placenta, adipose tissue, spinal cord, umbilical cord tissue, and blood (Kou et al., 2022). Due to its low immunogenicity, versatile differentiation capacity, and notable homing ability, it exhibits considerable promise for research in the fields of CVD, nervous system, and hematological disorders (Zhuang et al., 2022). Due to its advantageous properties, the MSC-based drug delivery system has emerged as a promising therapeutic option. Nevertheless, the use of cells as drug carriers presents several challenges, including unpredictable differentiation incidents, infection, cell embolism, storage, and production issues (Su et al., 2021). The exosomes, being the secretion of MSCs, possess the inherent benefits of MSCs while also addressing the limitations associated with MSCs as vehicles for drug delivery (Tang et al., 2021).

Exosomes, classified as extracellular vesicles (EVs), exhibit a size range of approximately 40–160 nm and are released by many eukaryotic cells. By fusing multivesicular bodies across the plasma membrane, these are generated, subsequently liberating their intracellular contents into the extracellular environment (Kalluri and LeBleu, 2020). Extensive study has been conducted on the properties of exosomes and their prospective applications as delivery vehicles for small molecule treatment (Liu et al., 2018a). Exosomes can be easily obtained from different tissues in the body and circulate freely in the bloodstream. Their contents have different impacts based on the type and health of the cell they come from. Given their distinct attributes and mechanisms, they are pivotal elements in controlling cardiovascular function and have a significant impact on nearly all aspects of cardiovascular pathology (Zheng et al., 2021a). Exosomes transport a diverse range of micro (mi)RNAs that directly impact several key factors of CVD, including angiogenesis, hypertrophy, apoptosis, damage, fibrosis, and repair. Exosomes generated from MSCs are vital to MSC-based treatment of CVDs, including as MI and reperfusion damage. In contrast to MSC transplantation, the administration of exosomes derived from MSCs has demonstrated therapeutic potential for CVDs, including the ability to prolong cardiomyocyte survival and prevent apoptosis. Consequently, exosomes derived from MSCs appear to be a viable strategy for the treatment of CVDs (Arslan et al., 2013). As a result of the active secretion of exosomes by numerous types of MSCs, they have garnered considerable interest in the context of CVD. They facilitate the transfer of cytoplasmic cargo across cells and have therapeutic and diagnostic applications (Hirai et al., 2020). An illustrative instance can be found in the study conducted by Mayourian et al., wherein they discovered that exosomes derived from human MSCs (hMSCs) affect cardiac contraction by mediating the excitation–contraction coupling of the heart via miR-21-5p, thereby regulating cardiac contraction (Mayourian et al., 2018). Furthermore, there has been growing interest in utilizing exosomes as a promising nanoscale platform for the targeted delivery of therapeutic drugs or genes. This approach holds great potential for targeted treatment of cardiac diseases, particularly when employing artificially enhanced exosomes with superior cardiac targeting capabilities (Wan et al., 2020). Additional techniques, such as the modification of polypeptides on exosomes, may also be employed to enhance the specificity of cardiac targeting. Engineered exosomes possess distinct features as natural nanoparticles (NPs) that distinguish them from other synthetic nanocarriers. This unique feature enables them to serve as a novel approach for the interventional treatment and early diagnosis of CVD. Specifically, it demonstrated efficacy in promoting the differentiation of cells, preventing apoptosis, and facilitating targeted modification for cardiac homing through their paracrine effect. These effects could inhibit inflammatory responses, mitigate fibrosis, and enhance heart homing, thereby offering promising therapeutic benefits for CVD. This review will examine the current developments, significant obstacles, and opportunities for the applicability of exosomes derived from MSCs. This review aims to provide valuable insights into the potential advancements in the design and development of exosomes derived from MSCs, as well as the prospects for their therapeutic application.

EVs are classified based on their size, specifically their diameter. These categories include apoptotic bodies, which have a diameter greater than 1,000 nm; microvesicles, ranging from 100 to 1,000 nm in diameter; and exosomes, with a diameter between 30 and 150 nm (Gurunathan et al., 2019). They were discovered in a variety of physiological fluids, including milk, saliva, urine, blood, and amniotic fluid. It is now recognized that EVs play a role in pathological and physiological processes by mediating intracellular communication (Minciacchi et al., 2015). As therapeutic nanocarriers and non-invasive diagnostic biomarkers for the treatment of numerous diseases, including cancer, cardiovascular dysfunction, and neurodegeneration, EVs exhibit potential in a number of medical applications (Zhang et al., 2019a). Exosomes are generated via the process of endosomal membrane inward budding, leading to the development of ILVs, or intraluminal vesicles. These ILVs subsequently undergo conversion into multivesicular bodies (MVBs) Figure 1 (Yuan et al., 2022). The fusion process encompasses the participation of multiple Rab GTPases, while the discharge of ILVs into the endosomal lumen is facilitated by the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery (Dixson et al., 2023). Endosomal membrane ubiquitinated proteins are recognized and sequestered by ESCRT 0, which in turn recruits ESCRT I and II. Ubiquitin functions as a signaling molecule that facilitates the transportation of membrane proteins or impaired cellular constituents to the lysosome for disintegration. Additionally, it acts as a signal for the sorting of exosomal cargo on the endosome membrane (Zhang et al., 2021). MVB is capable of fusing with either lysosomes for deterioration or the plasma membrane to liberate exosomes. The initiation of intraluminal membrane budding is facilitated by the binding of ESCRT I and II to the endosomal membrane’s outer surface near the ubiquitinated protein cargos. This binding process selectively targets these cargos to be included within the newly-formed intraluminal buds in the MVB. The procedure is completed by ESCRT III sequestering MVB proteins. Nevertheless, inhibiting the ESCRT pathway did not prevent MVB production, indicating the existence of an ESCRT-independent process. When ALIX and syntenin co-accumulate with exosomes, ubiquitous transmembrane proteins called syndecans directly control ILVs during exosome production (Li et al., 2022a). By encouraging MVB budding and enriching exosomes with CD63, proteolipoprotein, TSG101, and CD81, neutral sphingomyelinase (nSMase) promotes the production of ILVs.

A lipid bilayer membrane encapsulates exosomes, which are composed of ceramide, sphingomyelin, and cholesterol. Certain lipid constituents, such as prostaglandins and phosphatidylserine, might be involved in exosome function (Qiao et al., 2023). The tetraspanin family, including CD63, CD9, and CD81 represents the prevailing proteins that function as markers on the surface of exosomes (Zhu et al., 2023). Heat shock proteins, membrane transporters, fusion proteins, lipid-related proteins, phospholipases, and MVB biogenesis proteins are among the other frequent proteins (Gupta et al., 2022). Exosomes are known to encompass microRNAs (miRNAs) and mRNAs. Endocytosis of exosomes by recipient cells can induce protein expression changes in those cells due to the genetic information conveyed by the RNAs (Li et al., 2023a). Exosomes, a cellular entity, possess the potential for application in disease detection, drug administration, and therapeutic interventions owing to their distinctive bioactive compounds. Non-invasive isolation of these biomarkers from patients renders them promising candidates for diagnostic purposes in several diseases, including cancer, metabolic conditions, neurodegenerative, and infectious diseases (Li et al., 2022b; Motallebnezhad et al., 2022). Exosomes also have potential drug delivery features, such as the ability to penetrate the blood-brain barrier and resist degradation by RNase activity during migration (Li et al., 2022b). Exosomes possess a structural resemblance to liposomes, hence affording protection to their payload against the external environment. In addition, they may serve as a viable substitute for cell treatment due to their enhanced safety and controllability relative to therapeutic approaches employing live cells (Ragni et al., 2022). In contrast to cells, exosomes do not undergo mutation, replication, or promote metastasis. However, it is essential to conduct careful verification of the correlation that exists between the biomarker and the disease.

The accurate isolation of exosomes is of utmost importance in the assessment of their biological functions. Nevertheless, the isolation of exosomes can provide challenges due to their diverse content, varying sizes, many sources, and distinct functions Figure 2 (Chen et al., 2022). Numerous current isolation techniques exhibit limitations in achieving complete separation of exosomes and extracellular vesicles, as well as lipoproteins originating from nonendosomal pathways, due to their comparable physicochemical characteristics (Nguyen et al., 2019). Consequently, the purity of exosomes may be diminished. The efficient enrichment of exosomes holds significant importance, prompting the selection of diverse isolation methods designed for specific applications and objectives. The following methods are frequently employed: polymer precipitation, size-based isolation, immunoaffinity capture, and ultracentrifugation (Li et al., 2017; Luo et al., 2018a).

Deriving and target cells exhibit distinct mechanisms of exosome binding and uptake. Target cells internalize them by phagocytosis, endocytosis, micropinocytosis, and membrane fusion. The surface molecules, including tetraspanins, proteoglycans, integrins, and lectins, are of utmost importance in facilitating these activities (He et al., 2018). Surface modification is the primary method employed to impart myocardial-targeting specificity to exosomes, given the established evidence of differential protein expression between ischemic and normal myocardium (Thupakula et al., 2022). The targeting performance of exosomes has been enhanced by engineering them to over-express surface peptides with ischemic myocardial selectivity. Numerous myocardial homing peptides have been discovered and validated using in vivo biopanning and phage display methodologies, which are commonly employed for the detection of cell-targeting peptides (CTP). These peptides exhibit the ability to specifically target ischemic myocardium (Wang et al., 2021a).

Surface modification can be accomplished using several techniques, including biological, chemical, and physical processes. In the context of biological modification, gene transfer vectors, such as lentiviruses or adeno-associated viruses (AAVs), can be employed to introduce the genetic sequences encoding a myocardium-targeting peptide into the genome of exosome-donor cells. This genetic modification enables the host cells to express a peptide that facilitates homing to the myocardium. The myocardial homing peptide is subsequently combined with exosome surface-expressed transmembrane proteins (Witwer and Wolfram, 2021). The lysosome-associated membrane glycoprotein 2B (LAMP-2B) is a member of the lysosomal-associated membrane protein (LAMP) family and is prominently expressed on the membrane of EVs. It is widely utilized as a membrane protein in various applications (Salunkhe et al., 2020). The protein consists of two distinct regions: an extramembrane domain located at the N-terminus and a transmembrane domain located at the C-terminus. To generate a specific targeting effect, the targeting peptide can be combined with the extracellular domain of LAMP-2B at the N-terminus. Cardiac-targeting peptide (CTP)-Lamp2B vectors were introduced into HEK 293 cells by Kim et al. to produce CTP-expressing EVs (Kim et al., 2018). The efficiency at which CTP-expressing EVs are distributed to the heart was enhanced in both in vitro and in vivo settings. In contrast to conventional EVs, the EVs engineered with myocardium-targeting peptides showed a notable increase in their ability to specifically target ischemic myocardium. This led to a noteworthy reduction of cardiomyocyte apoptosis and inflammation, as well as an enhancement in angiogenesis and a reduction in infarct size in a mouse model of MI (Figure 3A). Mentkowski et al. utilized a comparable methodology in their study, wherein they genetically modified cardio-sphere-derived cells (CDCs) to incorporate the expression of Lamp2b. This was subsequently fused with a peptide specific to cardiomyocytes, namely, WLSEAGPVVTVRALRGTGSW (Mentkowski and Lang, 2019). The EVs extracted from the aforementioned on the surface led to an increased cardiac retention.

Chemical modifications can be applied to the surface of exosomes after their isolation. In contrast to the biological modification approach, chemical reactions exhibit greater speed, efficiency, and simplicity. In their study, Zhu et al. employed bio-orthogonal chemistry to conjugate exosomes with a peptide that specifically targets the ischemic myocardium. The researchers observed that the modified exosomes exhibited a notable affinity for the ischemia lesions in the injured heart, leading to a significant cardioprotective effect during MI (Zhu et al., 2018). In a previous study, Antes et al. introduced a novel method called “cloaking” to effectively incorporate targeting molecules onto the surfaces of exosomes through a membrane anchoring platform (Antes et al., 2018). The cloaking system is made up of three different components: a polyethylene glycol spacer, A conjugated platform molecule of streptavidin, and a phospholipid membrane anchor made of DMPE. Any biotinylated molecule can be attached to the platform molecule to decorate exosomes. By conjugating exosomes with cardiac homing peptide via a dioleoylphosphatidylethanolamine N-hydroxysuccinimide (DOPE-NHS) linker, Vandergriff et al. showed enhanced therapeutic results and increased homing efficacy of the injured heart Figure 3B (Vandergriff et al., 2018).

Membrane fusion is a physical method of modifying the surface of exosomes, as opposed to chemical or genetic methods. Zhang et al. successfully produced monocyte mimetic exosomes by fusing MSC-derived exosomes with monocyte cell membranes via the fusion-extrusion technique (Zhang et al., 2020). These modified exosomes possessed the inflammatory targeting characteristics of monocytes, and they were able to penetrate damaged myocardium through the bloodstream. The aforementioned technique demonstrated notable efficacy in selectively targeting damaged myocardial tissue, resulting in enhanced therapeutic effects on heart function. Hu et al. combined MSC-derived exosomes and platelet membranes by extruding them via 200 nm filters, which improved their capacity to target injured tissue and enhanced the internalization of cells through macropinocytosis (Zhang et al., 2020). By modifying the exosomes with platelet membranes, they were able to increase their uptake by cardiomyocytes and endothelial cells while decreasing their uptake by the mononuclear phagocyte system in vivo.

Exosomes were endowed with enhanced targeting capabilities through surface peptide engineering. The effects of these technologies, however, on the biological characteristics of exosomes remain unknown. Additional research is required to determine whether the surface engineering performance may have undesirable effects, including immunogenic activities, or alter the typical functions of proteins in the exosome membrane. Modifying the cells that produce exosomes is a laborious and time-consuming process, and these methods have the potential to compromise the integrity and stability of the exosome membrane or result in a poor exosome yield (Lee et al., 2016; Armstrong et al., 2017). Furthermore, surface modification is incapable of simultaneously loading multiple surface peptides. Peptides exposed on the surface of exosomes are also unstable and susceptible to degradation (Lee et al., 2016). Hung et al. provided evidence that the fusion of LAMP-2B with membrane display could potentially result in the loss of ligands (Pessentheiner et al., 2013). Glycosylation motif–containing designed targeted peptide–Lamp2b fusion proteins could be useful in protecting peptides from degradation.

Exosomes have been utilized as biocarriers for the delivery of various therapeutic agents, including macromolecules, noncoding RNA (ncRNAs), and bioactive proteins in the context of CVD treatment. The biological origins of exosomes, including endothelial cells, fibroblasts, and smooth muscle cells, play an essential role in the cardiac system. Exosomes have favorable characteristics such as low biocompatibility and immunogenicity, rendering them highly promising as drug carriers in the field of medicine and therapeutic interventions (Liu et al., 2021a). The heterogeneity of natural exosomes restricts their applicability in CVD. Immunosuppressive, immunomodulatory, and regenerative effects of exosomes are improved by preconditioning other cells or stem cells triggered by chemicals, hypoxia, and cytokines (Zhang et al., 2019b). Tumor necrosis factor, deferoxamine, nitric oxide, lipopolysaccharides (LPS), and interferon increase the effectiveness of exosomes. Similar improvements were observed when cytokines, including hypoxia-inducible factors (HIF) and interleukins (ILs), were stimulated (Nocera et al., 2019). The effectiveness of exosomes is further enhanced by ultraviolet induction and miRNAs (Hegyesi et al., 2019). The therapeutic efficiency of exosomes is enhanced through stem cell surface modification and gene transfection (Bu et al., 2021).

Stem cells-derived exosomes possess a wide range of functional RNAs, therefore presenting the potential for utilizing exosomes in facilitating the differentiation process of endothelial progenitor cells into smooth muscle cells, vascular endothelium cells, and cardiomyocytes within the damaged myocardium (Ringuette Goulet et al., 2018). Through the delivery of mRNA and miRNA, exosomes produced from MSCs, ESCs, EPCs, ADSCs, and iPSCs can affect cardiac protection (He et al., 2020).

In conclusion, exosomes emerged as important mediators of intercellular communication, demonstrating a wide array of potential uses in the physiological and pathological mechanisms of CVD. However, for exosomes to reach their maximum potential, sensitive detection, accurate characterization, and efficient isolation are required. Exosomes are crucial in the treatment and diagnosis of CVD. In addition, exosomes have the potential to serve as biological vehicles for the delivery of therapeutic genes and drugs in the treatment of CVD. Stem cell-derived exosomes can specifically stimulate angiogenesis, inhibit apoptosis, and alleviate stress-induced damage. Furthermore, bioengineered exosomes can improve their targeting capability, resulting in a rise in accumulation inside the cardiovascular system. This demonstrates significant promise as a customized therapeutic strategy for enhancing outcomes in patients with CVD.

Exosomes exhibit significant potential as vehicles for drug delivery due to their inherent membrane stability and targeted characteristics. Exosomal ncRNAs (circRNA, lncRNA, and tRF) are difficult to detect due to the presence of confounding interfering factors; hence, their therapeutic utility is limited. Exosomes are regarded as a natural drug delivery method, even though they can be modified to contain ncRNA for gene transmission or be modified with homing peptides to enhance cardiac targeting. In comparison to stem cell therapy, which carries the danger of immunogenicity and tumorigenicity, modified exosomes provide the potential for therapeutic utilization in CVD treatment. However, significant progress is still required to improve the loading efficiency and targeted modification of exosomes. This includes enhancing targeting and stability as well as refining cell pretreatment techniques (Wang et al., 2021c). Notably, there are still obstacles to overcome regarding the use of exosomes for gene or drug delivery. Several challenges persist in the field, including a poor extraction rate, the difficulty in achieving high concentrations and high purity of exosomes, as well as concerns regarding their long-lasting efficacy and safety. The potential impact of targeted modification on the structural integrity of exosomes during large-scale synthesis remains uncertain. Since in vitro and in vivo findings support the methods, ongoing research is conducted to resolve the difficulties. Current research focuses on optimizing administration routes, preparing formulations with excellent in vivo stability, improving target specificity, engineering exosomes without altering their biophysical and biochemical properties, etc. As a result, scalable manufacturing procedures are necessary to produce exosomes quickly, efficiently, and reliably if they are to be used as therapeutic carriers. Mass production of exosomes can be achieved by many techniques, including polymer-based precipitation, aqueous twophase systems, size exclusion chromatography, and ultrafiltration (Charoenviriyakul et al., 2017). The reaching large-scale desired exosomes for clinical usage is a main challenge.

Emerging technologies are crucial in enabling the detection and tracking of exosomes, as well as in vivo monitoring and analysis (Charoenviriyakul et al., 2017). Optical sensors and magnetically labeled particles hold tremendous potential for exosome detection and in vivo monitoring (Liu T. et al., 2020b). Since exosome technology is already being utilized more in the diagnosis and treatment of disease, researchers are encouraged to focus more of their efforts on overcoming the obstacles and limits in the field (Verweij et al., 2019). Several challenges hinder the progress of implementing exosomes in clinical applications. These include the absence of standardized protocols for isolating and analyzing these microvesicles, as well as the variability in yield caused by factors such as extraction methods, human error, storage conditions, and equipment type (Yang et al., 2023).

Native exosomes possess a vast array of proteins and nucleic acid constituents, which exhibit inherent therapeutic properties, hence classifying the exosomes as biological products. Despite the clinical validation of exosomes, regulatory agencies have yet to grant approval to any exosomal products (Whitford and Guterstam, 2019). Another crucial obstacle in exosome drug delivery is to guarantee that exosome-based therapies fulfill the criteria set by regulatory authorities to ensure clinical approval. Compared to other types of nanomedicines, the regulatory considerations for exosome-based therapeutics have not been tackled thoroughly to date. Although research and clinical studies related to the use of exosome-based therapeutics for drug delivery are still in their infancy, the on-demand methods used for advanced understanding and systemic characterization of exosomes will address the challenges and clinical transition issues of exosome-based therapeutics. Scalable cell culture conditions and methods for isolating and purifying exosomes are necessary for the effort to put therapeutic exosomes into industrial-scale production and clinical application. Due to high development expenses and the uncertainty of meeting regulatory and marketing standards, the use of large-scale stem cell cultures could potentially impede the production of stable and effective products. Similarly, there are few opportunities for supplying a large amount of cell-culture-conditioned medium to scale up exosome synthesis. To determine the optimal scaling-up conditions for therapeutically pertinent exosomes, it has proven challenging to obtain a satisfactory yield of high-purity exosomes during large-scale production. It is imperative to direct attention to the effectiveness and safety of exosomes to facilitate their utilization in clinical settings. The number of registered experiments conducted on exosomes and EVs is fewer than 200 (Stine et al., 2020). Exosomes derived from MSCs are scalable to extremely high and clinically relevant concentrations, according to preclinical data. The therapeutic benefits of exosomes derived from MSCs have been validated in numerous preclinical investigations across a wide range of surgical subspecialties (Butreddy et al., 2021). Exosomes have been found and employed as diagnostic biomarkers in numerous clinical trials. Beyond their use as stem cell produced exosomes, in numerous clinical trials, exosomes have been shown to serve as both therapeutic agents and biological markers. A comprehensive search was conducted on ClinicalTrials.gov, utilizing the keywords ‘exosome therapy’, ‘exosome treatment’, and ‘exosome’ to yield 188 records. However, of these, only 60 (or 32%) relate specifically to interventional studies that use exosomes as therapeutic agents (Tan et al., 2024). In December 2019, a clinical trial using umbilical stem cell (UMSC) exosomes to treat dry eye symptoms was registered (NCT04213248). At present, a clinical trial (NCT02138331) is being conducted to assess the impact of repetitive intravenous infusions of MSC exosomes derived from UCB blood on individuals with T1DM (Lee et al., 2021). Multiple clinical trials have been conducted on patients to validate the clinical advantages. Of these seven published clinical studies and fourteen ongoing clinical trials (as of September 2022) have evaluated MSC-derived exosomes as a therapeutic agent against various diseases, including stroke, Alzheimer’s disease, type 1 diabetes, kidney diseases, acute respiratory distress syndrome (ARDS), graft-versus-host disease (GvHD), and osteoarthritis (Lotfy et al., 2023). Exosome-based clinical trials are currently in progress. Exosomes generated from dendritic cells and mesenchymal cells are the primary types of exosomes utilized in clinical trials. However, the lack of ideal procedures for exosome manufacturing, isolation, and storage limits the clinical application of mesenchymal-cell-derived exosomes. To assess the effectiveness of exosome therapy, reliable characterization techniques, administration schedules, and cell culture conditions must be developed (Mendt et al., 2019). The identification of urinary exosomal proteins as a means of diagnosing autoimmune thyroid heart disease, as well as the use of exosomes derived from epicardial fat as atrial fibrillation biomarkers, have been explored. Clinical trials have been conducted, and ongoing recruitment efforts are focused on exploring the potential of exosomal miRNA in patients with MI. Despite the aforementioned limitations, exosomes have demonstrated a wide array of potential regarding the ongoing advancement of cell-based drug delivery systems and the clinical use of nano-biomimetic drug delivery systems. The potential success of clinical trials related to the treatment of exosomes has yet to be determined.