Stroke is a challenging neurological condition caused by interrupted blood flow to the brain and presents substantial global health concerns due to its prevalence and limited treatment options. Exosomes, tiny vesicles released by cells, are gaining attention for their potential in targeted drug delivery and as diagnostic and therapeutic biomarkers for stroke. This article outlines recent advances in exosome-based drug delivery systems and examines their application in managing stroke. Stroke presents with diverse symptoms depending on the brain region affected, and current treatments primarily aim to restore blood flow and manage risk factors. Exosomes exhibit a unique structure and composition and contain bioactive molecules. Their ability to cross the blood-brain barrier and target specific cells makes them promising candidates for precise drug delivery in stroke therapy. Exosomes contribute extensively to stroke pathophysiology and present considerable therapeutic promise by promoting neuroprotection and assisting in brain repair mechanisms. They can be engineered to carry various therapeutic substances, such as small molecules, enabling highly specific targeted delivery. Furthermore, the molecular compositions of exosomes reflect the pathological changes observed in stroke, indicating their potential use as biomarkers for early diagnosis, monitoring of disease progression, and creating individualized treatment strategies. Despite promising developments, challenges remain in optimizing exosome production, purification, and cargo loading. Further investigations into their biological mechanisms and clinical validation are crucial for translating their potential into tangible benefits for patients. This article highlights recent advances and future prospects in exosome research, underscoring their application as novel diagnostic and therapeutic tools in stroke management.

One of the major global causes of death and disability is ischemic stroke (IS). Mesenchymal stem cells (MSCs) emerge as a cell-based therapy for numerous diseases. Recently, research on the role of MSCs in ischemic stroke has developed rapidly worldwide. Bibliometric analysis of MSCs for IS has not yet been published, though.

Through bibliometric analysis, the aim of this study was to assess the current state of research on MSCs in the field of ischemic stroke research worldwide and to identify important results, major research areas, and emerging trends.

Publications related to MSCs in ischemic stroke from January 1, 2002, to December 31, 2022, were obtained from the Web of Science Core Collection (WoSCC). We used HistCite, VOSViewer, CiteSpace, and Bibliometrix for bibliometric analysis and visualization. We employed the Total Global Citation Score (TGCS) to assess the impact of publications.

The bibliometric analysis included a total of 2,048 publications. The 1,386 papers used in this study were authored by 200 individuals across 200 organizations in 72 countries, published in 202 journals. Cesar V Borlongan published the most documents among high-productivity authors. Michael Chopp was the author with the highest average number of citations per paper, with an average paper citation time of 118.54. We found that research of MSCs in ischemic stroke developed rapidly starting in 2008. Neurosciences were the most productive journals, and Chinese researchers have produced the most research papers in this subject. The most cited article is "Systemic administration of exosomes released from mesenchymal stromal cells promotes functional recovery and neurovascular plasticity after stroke in rats".

This study uses both numbers and descriptions to thoroughly review the research on MSCs related to IS. This information provides valuable experience for researchers to carry out MSCs' work on IS.

The critical role of the immune system in brain function and dysfunction is well recognized, yet development of immune therapies for psychiatric diseases has been slow due to concerns about iatrogenic immune deficiencies. These concerns are emphasized by the lack of objective diagnostic tools in psychiatry. A promise to resolve this conundrum lies in the exploitation of extracellular vesicles (EVs) that are physiologically produced or can be synthetized. EVs regulate recipient cell functions and offer potential for EVs-based therapies. Intranasal EVs administration enables the targeting of specific brain regions and functions, thereby facilitating the design of precise treatments for psychiatric diseases. The development of such therapies requires navigating four dynamically interacting networks: neuronal, glial, immune, and EVs. These networks are profoundly influenced by brain fluid distribution. They are crucial for homeostasis, cellular functions, and intercellular communication. Fluid abnormalities, like edema or altered cerebrospinal fluid (CSF) dynamics, disrupt these networks, thereby negatively impacting brain health. A deeper understanding of the above-mentioned four dynamically interacting networks is vital for creating diagnostic biomarker panels to identify distinct patient subsets with similar neuro-behavioral symptoms. Testing the functional pathways of these biomarkers could lead to new therapeutic tools. Regulatory approval will depend on robust preclinical data reflecting progress in these interdisciplinary areas, which could pave the way for the design of innovative and precise treatments. Highly collaborative interdisciplinary teams will be needed to achieve these ambitious goals.

Stroke is characterized with high morbidity, mortality and disability all over the world, and one of its core pathologies is blood-brain barrier (BBB) dysfunction. BBB plays a crucial physiological role in protecting brain tissues and maintaining homeostasis in central nervous system (CNS). BBB dysfunction serves as a key factor in the development of cerebral edema, inflammation, and further neurological damage in stroke patients. Currently, stem cells and their derived exosomes have shown remarkable potential in repairing the damaged BBB and improving neurological function after stroke. Stem cells repair the integrity of BBB through anti-inflammatory, antioxidant, angiogenesis and regulation of intercellular signaling mechanisms, while stem cell-derived exosomes, as natural nanocarriers, further enhance the therapeutic effect by carrying active substances such as proteins, RNAs and miRNAs. This review will present the latest research advances in stem cells and their exosomes in stroke treatment, as well as the challenges of cell source, transplantation timing, dosage, and route of administration in clinical application, aiming to discuss their mechanisms of repairing BBB integrity and potential for clinical application, and proposes future research directions. Stem cells and exosomes are expected to provide new strategies for early diagnosis and precise treatment of stroke, and promote breakthroughs in the field of stroke.

Exosomes are small extracellular vesicles naturally secreted by cells into body fluids, enriched with bioactive molecules such as RNAs, proteins, and lipids. These nanosized vesicles play a crucial role in physiological and pathological processes by facilitating intercellular communication and modulating cellular responses, particularly within the central nervous system (CNS). Their ability to cross the blood-brain barrier and reflect the characteristics of their parent cells makes exosomal cargo a promising candidate for biomarkers in the early diagnosis and clinical assessment of neurological conditions. This review offers a comprehensive overview of current knowledge on the characterization of mammalian-derived exosomes, their application as drug delivery systems for neurological disorders, and ongoing clinical trials involving exosome-loaded cargo. Despite their promising attributes, a significant challenge remains the lack of standardized isolation methods, as current techniques are often complex, costly, and require sophisticated equipment, affecting the scalability and affordability of exosome-based therapies. The review highlights the engineering potential of exosomes, emphasizing their ability to be customized for targeted therapeutic delivery through surface modification or conjugation. Future advancements in addressing these challenges and leveraging the unique properties of exosomes could lead to innovative and effective therapeutic strategies in neurology.

Although thrombolytic therapy has enjoyed relative success, limitations remain, such as a narrow therapeutic window and inconsistent efficacy. Consequently, there is a pressing need to develop novel therapeutic approaches. In recent years, extracellular vesicles (EVs) have garnered increasing attention as a potential alternative to stem cell therapy. Because of their ability to cross the blood-brain barrier and exert neuroprotective effects in cerebral ischemia and hemorrhage, the exploration of EVs for clinical application in stroke treatment is expanding. EVs are characterized by high heterogeneity, with their composition closely mirroring that of their parent cells. This property enables EVs to distinguish between cerebral ischemia and hemorrhage, thus facilitating a more rapid and accurate diagnosis. Additionally, EVs can be engineered to carry specific molecules, such as miRNAs, targeting them to specific cells, potentially enhancing the therapeutic outcome and improving stroke prognosis. In this review, we will also explore the methodologies for the isolation and extraction of EVs, critically evaluating the advantages and disadvantages of various commonly employed separation techniques. Furthermore, we will briefly address current EV preservation and administration methods, providing a comprehensive overview of the state of EV-based therapies in stroke treatment.

We examined whether combined exogenous mitochondria (ExMito) and cellular prion protein overexpression (Ove-PrPC) in adipose-derived mesenchymal stem cell (Ove-PrPC in ADMSCs) therapy is superior to a single therapy for protecting the brain against intracranial hemorrhage (ICH) in rats. In vitro, compared with the control group, ExMito transfusion into recipient cells (i.e., N2a cells) significantly increased under hypoxic conditions (P < 0.001) and augmented ρ0 cell proliferation and cell-cycle activation (P < 0.001). PrPC-OE in ADMSCs exhibited higher resistance to H2O2-induced cell senescence and mitochondrial and DNA damage compared to ADMSCs (P < 0.001). Rats were categorized into group 1 (sham-control), 2 (ICH), 3 [ICH + ExMito (350 μg) by intracranial injection at 3 h after ICH], 4 [ICH + PrPC-OE in ADMSCs (6.0 × 105 cells) and intracranial injection and 1.2 × 106 cells by intravenous injection)], and 5 (ICH + combined ExMito + PrPC-OE in ADMSCs). By day 28, the brain infarct volume, brain infarct area, inflammatory cell infiltration, and biomarkers for DNA and mitochondrial damage were highest in group 2, lowest in group 1, and significantly lower in group 5 than in groups 3 and 4. NeuN cells exhibited the opposite pattern for brain infarct volume, and neurological function (corner test) significantly improved in groups 3 and 4, with further improvement in group 5 compared with that in group 2 (P < 0.0001). Combined ExMito + PrPC-OE ADMSCs therapy was superior to either therapy alone in mitigating the ICH-induced brain damage.

Mesenchymal stem cell (MSC) -derived exosomes, especially adipose-derived mesenchymal stem cell exosomes (ADSC-Exos), have emerged as a promising alternative for skin damage repair with anti-inflammatory, angiogenic and cell proliferation effects while overcoming some of the limitations of MSC. However, the mechanism by which ADSC-Exos regulates inflammatory cells during wound healing remains unclear. This study investigated how ADSC-Exos regulate macrophages to promote wound healing.

ADSC-Exos were isolated using ultracentrifugation, with subsequent quantification of exosomes particle number. To investigate their role in wound healing, the effects of ADSC-Exos on inflammation, angiogenesis, collagen deposition and macrophage polarization were evaluated through immunohistochemical staining, immunofluorescence and western blotting. Changes in gene expression associated with ADSC-Exos-induced macrophage polarization were analyzed using qPCR. RNA sequencing was performed to identify differentially expressed genes affected by ADSC-Exos. The critical role of IL-33 in the wound healing process was further confirmed using Il33-/- mice. Additionally, co-culture experiments were conducted to explore the effects of IL-33 on keratinocyte proliferation, collagen deposition and epithelialization.

ADSC-Exos inhibited the expression of TNF-α and IL-6, induced M2 macrophage polarization, promoted collagen deposition and angiogenesis, and accelerated wound healing. RNA sequencing identified IL-33 as a key mediator in this process. In Il33-/- mice, impaired wound healing and decreased M2 macrophage polarization were observed. The co-culture experiments showed that IL-33 enhanced keratinocyte function through activation of the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of ADSC-Exos in wound healing by modulating IL-33.

ADSC-Exos promote wound healing by regulating macrophage polarization and enhancing IL-33 release which drives keratinocyte proliferation, collagen deposition and epithelialization via the Wnt/β-catenin signaling pathway. These findings provide a mechanistic basis for the therapeutic potential of ADSC-Exos in tissue repair and regeneration.

Globally, there are 15 million stroke patients each year who have significant neurological deficits. Today, there are no treatments that directly address these deficits. With demographics shifting to an older population, the problem is worsening. Therefore, it is crucial to develop feasible therapeutic treatments for stroke. In this study, we tested exosomes derived from embryonic endothelial progenitor cells (eEPC) to assess their therapeutic efficacy in a rat model of ischemic stroke. Importantly, we have developed purification methods aimed at producing robust and scalable exosomes suitable for manufacturing clinical grade therapeutic exosomes. We characterized exosome cargos including RNA-seq, miRNAs targets, and proteomic mass spectrometry analysis, and we found that eEPC-exosomes were enhanced with angiogenic miRNAs (i.e., miR-126), anti-inflammatory miRNA (i.e., miR-146), and anti-apoptotic miRNAs (i.e., miR-21). The angiogenic activity of diverse eEPC-exosomes sourced from a panel of eEPC production lines was assessed in vitro by live-cell vascular tube formation and scratch wound assays, showing that several eEPC-exosomes promoted the proliferation, tube formation, and migration in endothelial cells. We further applied the exosomes systemically in a rat middle cerebral artery occlusion (MCAO) model of stroke and tested for neurological recovery (mNSS) after injury in ischemic animals. The mNSS scores revealed that recovery of sensorimotor functioning in ischemic MCAO rats increased significantly after intravenous administration of eEPC-exosomes and outpaced recovery obtained through treatment with umbilical cord stem cells. Finally, we investigated the potential mechanism of eEPC-exosomes in mitigating ischemic stroke injury and inflammation by the expression of neuronal, endothelial, and inflammatory markers. Taken together, these data support the finding that eEPCs provide a valuable source of exosomes for developing scalable therapeutic products and therapies for stroke and other ischemic diseases.

Ischemic stroke (IS) remains a leading cause of mortality and long-term disability worldwide, with limited therapeutic options available. Despite the success of early interventions, such as tissue-type plasminogen activator administration and mechanical thrombectomy, many patients continue to experience persistent neurological deficits. The pathophysiology of IS is multifaceted, encompassing excitotoxicity, oxidative and nitrosative stress, inflammation, and blood-brain barrier disruption, all of which contribute to neural cell death, further complicating the treatment of IS. Recently, extracellular vesicles (EVs) secreted naturally by various cell types have emerged as promising therapeutic agents because of their ability to facilitate selective cell-to-cell communication, neuroprotection, and tissue regeneration. Furthermore, engineered EVs, designed to enhance targeted delivery and therapeutic cargo, hold the potential to improve their therapeutic benefits by mitigating neuronal damage and promoting neurogenesis and angiogenesis. This review summarizes the characteristics of EVs, the molecular mechanisms underlying IS pathophysiology, and the emerging role of EVs in IS treatment at the molecular level. This review also explores the recent advancements in EV engineering, including the incorporation of specific proteins, RNAs, or pharmacological agents into EVs to enhance their therapeutic efficacy.

Stroke is the second leading cause of death worldwide, and its incidence is rising rapidly. Acute ischemic stroke is a subtype of stroke that accounts for the majority of stroke cases and has a high mortality rate. An effective treatment for stroke is to minimize damage to the brain's neural tissue by restoring blood flow to decreased perfusion areas of the brain. Many reports have concluded that both oxidative stress and excitotoxicity are the main pathological processes associated with ischemic stroke. Current measures to protect the brain against serious damage caused by stroke are insufficient. For this reason, it is important to investigate oxidative and antioxidant strategies to reduce oxidative damage. This review focuses on studies assessing the concentration of oxidative stress biomarkers and the level of antioxidants (enzymatic and non-enzymatic) and their impact on the clinical prognosis of patients after stroke. Mechanisms related to the production of ROS/RNS and the role of oxidative stress in the pathogenesis of ischemic stroke are presented, as well as new therapeutic strategies aimed at reducing the effects of ischemia and reperfusion.

Extracellular vesicles (EVs) are vital for cell-to-cell communication, transferring proteins, lipids, and nucleic acids in various physiological and pathological processes. They play crucial roles in immune modulation and tissue regeneration but are also involved in pathogenic conditions like inflammation and degenerative disorders. EVs have heterogeneous populations and cargo, with numerous subpopulations currently under investigations. EV therapy shows promise in stimulating tissue repair and serving as a drug delivery vehicle, offering advantages over cell therapy, such as ease of engineering and minimal risk of tumorigenesis. However, challenges remain, including inconsistent nomenclature, complex characterization, and underdeveloped large-scale production protocols. This review highlights the recent advances and significance of EVs heterogeneity, emphasizing the need for a better understanding of their roles in disease pathologies to develop tailored EV therapies for clinical applications in neurological disorders.

Recently, the therapeutic potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) has been extensively studied in both human and veterinary medicine. EVs are nano-sized particles containing biological components commonly found in other biological materials. For that reason, EV isolation and characterization are critical to draw precise conclusions during their investigation. Research on EVs within veterinary medicine is still considered in its early phases, yet numerous papers were published in recent years. The conventional adult tissues for deriving MSCs include adipose tissue and bone marrow. Nonetheless, alternative sources such as synovial fluid, endometrium, gingiva, and milk have also been intermittently used. Fetal adnexa are amniotic membrane/fluid, umbilical cord and Wharton's jelly. Cells derived from fetal adnexa exhibit an intermediate state between embryonic and adult cells, demonstrating higher proliferative and differentiative potential and longer telomeres compared to cells from adult tissues. Summarized here are the principal and recent preclinical and clinical studies performed in domestic animals such as horse, cattle, dog and cat. To minimize the use of antibiotics and address the serious issue of antibiotic resistance as a public health concern, they will undoubtedly also be utilized in the future to treat infections in domestic animals. A number of concerns, including large-scale production with standardization of EV separation and characterization techniques, must be resolved for clinical application.

Exosomes are small vesicles containing proteins, nucleic acids, and biological lipids, which are responsible for intercellular communication. Studies have shown that exosomes can be utilized as effective drug delivery vehicles to accurately deliver therapeutic substances to target tissues, enhancing therapeutic effects and reducing side effects. Mesenchymal stem cells (MSCs) are a class of stem cells widely used for tissue engineering, regenerative medicine, and immunotherapy. Exosomes derived from MSCs have special immunomodulatory functions, low immunogenicity, the ability to penetrate tumor tissues, and high yield, which are expected to be engineered into efficient drug delivery systems. Despite the promising promise of MSC-derived exosomes, exploring their optimal preparation methods, drug-loading modalities, and therapeutic potential remains challenging. Therefore, this article reviews the related characteristics, preparation methods, application, and potential risks of MSC-derived exosomes as drug delivery systems in order to find potential therapeutic breakthroughs.

The state of well-being and health of our body is regulated by the fine osmotic and biochemical balance established between the cells of the different tissues, organs, and systems. Specific districts of the human body are defined, kept in the correct state of functioning, and, therefore, protected from exogenous or endogenous insults of both mechanical, physical, and biological nature by the presence of different barrier systems. In addition to the placental barrier, which even acts as a linker between two different organisms, the mother and the fetus, all human body barriers, including the blood-brain barrier (BBB), blood-retinal barrier, blood-nerve barrier, blood-lymph barrier, and blood-cerebrospinal fluid barrier, operate to maintain the physiological homeostasis within tissues and organs. From a pharmaceutical point of view, the most challenging is undoubtedly the BBB, since its presence notably complicates the treatment of brain disorders. BBB action can impair the delivery of chemical drugs and biopharmaceuticals into the brain, reducing their therapeutic efficacy and/or increasing their unwanted bioaccumulation in the surrounding healthy tissues. Recent nanotechnological innovation provides advanced biomaterials and ad hoc customized engineering and functionalization methods able to assist in brain-targeted drug delivery. In this context, lipid nanocarriers, including both synthetic (liposomes, solid lipid nanoparticles, nanoemulsions, nanostructured lipid carriers, niosomes, proniosomes, and cubosomes) and cell-derived ones (extracellular vesicles and cell membrane-derived nanocarriers), are considered one of the most successful brain delivery systems due to their reasonable biocompatibility and ability to cross the BBB. This review aims to provide a complete and up-to-date point of view on the efficacy of the most varied lipid carriers, whether FDA-approved, involved in clinical trials, or used in in vitro or in vivo studies, for the treatment of inflammatory, cancerous, or infectious brain diseases.

Stroke is the number one cause of morbidity in the United States and number two cause of death worldwide. There is a critical unmet medical need for more effective treatments of ischemic stroke, and this need is increasing with the shift in demographics to an older population. Recently, several studies have reported the therapeutic potential of stem cell-derived exosomes as new candidates for cell-free treatment in stoke. This review focuses on the use of stem cell-derived exosomes as a potential treatment tool for stroke patients. Therapy using exosomes can have a clear clinical advantage over stem cell transplantation in terms of safety, cost, and convenience, as well as reducing bench-to-bed latency due to fewer regulatory milestones. In this review article, we focus on (1) the therapeutic potential of exosomes in stroke treatment, (2) the optimization process of upstream and downstream production, and (3) preclinical application in a stroke animal model. Finally, we discuss the limitations and challenges faced by exosome therapy in future clinical applications.

Extracellular vesicles (EVs) are nano-sized, membranous transporters of various active biomolecules with inflicting phenotypic capabilities, that are naturally secreted by almost all cells with a promising vantage point as a potential leading drug delivery platform. The intrinsic characteristics of their low toxicity, superior structural stability, and cargo loading capacity continue to fuel a multitude of research avenues dedicated to loading EVs with therapeutic and diagnostic cargos (pharmaceutical compounds, nucleic acids, proteins, and nanomaterials) in attempts to generate superior natural nanoscale delivery systems for clinical application in therapeutics. In addition to their well-known role in intercellular communication, EVs harbor microRNAs (miRNAs), which can alter the translational potential of receiving cells and thus act as important mediators in numerous biological and pathological processes. To leverage this potential, EVs can be structurally engineered to shuttle therapeutic miRNAs to diseased recipient cells as a potential targeted 'treatment' or 'therapy'. Herein, this review focuses on the therapeutic potential of EV-coupled miRNAs; summarizing the biogenesis, contents, and function of EVs, as well as providing both a comprehensive discussion of current EV loading techniques and an update on miRNA-engineered EVs as a next-generation platform piloting benchtop studies to propel potential clinical translation on the forefront of nanomedicine.

Ischemic stroke (IS) is a neurological condition characterized by severe long-term consequences and an unfavorable prognosis for numerous patients. Despite advancements in stroke treatment, existing therapeutic approaches possess certain limitations. However, accumulating evidence suggests that mesenchymal stem/stromal cells (MSCs) hold promise as a potential therapy for various neurological disorders, including IS, owing to their advantageous properties, such as immunomodulation and tissue regeneration. Additionally, MSCs primarily exert their therapeutic effects through the release of extracellular vesicles (EVs), highlighting the significance of their paracrine activities. These EVs are small double-layered phospholipid membrane vesicles, carrying a diverse cargo of proteins, lipids, and miRNAs that enable effective cell-to-cell communication. Notably, EVs have emerged as attractive substitutes for stem cell therapy due to their reduced immunogenicity, lower tumorigenic potential, and ease of administration and handling. Hence, this review summarizes the current preclinical and clinical studies performed to investigate the safety and therapeutic potential of MSCs and their EVs derived from different sources, including bone marrow, adipose tissue, umbilical cord blood, and Wharton's jelly in IS.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-β protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Mesenchymal stem cells (MSCs) possess a role in tissue regeneration and homeostasis because of inherent immunomodulatory capacity and the production of factors that encourage healing. There is substantial evidence that MSCs' therapeutic efficacy is primarily determined by their paracrine function including in cancers. Extracellular vesicles (EVs) are basic paracrine effectors of MSCs that reside in numerous bodily fluids and cell homogenates and play an important role in bidirectional communication. MSC-derived EVs (MSC-EVs) offer a wide range of potential therapeutic uses that exceed cell treatment, while maintaining protocell function and having less immunogenicity. We describe characteristics and isolation methods of MSC-EVs, and focus on their therapeutic potential describing its roles in tissue repair, anti-fibrosis, and cancer with an emphasis on the molecular mechanism and immune modulation and clinical trials. We also explain current understanding and challenges in the clinical applications of MSC-EVs as a cell free therapy.

Exosomes are the smallest subset of extracellular signaling vesicles secreted by most cells with the ability to communicate with other tissues and cell types over long distances. Their use in regenerative medicine has gained tremendous momentum recently due to their ability to be utilized as therapeutic options for a wide array of diseases/conditions. Over 5000 publications are currently being published yearly on this topic, and this number is only expected to dramatically increase as novel therapeutic strategies continue to be developed. Today exosomes have been applied in numerous contexts including neurodegenerative disorders (Alzheimer's disease, central nervous system, depression, multiple sclerosis, Parkinson's disease, post-traumatic stress disorders, traumatic brain injury, peripheral nerve injury), damaged organs (heart, kidney, liver, stroke, myocardial infarctions, myocardial infarctions, ovaries), degenerative processes (atherosclerosis, diabetes, hematology disorders, musculoskeletal degeneration, osteoradionecrosis, respiratory disease), infectious diseases (COVID-19, hepatitis), regenerative procedures (antiaging, bone regeneration, cartilage/joint regeneration, osteoarthritis, cutaneous wounds, dental regeneration, dermatology/skin regeneration, erectile dysfunction, hair regrowth, intervertebral disc repair, spinal cord injury, vascular regeneration), and cancer therapy (breast, colorectal, gastric cancer and osteosarcomas), immune function (allergy, autoimmune disorders, immune regulation, inflammatory diseases, lupus, rheumatoid arthritis). This scoping review is a first of its kind aimed at summarizing the extensive regenerative potential of exosomes over a broad range of diseases and disorders.

Extracellular vesicles (EVs) derived from adipose-derived stem cells (ADSC-EVs) hold great promise for ischemic stroke treatment, but their therapeutic efficacy is greatly limited due to insufficient targeting ability. Previous reports focused on single ischemic targeting or blood-brain barrier (BBB) penetration, precise delivery to the brain parenchyma has not been fully considered. This study leveraged the targeting ability of RGD peptide and the cell penetrating ability of Angiopep-2 peptide to deliver ADSC-EVs precisely to the impaired brain parenchyma. We found that dual-modified EVs (RA-EVs) significantly enhanced the transcellular permeability across BBB in vitro, and not only targeted ischemic blood vessels but also achieved rapid accumulation in the ischemic lesion area after intravenous administration in vivo. RA-EVs further decreased the infarct volume, apoptosis, BBB disruption, and neurobehavioral deficits. RNA sequencing revealed the molecular regulation mechanism after administration. These findings demonstrate that dual-modification optimizes brain parenchymal targeting and highlights the significance of recruitment and penetration as a previously unidentified strategy for harnessing EVs for therapeutic delivery in ischemic stroke.

Exosome-based treatments are gaining traction as a viable approach to addressing the various issues faced by an ischemic stroke. These extracellular vesicles, mainly produced by Mesenchymal Stem Cells (MSCs), exhibit many properties with substantial therapeutic potential. Exosomes are particularly appealing for stroke therapy because of their low immunogenicity, effective cargo transport, and ability to cross the blood-brain barrier. Their diverse effects include neuroprotection, angiogenesis stimulation, inflammatory response modulation, and cell death pathway attenuation, synergistically promoting neuronal survival, tissue regeneration, and functional recovery. Exosomes also show potential as diagnostic indicators for early stroke identification and customized treatment options. Despite these promising qualities, current exosome-based therapeutics have some limitations. The heterogeneity of exosome release among cell types, difficulty in standardization and isolation techniques, and complications linked to dosage and targeted administration necessitates extensive investigation. It is critical to thoroughly understand exosomal processes and their complicated interactions within the cellular milieu. To improve the practicality and efficacy of exosome-based medicines, research efforts must focus on improving production processes, developing robust evaluation criteria, and developing large-scale isolation techniques. Altogether, exosomes' multifunctional properties offer a new route for transforming stroke treatment and significantly improving patient outcomes.

Objective: To investigate the effect of MicroRNA-146a modified adipose-derived stem cell exosomes on the proliferation and migration of fibroblasts and the therapeutic effect on wound healing. Methods: Culture and identification of human adipose-derived stem cells (hASCs), miRNA-146a minic vector was constructed and transfected into hASCs, the exosomes of the empty group and overexpression group were extracted, identified, and quantitatively analyzed after 24 h of successful transfection. The exosomes were added into National Institute of Health Mouse Embryonic Fibroblasts (NIH/3T3) and cultured for 48 h, the proliferation and migration ability of NIH/3T3 fibroblasts was detected. The expression of serpin family H member 1 (SERPINH1) and phosphorylated extracellular regulated protein kinase (p-ERK) was detected by Western blot. The model of back wound was established. The exosomes were injected into 4 different sites with the shape of "cross" around the wound, and the scar diameter of the skin defect was measured at 3, 7, and 11 days, the skin of the defect was taken on the 14th day. platelet endothelial cell adhesion molecule-1 (CD31) was detected by immunofluorescence staining to evaluate angiogenesis, and Western blot was used to detect the expression of SERPINH1 and p-ERK. Results: The miR-146a mimic-exosome promoted the proliferation and migration of fibroblasts, and the expression of SERPINH1 and p-ERK2 was up-regulated. After the rats were treated with exosomes, the wound area decreased rapidly, neovascularization was promoted, and the expression of SERPINH1 and p-ERK2 was up-regulated. Conclusions: MicroRNA-146a modified adipose stem cell exosomes could regulate the expression of SERPINH1 and p-ERK, promote the migration and proliferation of fibroblasts, and neovascularization to promote the wound healing of rat back.

Herein, we investigate the bioactivity of small extracellular vesicles (sEVs), focusing on their local effect in the brain. sEVs from mononuclear cells (MNCs) showed superior effects in vitro to sEVs from mesenchymal stem cells (MSCs) and were able to promote neuroprotection and decrease microglia reactivity in a stroke mouse model.

Due to their characteristics, mesenchymal stem cells (MSCs) are considered a potential therapy for brain tissue injury or degeneration. Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings. Moreover, due to the ability of MSCs to respond differently depending on their microenvironment, preconditioning of MSCs has been used to modulate their composition and, consequently, their therapeutic potential. The different strategies used to modulate the MSC secretome were also reviewed. Although secretome administration was effective in improving functional impairments, regeneration, neuroprotection, and reducing inflammation in brain tissue, a high variability in secretome preparation and administration was identified, compromising the transposition of preclinical data to clinical studies. Indeed, there are no reports of the use of secretome in clinical trials. Despite the existing limitations and lack of clinical data, secretome administration is a potential tool for the treatment of various diseases that impact the CNS.

Neurodegenerative diseases represent a growing burden on healthcare systems worldwide. Mesenchymal stem cells (MSCs) have shown promise as a potential therapy due to their neuroregenerative, neuroprotective, and immunomodulatory properties, which are, however, linked to the bioactive substances they release, collectively known as secretome. This paper provides an overview of the most recent research on the safety and efficacy of MSC-derived secretome and extracellular vesicles (EVs) in clinical (if available) and preclinical models of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, acute ischemic stroke, and spinal cord injury. The article explores the biologically active substances within MSC-secretome/EVs, the mechanisms responsible for the observed therapeutic effects, and the strategies that may be used to optimize MSC-secretome/EVs production based on specific therapeutic needs. The review concludes with a critical discussion of current clinical trials and a perspective on potential future directions in translating MSC-secretome and EVs into the clinic, specifically regarding how to address the challenges associated with their pharmaceutical manufacturing, including scalability, batch-to-batch consistency, adherence to Good Manufacturing Practices (GMP) guidelines, formulation, and storage, along with quality controls, access to the market and relative costs, value for money and impact on total expenditure.

This study tested the hypothesis that inflammatory and interleukin (IL)-17 signalings were essential for acute liver ischemia (1 h)-reperfusion (72 h) injury (IRI) that was effectively ameliorated by adipose-derived mesenchymal stem cells (ADMSCs) and tacrolimus.

Adult-male SD rats (n = 50) were equally categorized into groups 1 (sham-operated-control), 2 (IRI), 3 [IRI + IL-17-monoclonic antibody (Ab)], 4 (IRI + tacrolimus), 5 (IRI + ADMSCs) and 6 (IRI + tacrolimus-ADMSCs) and liver was harvested at 72 h.

The main findings included: (1) circulatory levels: inflammatory cells, immune cells, and proinflammatory cytokines as well as liver-damage enzyme at the time point of 72 h were highest in group 2, lowest in group 1 and significantly lower in group 6 than in groups 3 to 5 (all p < 0.0001), but they did not differ among these three latter groups; (2) histopathology: the liver injury score, fibrosis, inflammatory and immune cell infiltration in liver immunity displayed an identical pattern of inflammatory cells among the groups (all p < 0.0001); and (3) protein levels: upstream and downstream inflammatory signalings, oxidative-stress, apoptotic and mitochondrial-damaged biomarkers exhibited an identical pattern of inflammatory cells among the groups (all p < 0.0001).

Our results obtained from circulatory, pathology and molecular-cellular levels delineated that acute IRI was an intricate syndrome that elicited complex upstream and downstream inflammatory and immune signalings to damage liver parenchyma that greatly suppressed by combined tacrolimus and ADMSCs therapy.

Stroke represents the second leading cause of death and the primary cause of long-term disability in humans. The transplantation of mesenchymal stem cells (MSC) reportedly improves functional outcomes in animal models of cerebral ischemia. Here, we evaluate the neuroprotective potential of extracellular vesicles secreted from human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPS-MSC-EV) using preclinical cell-based and animal-based models of ischemic strokes.

hiPS-MSC-EV were isolated using an ultrafiltration method. HT22 cells were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) injury for 2 h, followed by treatment with hiPS-MSC-EV (100 μg/mL). Male C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) followed by an intravenous injection of hiPS-MSC-EV (100 μg) at three distinct time points.

Our experimental approach revealed hiPS-MSC-EV promoted HT22 cell proliferation, reduced apoptosis, and altered cellular morphology following OGD/R. In addition, hiPS-MSC-EV reduced the volume of infarcts, improved spontaneous movement abilities, and enhanced angiogenesis by expressing the VEGF and CXCR4 proteins in the infarcted hemisphere of the MCAO-treated mouse model.

Our findings provide evidence of the potential neuroprotective effects of hiPS-MSC-derived extracellular vesicles (hiPS-MSC-EVs) in both in vitro and in vivo mouse models of ischemic stroke. These results suggest that hiPS-MSC-EVs may play a role in neurorestoration and offer insights into potential cell-free strategies for addressing cerebral ischemia.

To explore whether local transplantation of mesenchymal stem cells (MSCs) in temporal muscle can promote collateral angiogenesis and to analyze its main mechanisms of promoting angiogenesis.

Bilateral carotid artery stenosis (BCAS) treated mice were administrated with encephalo-myo-synangiosis (EMS), and bone marrow mesenchymal stem cells (BMSCs) were transplanted into the temporal muscle near the cerebral cortex. On the 30th day after EMS, the Morris water maze, immunofluorescence, laser speckle imaging, and light sheet microscopy were performed to evaluate angiogenesis; In addition, rats with bilateral common carotid artery occlusion were also followed by EMS surgery, and BMSCs from GFP reporter rats were transplanted into the temporal muscle to observe the survival time of BMSCs. Then, the concentrated BMSC-derived conditioned medium (BMSC-CM) was used to stimulate HUVECs and BMECs for ki-67 immunocytochemistry, CCK-8, transwell and chick chorioallantoic membrane assays. Finally, the cortical tissue near the temporal muscle was extracted after EMS, and proteome profiler (angiogenesis array) as well as RT-qPCR of mRNA or miRNA was performed.

The results of the Morris water maze 30 days after BMSC transplantation in BCAS mice during the EMS operation, showed that the cognitive impairment in the BCAS + EMS + BMSC group was alleviated (P < 0.05). The results of immunofluorescence, laser speckle imaging, and light sheet microscopy showed that the number of blood vessels, blood flow and astrocytes increased in the BCAS + EMS + BMSC group (P < 0.05). The BMSCs of GFP reporter rats were applied to EMS and showed that the transplanted BMSCs could survive for up to 14 days. Then, the results of ki-67 immunocytochemistry, CCK-8 and transwell assays showed that the concentrated BMSC-CM could promote the proliferation and migration of HUVECs and BMECs (P < 0.05). Finally, the results of proteome profiler (angiogenesis array) in the cerebral cortex showed that the several pro-angiogenesis factors (such as MMP-3, MMP-9, IGFBP-2 or IGFBP-3) were notably highly expressed in MSC transplantation group compared to others.

Local MSCs transplantation together with EMS surgery can promote angiogenesis and cognitive behavior in chronic brain ischemia mice. Our study illustrated that MSC local transplantation can be the potential therapeutical option for improving EMS treatment efficiency which might be translated into clinical application.

Extracellular vesicles (EVs) are promising therapeutic modalities for treating neurological conditions. EVs facilitate intercellular communication among brain cells under normal and abnormal physiological conditions. The potential capability of EVs to pass through the blood-brain barrier (BBB) makes them highly promising as nanocarrier contenders for managing stroke. EVs possess several potential advantages compared to existing drug-delivery vehicles. These advantages include their capacity to surpass natural barriers, target specific cells, and stability within the circulatory system. This review explores the trafficking and cellular uptake of EVs and evaluates recent findings in the field of EVs research. Additionally, an overview is provided of the techniques researchers utilize to bioengineer EVs for stroke therapy, new results on EV-BBB interactions, and the limitations and prospects of clinically using EVs for brain therapies. The primary objective of this study is to provide a comprehensive analysis of the advantages and challenges related to engineered EVs drug delivery, specifically focusing on their application in the treatment of stroke.

Circulating extracellular vesicles (EVs) are proposed to participate in enhancing pathways of recovery after stroke through paracrine signaling. To verify this hypothesis in a proof-of-concept study, blood-derived allogenic EVs from rats and xenogenic EVs from humans who experienced spontaneous good recovery after an intracerebral hemorrhage (ICH) were administered intravenously to rats at 24 h after a subcortical ICH. At 28 days, both treatments improved the motor function assessment scales score, showed greater fiber preservation in the perilesional zone (diffusion tensor-fractional anisotropy MRI), increased immunofluorescence markers of myelin (MOG), and decreased astrocyte markers (GFAP) compared with controls. Comparison of the protein cargo of circulating EVs at 28 days from animals with good vs. poor recovery showed down-expression of immune system activation pathways (CO4, KLKB1, PROC, FA9, and C1QA) and of restorative processes such as axon guidance (RAC1), myelination (MBP), and synaptic vesicle trafficking (SYN1), which is in line with better tissue preservation. Up-expression of PCSK9 (neuron differentiation) in xenogenic EVs-treated animals suggests enhancement of repair pathways. In conclusion, the administration of blood-derived EVs improved recovery after ICH. These findings open a new and promising opportunity for further development of restorative therapies to improve the outcomes after an ICH.

Exosome therapy has been theorized to be safer, more effective, and less cumbersome in replacing stem cell therapies for tissue repair and regeneration. There remains considerable uncertainty on whether exosome therapy is efficacious and safe for recovery from brain injury due to cerebral infarction. There is growing consensus that systematic reviews of data, from preclinical studies which yielded conflicting and confusing results, can provide valuable directions for novel therapeutic options for several clinical conditions. This study systematically evaluated the efficacy of exosome therapy in ischemic stroke in preclinical studies in rodent models.

We reviewed existing literature on exosome therapy in rodent stroke models from various databases, and reviewed the interventional measures, and outcome measures systematically, with changes in the infarct volume and functional scores as outcome parameters. Seventeen homogeneous studies were found qualitatively acceptable for meta-analysis. The study used software RevMan 5.3 to conduct the meta-analysis (PROSPERO Register Number: CRD42022314138) RESULTS: Compared to placebo, exosomes treated ischemic stroke models showed significantly reduced brain infarct volume and improved functional recovery on days 7 and 28. Though there are no safety concerns reported in any preclinical studies, there is insufficient data to make robust conclusions on the therapy's safety.

Therapy with subcellular exosomes is a promising treatment to be explored further in animal ischemic stroke models to arrive at robust conclusions for its safety and therapeutic dosage. This must precede Phase I and II- human randomized clinical trials to establish the safety and proof of concept of efficacy of exosome therapy in human ischemic stroke.

Background: Stroke is one of the leading causes of mortality and permanent disability worldwide. However, the current stroke treatment has a limited effect. Therefore, a new treatment is urgently needed. Stem cell therapy is a cutting-edge treatment for stroke patients. This study aimed to gain better understanding of global stem cell trends in stroke via a bibliometric analysis. Methods: We used the Web of Science Core Collection to search pertinent articles about stem cells in stroke published between 2004 and 2022. Analysis was conducted using CiteSpace, VOSviewer, and the R package "bibliometrix" to identify publication outputs, countries/regions, institutions, authors/co-cited authors, journals/co-cited journals, co-cited references, and keywords. Results: A total of 6,703 publications were included in the bibliometric analysis. The total number of citations significantly and rapidly increased between 2004 and 2022, with the most pronounced growth pattern observed in the period of 2008-2009. In terms of authoritarian countries, the USA had the most publications among the countries. As for institutions and authors, the most prolific institution was the University of South Florida, followed by Oakland University and then Shanghai Jiao Tong University, and Chopp, M. and Borlongan, Cesario V, had the most output among the authors. Regarding the journals, Cell Transplantation had the highest publication, followed by Brain Research. As for references, "Mesenchymal stem cells as trophic mediators" was the most frequently cited (2,082), and the article entitled Neuronal replacement from endogenous precursors in the adult brain after stroke had the strongest burstiness (strength = 81.35). Emerging hot words in the past decade included "adhesion molecule," "mesenchymal stromal cell," "extracellular vesicle," "pluripotent stem cells," "signaling pathway," "plasticity," and "exosomes." Conclusion: Between 2004 and 2022, the terms "neurogenesis," "angiogenesis," "mesenchymal stem cells," "extracellular vesicle," "exosomes," "inflammation," and "oxidative stress" have emerged as the hot research areas for research on stem cells in stroke. Although stem cells exert a number of positive effects, the main mechanisms for mitigating the damage caused by stroke are still unknown. Clinical challenges may include complicating factors that can affect the efficacy of stem cell therapy, which are worth a deep exploration.

Adipose-derived mesenchymal stem cells (ADMSCs) are a type of pluripotent somatic stem cells that differentiate into various cell types such as osteoblast, chondrocyte, and neuronal cells. ADMSCs as donor cells are used to produce regenerative medicines at hospitals and clinics. However, it has not been reported that ADMSCs were differentiated to a specific type of neuron with a peptide. Here, we report that ADMSCs differentiate to the cholinergic phenotype of neurons by the SOCS7-derived BC-box motif peptide. At operations for patients with neurological disorders, a small amount of subcutaneous fat was obtained. Two weeks later, adipose-derived mesenchymal stem cells (ADMSCs) were isolated and cultured for a further 1 to 2 weeks. Flow cytometry analysis for characterization of ADMSCs was performed with CD73, CD90, and CD105 as positive markers, and CD14, CD31, and CD56 as negative markers. The results showed that cultured cells were compatible with ADMSCs. Immunocytochemical studies showed naïve ADMSCs immunopositive for p75NTR, RET, nestin, keratin, neurofilament-M, and smooth muscle actin. ADMSCs were suggested to be pluripotent stem cells. A peptide corresponding to the amino-acid sequence of BC-box motif derived from SOCS7 protein was added to the medium at a concentration of 2 μM. Three days later, immunocytochemistry analysis, Western blot analysis, ubiquitination assay, and electrophysiological analysis with patch cramp were performed. Immunostaining revealed the expression of neurofilament H (NFH), choline acetyltransferase (ChAT), and tyrosine hydroxylase (TH). In addition, Western blot analysis showed an increase in the expression of NFH, ChAT, and TH, and the expression of ChAT was more distinct than TH. Immunoprecipitation with JAK2 showed an increase in the expression of ubiquitin. Electrophysiological analysis showed a large holding potential at the recorded cells through path electrodes. The BC-box motif peptide derived from SOCS7 promoted the cholinergic differentiation of ADMSCs. This novel method will contribute to research as well as regenerative medicine for cholinergic neuron diseases.

Traumatic spinal cord injury (SCI) is a highly destructive disease in human neurological functions. Adipose-derived mesenchymal stem cells (ADMSCs) have tissue regenerations and anti-inflammations, especially with prion protein overexpression (PrPc^OE ). Therefore, this study tested whether PrPc^OE -ADMSCs therapy offered benefits in improving outcomes via regulating nod-like-receptor-protein-3 (NLRP3) inflammasome/DAMP signalling after acute SCI in rats. Compared with ADMSCs only, the capabilities of PrPc^OE -ADMSCs were significantly enhanced in cellular viability, anti-oxidative stress and migration against H₂ O₂ and lipopolysaccharide damages. Similarly, PrPc^OE -ADMSCs significantly inhibited the inflammatory patterns of Raw264.7 cells. The SD rats (n = 32) were categorized into group 1 (Sham-operated-control), group 2 (SCI), group 3 (SCI + ADMSCs) and group 4 (SCI + PrPc^OE -ADMSCs). Compared with SCI group 2, both ADMSCs and PrPc^OE -ADMSCs significantly improved neurological functions. Additionally, the circulatory inflammatory cytokines levels (TNF-α/IL-6) and inflammatory cells (CD11b/c+/MPO+/Ly6G+) were highest in group 2, lowest in group 1, and significantly higher in group 3 than in group 4. By Day 3 after SCI induction, the protein expressions of inflammasome signalling (HGMB1/TLR4/MyD88/TRIF/c-caspase8/FADD/p-NF-κB/NEK7/NRLP3/ASC/c-caspase1/IL-ß) and by Day 42 the protein expressions of DAMP-inflammatory signalling (HGMB1/TLR-4/MyD88/TRIF/TRAF6/p-NF-κB/TNF-α/IL-1ß) in spinal cord tissues displayed an identical pattern as the inflammatory patterns. In conclusion, PrPc^OE -ADMSCs significantly attenuated SCI in rodents that could be through suppressing the inflammatory signalling.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease associated with impaired organ functions that can seriously affect the daily life of patients. Recent SLE therapies frequently elicit adverse reactions and side effects in patients, and clinical heterogeneity is considerable. Mesenchymal stromal cells (MSCs) have anti-inflammatory, tissue repair, and immunomodulatory properties. Their ability to treat autoimmune diseases largely depends on secreted extracellular vesicles, especially exosomes. The effects of exosomes and microRNAs (miRNAs) on SLE have recently attracted interest. This review summarizes the applications of MSCs derived from bone marrow, adipocyte tissue, umbilical cord, synovial membrane, and gingival tissue, as well as exosomes to treating SLE and the key roles of miRNAs. The efficacy of MSCs infusion in SLE patients with impaired autologous MSCs are reviewed, and the potential of exosomes and their contents as drug delivery vectors for treating SLE and other autoimmune diseases in the future are briefly described.

Ischemic stroke (IS) is the leading cause of long-term disability in the world and characterized by high morbidity, recurrence, complications, and mortality. Due to the lack of early diagnostic indicators, limited therapeutic measures and inadequate prognostic indicators, the diagnosis and treatment of IS remains a particular challenge at present. It has recently been reported that exosomes (EXOs) play a significant role in the pathogenesis and treatment of IS. The purpose of this paper is to probe the role of EXOs in diagnostic biomarkers and therapeutic measures for IS and to provide innovative ideas for improving the prognosis of IS.

Exosomes are lipid bilayer vesicles that contain multiple macromolecules secreted by the parent cells and play a vital role in intercellular communication. In recent years, the function of exosomes in cerebrovascular diseases (CVDs) has been intensively studied. Herein, we briefly review the current understanding of exosomes in CVDs. We discuss their role in the pathophysiology of the diseases and the value of the exosomes for clinical applications as biomarkers and potential therapies.

To investigate the current status and development trend of research on exosomes in cardiovascular disease (CVD) using bibliometric analysis and to elucidate trending research topics.

Research articles on exosomes in CVD published up to April 2022 were retrieved from the Web of Science database. Data were organized using Microsoft Office Excel 2019. CiteSpace 6.1 and VOSviewer 1.6.18 were used for bibliometric analysis and result visualization.

Overall, 256 original research publications containing 190 fundamental research publications and 66 clinical research publications were included. "Extracellular vesicle" was the most frequent research keyword, followed by "microrna," "apoptosis," and "angiogenesis." Most publications were from China (187, 73.05%), followed by the United States (57, 22.27%), the United Kingdom (7, 2.73%), and Japan (7, 2.73%). A systematic review of the publications revealed that myocardial infarction and stroke were the most popular topics and that exosomes and their contents, such as microRNAs (miRNAs), play positive roles in neuroprotection, inhibition of autophagy and apoptosis, promotion of angiogenesis, and protection of cardiomyocytes.

Research on exosomes in CVD has attracted considerable attention, with China having the most published studies. Fundamental research has focused on CVD pathogenesis; exosomes regulate the progression of CVD through biological processes, such as the inflammatory response, autophagy, and apoptosis. Clinical research has focused on biomarkers for CVD; studies on using miRNAs in exosomes as disease markers for diagnosis could become a future trend.

Ischemic stroke (IS) is a known neurological complication of COVID-19 infection, which is associated with high mortality and disability. Following IS, secondary neuroinflammation that occurs can play both harmful and beneficial roles and lead to further injury or repair of damaged neuronal tissue, respectively. Since inflammation plays a pivotal role in the pathogenesis of COVID-19-induced stroke, targeting neuroinflammation could be an effective strategy for modulating the immune responses following ischemic events. Numerous investigations have indicated that the application of mesenchymal stem cells-derived extracellular vesicles (MSC-EVs) improves functional recovery following stroke, mainly through reducing neuroinflammation as well as promoting neurogenesis and angiogenesis. Therefore, MSC-EVs can be applied for the regulation of SARS-CoV-2-mediated inflammation and the management of COVID-19- related ischemic events. In this study, we have first described the advantages and disadvantages of neuroinflammation in the pathological evolution after IS and summarized the characteristics of neuroinflammation in COVID-19-related stroke. Then, we have discussed the potential benefit of MSC-EVs in the regulation of inflammatory responses after COVID-19-induced ischemic events.