Mesenchymal stromal/stem cell (MSC)-derived exosomes are nanoscale extracellular vesicles that have emerged as promising candidates for therapeutic and diagnostic applications because of their unique bioactive cargo, including proteins, lipids, and nucleic acids. These vesicles mitigate concerns of immunogenicity and tumorigenicity associated with MSC-based therapies and offer enhanced stability, higher scalability, and ease of modification. However, the use of MSC-derived exosomes in clinical practice is associated with challenges, including difficulties in isolation, characterization, and standardization. This review explores the biogenesis and structural properties of MSC-derived exosomes and discusses the molecular mechanisms underlying their therapeutic effects. It also discusses ongoing clinical trials on their applications in cancer, cardiovascular, neurological, and regenerative medicine. Preclinical and clinical data have demonstrated the potential of MSC-derived exosomes in enhancing tissue repair, reducing inflammation, and modulating immune responses. Despite these advancements, gaps in scalable production methods, regulatory guidelines, and therapeutic consistency must be addressed. Future innovations in bioengineering, manufacturing, and regulatory frameworks are essential to realize the full potential of MSC-derived exosomes in mainstream medicine.

The human placenta is a transient yet crucial organ that plays a key role in sustaining the relationship between the maternal and fetal organisms. Despite its historical classification as "biowaste," placental tissues have garnered increasing attention since the early 1900s for their significant medical potential, particularly in wound repair and surgical application. As ethical considerations regarding human placental derivatives have largely been assuaged in many countries, they have gained significant attention due to their versatile applications in various biomedical fields, such as biomedical engineering, regenerative medicine, and pharmacology. Moreover, there is a substantial trend toward various animal product substitutions in laboratory research with human placental derivatives, reflecting a broader commitment to advancing ethical and sustainable research methodologies. This review provides a comprehensive examination of the current applications of human placental derivatives, explores the mechanisms behind their therapeutic effects, and outlines the future potential and directions of this rapidly advancing field.

Multiple sclerosis (MS) is a progressive autoimmune disease characterized by massive inflammatory infiltration, demyelination, and subsequent axonal injury and neuronal damage in the central nervous system (CNS). The etiology of MS remains unclear and there is not yet a definitive therapeutic schedule for the disease. Bone marrow mesenchymal stem cells (BMSCs), exhibiting neuroimmune-modulatory functions to alleviate various autoimmune diseases, show great potential in the treatment of MS. However, the instability of BMSCs-mediated immunosuppression in vivo has limited their application. MiR181-a, a positive regulator of immune balance, which has a preference for T cells and B cells differentiation, but degrade rapidly upon entering systemic circulation due to their unstable molecular structure.

We propose a synergistic therapy approach that combines the penetrative targeting capability of BMSCs with the immuno-modulatory effects of miR181-a by overexpressing miR181-a to BMSCs through lentivirus packaging system. With this strategy, on the basis of the establishment of the experimental autoimmune encephalomyelitis (EAE) model, miR181-a overexpressing BMSCs (miR181a-BMSCs) would have a stronger immuno-modulatory treatment benefit, in terms of attenuating MS development.

Indicate that this method prolongs the modulatory effects of BMSCs and resulted in significantly enhancements of the proliferation of regulatory B cells (Bregs), regulatory T cells (Tregs) and the inhibition of Th17 cells compared to the traditional BMSCs group. Moreover, 10-fold miRNA's concentration in the exosome of miR181a-BMSCs, leading to an increased duration of miRNAs to exert their biological effects. By immunotherapy and synergistic treatment, the effectiveness of the treatment is significantly enhanced, showing consistent results in different groups of the animal model.

This strategy takes advantage of BMSCs and miRNA and thus presents an effective synergistic strategy for the treatment of autoimmune diseases.

Objective: Due to their anti-inflammatory and immunomodulatory capabilities, adipose-derived stem cells (ADSC) are currently considered a promising option for the management of rheumatoid arthritis (RA). To tackle the problems of immunogenicity and tumorigenicity linked to the direct use of cells, current research is focused on the development of effective nanomedicines utilizing ADSC-derived exosomes (ADSC-EXO) for cell-free regenerative medicine. Methods: Methotrexate (MTX) was loaded into mesoporous silica through physical adsorption to produce SiO2-MTX, with subsequent incorporation into ADSC-EXO via ultrasonication to produce AE@SiO2-MTX. Particle size, surface charge, and stability were characterized using dynamic light scattering (DLS) and zeta potential analysis. In vitro, the effects of the nanomaterials were evaluated by assessing the inverse polarization effect of AE@SiO2-MTX on RAW264.7 macrophages, as well as on the migration and invasion capabilities of fibroblast-like synovial cells (FLS). In vivo, targeting and therapeutic effects on joint inflammation were examined using adjuvant-induced arthritis (AIA) and collagen-induced arthritis (CIA) mouse models. Results: The AE@SiO₂-MTX demonstrated sustained drug release, high biocompatibility, and rapid cellular internalization. In vitro, the delivery system alleviated chronic inflammation by inducing macrophage polarization from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, as well as suppressing FLS migration and invasion. In vivo studies revealed that administration of ADSC-EXO outperformed ADSC transplantation in alleviating RA symptoms. Intravenously delivered AE@SiO₂-MTX exhibited targeted accumulation in inflamed joints, significantly reducing joint swelling, synovial hyperplasia, and bone/cartilage degradation in CIA model mice. Conclusions: The findings show that AE@SiO₂-MTX is a robust cell-free therapeutic platform for RA management. Synergy between the immunomodulatory properties of ADSC-EXO and MTX controlled release, this system can overcome the limitations of conventional cell therapies and achieve targeted anti-inflammatory and tissue-protective effects. This strategy offers a promising translational avenue for RA treatment.

Platelet-rich plasma-derived exosomes (PRP-Exos) have recently been considered an optimized strategy for diabetic wound treatment, yet the potential role of PRP-Exos in diabetic wound healing is still unclear. This study aims to investigate the potential mechanisms of PRP-Exos in diabetic wound healing and to utilize the hydrogel Pluronic F127 as a carrier to maintain the sustained release of encapsulated PRP-Exos. PRP-Exos were isolated from the blood of healthy individuals and characterized, followed by co-culturing with isolated diabetic human skin fibroblasts (Diabetes HSF). RNA sequencing (RNA-seq) was used to analyze the effect of PRP-Exos on the transcriptome of normal and Diabetes HSF, screening and validating the crucial mechanism and target gene. Then, a hydrogel composed of Pluronic F127 and PRP-Exos (PRP-Exos/Gel) was constructed and applied in the diabetic mouse models to evaluate the effect and mechanism. RNA-seq analysis revealed that PRP-Exos significantly upregulated the expression of FosB in Diabetes HSF. Further intervention in the expression of FosB in Diabetes HSF showed that knocking down FosB induced ferroptosis in Diabetes HSF, characterized by decreased cell viability, increased oxidative stress, and increased iron ion levels, along with downregulation of GPX4 and SLC7A11 expression, while ACSL4 expression was increased; conversely, overexpression of FosB had the opposite effect. Subsequently, adding PRP-Exos to FosB-knocked down Diabetes HSF significantly weakened the inhibitory effect of PRP-Exos on ferroptosis in diabetic fibroblasts. The synthesized PRP-Exos/Gel exhibited significant thermosensitivity and sustained release of exosomes. In animal experiments, the PRP-Exos/Gel showed significant anti-inflammatory effects, evidenced by an increased proportion of M2 macrophages and a decreased proportion of central granule cells in wound tissue, and inhibited fibroblast ferroptosis, thereby accelerating wound healing. Overall, the constructed PRP-Exos/Gel displays a continuous release of exosomes and promotes diabetic wound healing by suppressing inflammatory responses and fibroblast ferroptosis, which provides new insights and methods for the treatment of diabetic wounds.

Exosomes are extracellular vesicles, which are released into the extracellular space by all types of cells, especially stem cells. Compared with stem cells, exosomes are safer and can be considered one of the most promising therapeutic strategies for neurodegenerative disease. We examined the effect of exosomes derived from bone marrow mesenchymal stem cells (BM-MSC) on a rat model of Alzheimer's disease (AD). For this purpose, male Wistar rats weighing 220-250 g were used. For the induction of AD, rats received a daily dosage of 100 mg/kg Aluminum chloride (Alcl3) by oral gavage for 60 days. Also, Primary BM-MSC was extracted from the femora of Wistar rats (male, 100-150 g). Extracted exosomes were Characterized and Qualified using TEM Microscope and Zetasizer Nano. Specific markers of exosomes were evaluated by Flow cytometry. MSC-extracted exosomes (150 µg/µl) were injected 2 or 5 times into the animals via tail vein on specific days. Our data revealed that receiving exosomes significantly prevented AlCl3-induced enhancement of hippocampal APP gene expression, beta-amyloid plaque formation, impairment of passive avoidance learning and spatial memory. However, exosome injections in healthy subjects caused some negative effects such as spatial memory impairment. It seems, MSC-derived exosomes can be considered as a candidate to prevent AD progression.

Extracellular vesicles (EVs) derived from stem cells offer promising potential for cell-free therapy. However, refining their cargo for precise disease targeting and delivery remains challenging. This study employed chemical reprogramming via dual inhibition of transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) to expand salivary gland basal progenitor cells (sgBPCs). CD9-enriched (CD9+) EVs were then isolated from the sgBPC secretome concentrate using a dual microfluidic chip. Notably, CD9+ EVs demonstrated superior uptake by salivary epithelial cells compared to CD9-depleted (CD9-) EVs and total EVs. In vivo studies using a salivary gland (SG) obstruction mouse model and ex vivo studies in SG fibrosis organoids revealed that CD9+ EVs significantly enhanced anti-fibrotic effects over CD9- EVs and control treatments. The presence of miR-3162 and miR-1290 in CD9+ EVs supported their anti-fibrotic properties by downregulating ACVR1 expression. The chemical reprogramming culture method effectively expanded sgBPCs, enabling consistent and scalable EV production. Utilizing microfluidic chip-isolated CD9+ EVs and ductal delivery presents a targeted and efficient approach for anti-fibrotic SG regeneration.

When neurons are sufficiently stimulated, they generate electrical signals with rapid voltage changes, and information is transferred between neurons through neurites. Chitosan carbon dots (CS CDs) possess unique optical properties, excellent biocompatibility, and superior electron transfer capabilities, making them promising materials for nerve tissue repair and replacement. Studies have shown that exosome (EXO) secretion by PC12 cells and neurite formation are critical for neural tissue repair. However, the effects of CDs on EXO secretion and neurite formation in an electric field microenvironment remain poorly explored. This study utilized CS to synthesize CDs and examined their impact on EXO secretion by PC12 cells in an electric field microenvironment. Findings demonstrated that CS-citric acid (CA) CDs had an average particle size of 4.5 nm with a lattice spacing of 0.248 nm and primarily consisted of graphitized carbon nuclei, hydroxyl, and amino groups. CS-CA CDs played a critical role in facilitating neurite elongation, especially with an electric field intensity of about 50 V/m. The combination of CS-CA CDs and electric field enhanced GAP43 expression in EXO secreted by PC12 cells. These results suggest that CS CDs have great potential for nerve injury treatment, repair, and regeneration.

Hair loss is often associated with oxidative stress and mitochondrial dysfunction in human follicle dermal papilla cells (HFDPCs), resulting in impaired cellular function and follicle degeneration. Thus, many studies have been conducted on natural plants aimed at inhibiting hair loss. This study investigated the therapeutic potential of exosomes derived from the rhizomes of Iris germanica L. (Iris-exosomes) in HFDPCs damaged by dihydrotestosterone (DHT). Iris-exosomes significantly reduced reactive oxygen species (ROS) levels, restoring mitochondrial membrane potential and ATP production, thereby mitigating oxidative stress and improving mitochondrial function. These effects occurred alongside enhanced cellular processes critical for hair follicle regeneration, including increased cell migration, alkaline phosphatase (ALP) activity, and three-dimensional (3D) spheroid formation, which replicates the follicle-like microenvironment and promotes inductive potential. Furthermore, Iris-exosomes stimulated the Wnt/β-catenin signaling pathway by enhancing glycogen synthase kinase-3β (GSK-3β), AKT, and extracellular signal-regulated kinase (ERK), leading to β-catenin stabilization and nuclear translocation, thereby supporting the expression of genes essential for hair growth. Taken together, these findings suggest that Iris-exosomes can be promising ingredients for alleviating hair loss.

Gastrointestinal (GI) cancers, which predominantly manifest in the stomach, colorectum, liver, esophagus, and pancreas, accounting for approximately 35% of global cancer-related mortality. The advent of liquid biopsy has introduced a pivotal diagnostic modality for the early identification of premalignant GI lesions and incipient cancers. This non-invasive technique not only facilitates prompt therapeutic intervention, but also serves as a critical adjunct in prognosticating the likelihood of tumor recurrence. The wealth of circulating exosomes present in body fluids is often enriched with proteins, lipids, microRNAs, and other RNAs derived from tumor cells. These specific cargo components are reflective of processes involved in GI tumorigenesis, tumor progression, and response to treatment. As such, they represent a group of promising biomarkers for aiding in the diagnosis of GI cancer. In this review, we delivered an exhaustive overview of the composition of exosomes and the pathways for cargo sorting within these vesicles. We laid out some of the clinical evidence that supported the utilization of exosomes as diagnostic biomarkers for GI cancers and discussed their potential for clinical application. Furthermore, we addressed the challenges encountered when harnessing exosomes as diagnostic and predictive instruments in the realm of GI cancers.

Skin wound healing is a complex physiological process influenced by multiple factors, including the patient's overall health status. Exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-Exos) have demonstrated significant potential in enhancing wound repair. This study investigates the mechanisms through which hUCMSC-Exos facilitate skin wound healing and evaluates their potential application in combination with hydrogels for clinical treatment. Human foreskin fibroblasts (HFF-1) were treated with varying concentrations of hUCMSC-Exos to evaluate their impact on cell proliferation, assessed via the CCK-8 assay. Exosome uptake by HFF-1 cells was visualized using PKH-26 dye staining, while flow cytometry was employed to analyze cell cycle changes. Cell migration was evaluated through scratch and Transwell assays. Gene expression levels of Collagen I, Elastin, and Fibronectin were quantified by qRT-PCR, while Elastin secretion was measured by ELISA. Western blotting was used to examine proteins in the TGFβ1-Smad signaling pathway. The role of SP1 in regulating Elastin gene expression was investigated by testing the SP1 inhibitor Plicamycin and examining hUCMSC-Exos ability to counteract its effect. Additionally, a chromatin immunoprecipitation (ChIP) assay was performed to analyze SP1 binding at the Elastin gene promoter. In vivo, the efficacy of hUCMSC-Exos combined with hydrogels in promoting wound healing was assessed using a mouse skin wound model. hUCMSC-Exos significantly enhanced HFF-1 cell proliferation at concentrations exceeding 1 × 10⁹ particles/mL and increased the proportion of cells in the S and G2/M phases. HFF-1 cells readily absorbed these exosomes, leading to improved cell migration. Treatment with hUCMSC-Exos upregulated the gene expression of Collagen I, Fibronectin, and Elastin. The SP1 inhibitor Plicamycin reduced Elastin gene expression, an effect that was reversed by hUCMSC-Exos. In vivo, the combination of hUCMSC-Exos and hydrogels accelerated wound healing, enhanced collagen organization, and promoted the formation of elastic fibers and blood vessels. hUCMSC-Exos facilitate skin wound healing by promoting SP1 binding to the Elastin gene promoter, thereby upregulating Elastin expression and supporting extracellular matrix remodeling. These findings suggest a promising therapeutic role for hUCMSC-Exos in clinical applications for wound healing.

The treatment of congenital deformities, traumatic injuries, infectious diseases, and tumors in the craniomaxillofacial (CMF) region is complex due to the intricate nature of the tissues involved. Conventional treatments such as bone grafts and cell transplantation face limitations, including the need for multiple surgeries, complications, and safety concerns.

This paper aims to provide a comprehensive analysis of the role of exosomes (EXOs) in CMF and dental tissue regeneration and to explore their potential applications in regenerative dental medicine.

An extensive review of advancements in tissue engineering, materials sciences, and nanotechnology was conducted to evaluate the development of delivery systems for EXOs-based therapies. The analysis included how EXOs, as nanovesicles released by cells, can be modified to target specific cells or loaded with functional molecules for drug or gene delivery.

EXOs have emerged as a promising alternative to cell transplant therapy, offering a safer method for cell communication and epigenetic control. EXOs transport important proteins and genetic materials, facilitating intercellular communication and delivering therapeutics effectively. The potential of EXOs in personalized medicine, particularly in diagnosing, customizing treatment, and predicting patient responses, is highlighted.

EXO-mediated therapy holds significant potential for advancing tissue regeneration, offering targeted, personalized treatment options with reduced side effects. However, challenges in purification, production, and standardized protocols need to be addressed before its clinical application can be fully realized.

Chemotherapy combined with angiogenesis inhibition holds great promise in improving the therapeutic efficacy in cancer treatment. The aim of this study was to explore the effect of exosome blockade on tumor angiogenesis and chemotherapy efficacy.

Exosomes were extracted by ultracentrifugation, and the effect of exosomes on angiogenesis was evaluated by 4T1 mouse breast cancer cell line and the syngeneic mouse tumor model and immunofluorescence. The endocytosis of exosomes from vascular endothelial cells was evaluated in vitro by co-culture and immunofluorescence assays. Tube formation and CCK-8 assays were used to evaluate the effect of exosomes on angiogenesis in vitro. The effect of exosome blockade on the efficacy of doxorubicin was evaluated by 4T1 mouse breast cancer model, cancer cell-derived exosomes (Exo4T1), GW4869 and doxorubicin in vivo.

Exo4T1 can be efficiently endocytosed by vascular endothelial cells both in vitro and in vivo. Within the recipient endothelial cells, Exo4T1 elicited angiogenesis at least partially via promoting cell proliferation, as the exosomes were carrying cargos with pro-proliferation capacity. Blockade of exosome release through GW4869 significantly inhibited angiogenesis, increased the concentration of doxorubicin within the tumor, and sensitized the tumor to doxorubicin in the murine 4T1 syngeneic model, whereas the therapeutic effects were abrogated when Exo4T1 was additionally treated. Moreover, we found there was no synergy between GW4869 and pazopanib (PP, a traditional angiogenesis inhibitor).

Together, we here revealed that cancer-derived exosomes promote angiogenesis during cancer progression and GW4869 treatment would sensitize the cancer cells to doxorubicin at least partially via inhibiting angiogenesis.

Exosomes have shown good potential in ischemic injury disease treatments. However, evidence about their effect and molecular mechanisms in osteonecrosis of femoral head (ONFH) treatment is still limited. Here, we revealed the cell biology characters of ONFH osteonecrosis area bone tissue in single cell scale and thus identified a novel ONFH treatment approach based on M2 macrophages-derived exosomes (M2-Exos). We further show that M2-Exos are highly effective in the treatment of ONFH by modulating the phenotypes communication between neutrophil and endothelium including neutrophil extracellular traps formation and endothelial phenotype transition. Additionally, we identified that M2-Exos' therapeutic effect is attributed to the high content of miR-93-5p and constructed miR-93-5p overexpression model in vitro and in vivo based on lentivirus and adeno-associated virus respectively. Then we found miR-93-5p can not only reduce neutrophil extracellular traps formation but also improve angiogenic ability of endothelial cells. These results provided a new theoretical basis for the clinical application of ONFH therapeutic exosomes.

Alzheimer's disease (AD) is a neurodegenerative disorder associated with impaired cognitive function and memory loss. Currently, available therapeutics can effectively alleviate the symptoms of AD, but there is a lack of treatment to halt the progression of the disease. In recent years, exosomes have gained much attention due to their involvement in various neurological disorders. Exosomes are small extracellular vesicles comprising lipids, proteins, DNA, non-coding RNA, and mRNAs, can carry various therapeutic molecules, and are potential drug delivery vehicles. Exosomes are known as a double-edged sword due to their involvement in both the pathogenesis and management of AD. This review explores the function of exosomes in the pathophysiology, treatment, and diagnosis of AD, also emphasizing their potential as a targeted drug delivery carrier to the brain. This review seeks to provide novel perspectives to understand better the onset, targeted treatment, and diagnosis of AD using exosomes.

Acute kidney injury (AKI) is a rapid decline in renal function caused by ischemia/reperfusion (I/R), renal toxic injury, and sepsis. While the precise molecular mechanisms underlying AKI are still under investigation, current therapeutic approaches remain insufficient. In recent years, there has been growing evidence that mesenchymal stem cells (MSCs) have great potential in accelerating renal repair after AKI in various preclinical models, while there has been extensive research on extracellular vesicles (EVs) as therapeutic mediators in AKI models, and they are considered to be superior to MSCs as new regenerative therapies. EVs are nanoparticles secreted by various types of cells under physiological and pathological conditions. EVs derived from various sources possess biomarker potential and play crucial roles in mediating cellular communication between kidney cells and other tissue cells by transmitting signal molecules. These vesicles play a direct and indirect role in regulating the pathophysiological mechanisms of AKI and contribute to the occurrence, development, treatment, and repair of AKI. In this review, we briefly outline the essential characteristics of EVs, focus on the multiple molecular mechanisms currently involved in the protection of EVs against different types of AKI, and further discuss the potential targets of EVs from different sources in the treatment of AKI. Finally, we summarized the deficiencies in the production and treatment of EVs and the current strategies for improvement.

Bone defect, a common orthopedic condition, is characterized by a lengthy and impactful treatment period, posing a considerable challenge in clinical settings. Medical technology has advanced notably, and has effectively treated an increasing number of patients with bone defects. Consequently, there has been an explosion of research articles on bone regeneration, including a substantial number on the application of exosomes. Exosomes, especially those derived from stem cells, have been confirmed to be effective in bone regeneration and have garnered widespread attention in the last decade. Therefore, this study conducted a bibliometric analysis on publications related to the application of exosomes for bone regeneration. The objectives are to explore the development history and research hotspots in this field over the past 10 years, predict future development trends, and provide guidance for subsequent research.

The Web of Science Core Collection (WoSCC) database was searched for articles related to exosomes and bone regeneration published from 1 January 2014, to 31 December 2023. The collected literature was analyzed using software such as Microsoft Excel, CiteSpace 6.3R1, VOSviewer 1.6.20, and the bibliometric online platform (https://bibliometric.com).

A total of 3,004 articles published by 2,729 institutions from 68 countries were included in this study. The number of articles on the application of exosomes for bone regeneration has increased annually over the last decade. China was the most prolific country in this field, with a total of 1,468 papers; Shanghai Jiao Tong University (China) was the institution with the highest number of publications (117 publications). In terms of authors, Xin Wang, Yi Zhang, and Yang Wang were the three who published the highest number of papers, with 14 papers each. Co-citation analysis revealed that the article published by Valadi H in 2007 has the highest number of co-citations (270 times of quotation). Additionally, most research hotspots focused on the function of exosomes and the mechanism of action. Furthermore, the importance of osteoblast differentiation and angiogenesis in bone regeneration has also garnered significant attention from scholars in this field.

This study reviewed the research achievements on the application of exosomes for bone regeneration over the past 10 years, utilizing bibliometric analysis tools. It visualized the countries, institutions, authors, and journals that have made significant contributions to this field, revealed current research hotspots, and finally explored future development trends.

Advancements in artificial intelligence (AI) and machine learning (ML) have revolutionized the medical field and transformed translational medicine. These technologies enable more accurate disease trajectory models while enhancing patient-centered care. However, challenges such as heterogeneous datasets, class imbalance, and scalability remain barriers to achieving optimal predictive performance.

This study proposes a novel AI-based framework that integrates Gradient Boosting Machines (GBM) and Deep Neural Networks (DNN) to address these challenges. The framework was evaluated using two distinct datasets: MIMIC-IV, a critical care database containing clinical data of critically ill patients, and the UK Biobank, which comprises genetic, clinical, and lifestyle data from 500,000 participants. Key performance metrics, including Accuracy, Precision, Recall, F1-Score, and AUROC, were used to assess the framework against traditional and advanced ML models.

The proposed framework demonstrated superior performance compared to classical models such as Logistic Regression, Random Forest, Support Vector Machines (SVM), and Neural Networks. For example, on the UK Biobank dataset, the model achieved an AUROC of 0.96, significantly outperforming Neural Networks (0.92). The framework was also efficient, requiring only 32.4 s for training on MIMIC-IV, with low prediction latency, making it suitable for real-time applications.

The proposed AI-based framework effectively addresses critical challenges in translational medicine, offering superior predictive accuracy and efficiency. Its robust performance across diverse datasets highlights its potential for integration into real-time clinical decision support systems, facilitating personalized medicine and improving patient outcomes. Future research will focus on enhancing scalability and interpretability for broader clinical applications.

The aging population has led to a global issue of osteoarthritis (OA), which not only impacts the quality of life for patients but also poses a significant economic burden on society. While biotherapy offers hope for OA treatment, currently available treatments are unable to delay or prevent the onset or progression of OA. Recent studies have shown that as nanoscale bioactive substances that mediate cell communication, exosomes from stem cell sources have led to some breakthroughs in the treatment of OA and have important clinical significance. This paper summarizes the mechanism and function of stem cell exosomes in delaying OA and looks forward to the development prospects and challenges of exosomes.

In the intricate landscape of cellular communication, small extracellular vesicles (sEVs) originating from endosomes play crucial roles as mediators and have garnered significant attention in theranostics. Our understanding of sEV biogenesis largely stems from studies on cancer cells, which are vital for diagnostics. However, in therapeutics, where mesenchymal stromal cell (MSC)-derived sEVs are emerging as investigational new drugs, their biogenesis pathways remain largely unexplored. This article explores the parallel narratives of sEV biogenesis in cancer cells and stem cells, specifically using HeLa cells and MSCs as model cell lines. This study investigated the roles of key proteins-hepatocyte growth factor-regulated tyrosine kinase substrate (HRS), signal-transducing adaptor molecule (STAM), tumor susceptibility gene 101 (TSG101), and ALG-2-interacting protein X (ALIX)-as identified in HeLa cells, in the context of MSC-sEV biogenesis. While these proteins show similarities across cell types, a discernible difference arises in their primary functions in regulating sEV biogenesis. The critical role of ALIX in MSC-sEV biogenesis, in particular, underscores its potential as a target for modulating sEVs' yield in regenerative therapies. Through this comparative analysis, we identified shared molecular signatures, offering insights to guide therapeutic interventions and unlock the regenerative potential of stem cells.

Current treatment of osteoarthritis (OA) mainly focused on treating symptoms. Exosome from Adipose-derived Mesenchymal Stem Cell (Ad-MSC) have been shown to delay degenerative process. This study aimed to investigate the clinical, radiological and histological impact of combined intra-articular (IA) hyaluronic acid (HA) and exosome Ad-MSCs in-vivo using a larger animal model with low-grade OA.

Eighteen male Ovies aries sheep underwent total lateral meniscectomy and conventional radiography was performed to confirm low-grade OA after 6 weeks. The sheep were divided into three groups, Group 1 (G1; n=6) received thrice exosome injections, G2 (n=6) received twice HA injection, and G3 (n=6) received both treatments with a 1-week interval after 10 days of meniscectomy. Clinical evaluations were conducted using the Clinical Lameness Score (CLS), radiographic with X-ray using OA score by Innes et al, while macroscopic evaluation by Osteoarthritis Research Society International (OARSI) scores.

Lameness parameter scored lowest in G3 significantly (2.0±0.0 VS 2.7±0.52 VS 2.7±0.52; p=0.024) at the second month although the overall CLS score did not significantly differ at the 3 rd month. The best improvement of conventional total OA radiographic score at the 3 rd month compared to all groups (5.2±1.17 vs 6.3±0.82 vs 6.7±1.03; p=0.053). Macroscopic OARSI evaluation showed no difference (p=0.711).

Combined repeated exosome Ad-MSC and HA IA injection proven to delay OA progression, however longer duration of follow up is required to evaluate its long-term effect.

Acetaminophen (APAP) overdose can cause severe liver injury and life-threatening conditions that may lead to multiple organ failure without proper treatment. N-acetylcysteine (NAC) is the accepted and prescribed treatment for detoxification in cases of APAP overdose. Nonetheless, in acute liver failure (ALF), particularly when the ingestion is substantial, NAC may not fully restore liver function. NAC administration in ALF has limitations and potential adverse effects, including nausea, vomiting, diarrhoea, flatus, gastroesophageal reflux, and anaphylactoid reactions. Mesenchymal stromal cell (MSC)-based therapies using paracrine activity show promise for treating ALF, with preclinical studies demonstrating improvement. Recently, MSC-derived extracellular vesicles (EVs) have emerged as a new therapeutic option for liver injury. MSC-derived EVs can contain various therapeutic cargos depending on the cell of origin, participate in physiological processes, and respond to abnormalities. However, most therapeutic EVs lack a distinct orientation upon entering the body, resulting in a lack of targeting specificity. Therefore, enhancing the precision of natural EV delivery systems is urgently needed. Thus, we developed an advanced targeting technique to deliver modified EVs within the body. Our strategy aims to employ bioorthogonal click chemistry to attach a targeting molecule to the surface of small extracellular vesicles (sEVs), creating exogenous chimeric antigen receptor-modified sEVs (CAR-sEVs) for the treatment. First, we engineered azido-modified sEVs (N3-sEVs) through metabolic glycoengineering by treating MSCs with the azide-containing monosaccharide N-azidoacetyl-mannosamine (Ac4ManNAz). Next, we conjugated N3-sEVs with a dibenzocyclooctyne (DBCO)-tagged single-chain variable fragment (DBCO-scFv) that targets the asialoglycoprotein receptor (ASGR1), thus producing CAR-sEVs for precise liver targeting. The efficacy of CAR-sEV therapy in ALF models by targeting ASGR1 was validated. MSC-derived CAR-sEVs reduced serum liver enzymes, mitigated liver damage, and promoted hepatocyte proliferation in APAP-induced injury. Overall, CAR-sEVs exhibited enhanced hepatocyte specificity and efficacy in ameliorating liver injury, highlighting the significant advancements achievable with cell-free targeted therapy.

Cardiovascular diseases (CVDs) are a leading cause of mortality worldwide. As a chronic inflammatory disease with a complicated pathophysiology marked by abnormal lipid metabolism and arterial plaque formation, atherosclerosis is a major contributor to CVDs and can induce abrupt cardiac events. The discovery of exosomes' role in intercellular communication has sparked a great deal of interest in them recently. Exosomes are involved in strategic phases of the onset and development of atherosclerosis because they have been identified to control pathophysiologic pathways including inflammation, angiogenesis, or senescence. This review investigates the potential role of stem cell-derived exosomes in atherosclerosis management. We briefly introduced atherosclerosis and stem cell therapy including stem cell-derived exosomes. The biogenesis of exosomes along with their secretion and isolation have been elaborated. The design engineering of exosomes has been summarized to present how drug loading and surface modification with targeting ligands can improve the therapeutic and targeting capacity of exosomes, demonstrating atheroprotective action. Moreover, the mechanism of action (endothelial dysfunction, reduction of dyslipidemia, macrophage polarization, vascular calcification, and angiogenesis) of drug-loaded exosomes to treat atherosclerosis has been discussed in detail. In the end, a comparative and balanced viewpoint has been given regarding the current challenges and potential solutions to advance exosome engineering for cardiovascular therapeutic applications.

Recent studies have highlighted that the microbiome is the essential factor that can modulate the clinical activity of immunotherapy. However, the role of the microbiome varies significantly across different immunotherapies, suggesting that it is critical to understand the precise function of the microbiome in each type of immunotherapy. While many previous studies primarily focus on summarizing the role of the microbiome in immune checkpoint inhibitors, we seek to explore a novel aspect of the microbiome in other immunotherapies such as mesenchymal stem cell therapy, chimeric antigen receptor T cell therapy, and antibodies-based therapy (e.g., adalimumab, infliximab, bevacizumab, denosumab, etc.) which are rarely summarized in previous reviews. Moreover, we highlight innovative strategies for utilizing microbiome and microbial metabolites to enhance the clinical response of immunotherapy. Collectively, we believe that our manuscript will provide novel insights and innovative approaches to the researchers, which could drive the development of the next generation of personalized therapeutic interventions using microbiomes.

As cell-free nanotherapeutics, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown potential therapeutic action against liver diseases. However, their effects on autoimmune hepatitis (AIH) are not yet well understood.

In this study, we utilized a well-established concanavalin A (Con A)-induced fulminant hepatitis mouse model to investigate the effects of MSC-EVs on AIH. We found that MSC-EVs provide significant protection against Con A-induced hepatitis in C57BL/6 male mice, with their effectiveness being critically dependent on the gut microbiota. MSC-EVs modulate the composition of the gut microbiota, particularly by increasing the abundance of norank_f__Muribaculaceae, and impact liver metabolic profiles, leading to significant amelioration of liver injury. The identification of Acetyl-DL-Valine as a protective metabolite underscores the therapeutic potential of targeting gut‒liver axis interactions in liver diseases.

Overall, our data demonstrate that MSC-EVs exhibit nanotherapeutic potential in Con A-induced hepatitis and provide new insights into the treatment of autoimmune hepatitis.

Alveolar macrophages (AMs) is critical to exacerbate acute lung injury (ALI) induced by lipopolysaccharide (LPS) via inhibiting inflammation, which could by shifted by mesenchymal stem cell-derived exosomes (MSC-exos). But the underlying rationale is not fully clarified. Our study aimed to analyze the significance of itaconic acid (ITA) in mediating the protective effects of MSC-exos on LPS-induced ALI.

MSC-exos were used to treat pulmonary microvascular endothelial cells (PMVECs) co-cultured with AMs under LPS stimulation. si-IRG1 was transfected to AMs. PMVEC permeability, apoptosis rates, and inflammatory cytokine levels were assessed. In vivo, C57BL/6 wild-type (WT) and Irg1-/- mice were employed to explore the protection of MSC-exos against LPS-induced ALI. The lung injury was determined by histological and biochemical assays. ITA levels were measured using gas chromatography-mass spectrometry. Western blot and flow cytometry analyses were performed to assess M1/M2 polarization.

Co-culture with AMs significantly increased PMVEC permeability, apoptosis rates, IL-6, TNF-α levels and Claudin-5 and ZO-1 expression induced by LPS treatment, which were attenuated by MSC-exos accompanied by enhanced ITA level. After si-IRG1 transfection, MSC-exos' protective efficacy was reversed, with suppressed M2 polarization. In vivo, MSC-exos alleviated alveolar structure disruption, pulmonary edema, inflammation and increased ITA concentration in WT mice but had reduced effects in Irg1-/- mice, with neglected M2 polarization.

ITA secretion facilitated the MSC-exos' protective benefits on LPS-induced PMVEC damage and ALI in mice by promoting AM M2 polarization, highlighting a potential therapeutic strategy for ALI and related inflammatory lung diseases.

hucMSC-exosomes can be engineered to strengthen their therapeutic potential, and the present study aimed to explore whether hypoxic preconditioning can enhance the angiogenic potential of hucMSC-exosomes in an experimental model of POF.

Primary hucMSCs and ROMECs were isolated from fresh tissue samples and assessed through a series of experiments. Exosomes were isolated from hucMSCs under normoxic or hypoxic conditions (norm-Exos and hypo-Exos, respectively) and then characterized using classic experimental methods. Based on a series of angiogenesis-related assays, we found that hypo-Exos significantly promoted ROMEC proliferation, migration, and tube formation and increased angiogenesis-promoting molecules in vitro. Histology, immunohistochemistry, and immunofluorescence experiments in a rat model of POF demonstrated that hypoxia pretreatment strengthens the therapeutic angiogenic effect of hucMSC-exosomes in vivo. Subsequently, high-throughput miRNA sequencing, qRT‑PCR analysis, and western blotting were employed to identify the potential molecular mechanism.

We found that hypo-Exos enhance endothelial function and angiogenesis via the transfer of miR-205-5p in vitro and in vivo. Finally, based on the results of bioinformatics analysis, dual luciferase reporter assays, and gain- and loss-of-function studies, we found evidence indicating that exosomal miR-205-5p enhances angiogenesis by targeting the PTEN/PI3K/AKT/mTOR signalling pathway. These results indicated for the first time that exosomes derived from hypoxia-conditioned hucMSCs strongly enhance angiogenesis via the transfer of miR-205-5p by targeting the PTEN/PI3K/AKT/mTOR signalling pathway.

Our findings provide a theoretical basis and demonstrate the potential application of a novel cell-free approach with stem cell-derived products in the treatment of POF.

Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration, influenced by a complex interplay of mechanical, biochemical, and molecular cues. Properties of the extracellular matrix (ECM) such as stiffness and alignment guide stem cell fate through mechanosensitive pathways, where forces like shear stress translate into biochemical signals, affecting cell behavior. Aging introduces senescence which disrupts the MuSC niche, leading to reduced regenerative capacity via epigenetic alterations and metabolic shifts. Transplantation further challenges MuSC viability, often resulting in fibrosis driven by dysregulated fibro-adipogenic progenitors (FAPs). Addressing these issues, scaffold designs integrated with pharmacotherapy emulate ECM environments, providing cues that enhance graft functionality and endurance. These scaffolds facilitate the synergy between mechanotransduction and intracellular signaling, optimizing MuSC proliferation and differentiation. Innovations utilizing human pluripotent stem cell-derived myogenic progenitors and exosome-mediated delivery exploit bioactive properties for targeted repair. Additionally, 3D-printed and electrospun scaffolds with adjustable biomechanical traits tackle scalability in treating volumetric muscle loss. Advanced techniques like single-cell RNA sequencing and high-resolution imaging unravel muscle repair mechanisms, offering precise mapping of cellular interactions. Collectively, this interdisciplinary approach fortifies tissue graft durability and MuSC maintenance, propelling therapeutic strategies for muscle injuries and degenerative diseases.

Crohn's disease perianal fistulas are often resistant to standard anti-tumor necrosis factor-α therapies. Mesenchymal stem cell-derived exosomes are extracellular vesicles with highly potent anti-inflammatory effects, and the previous phase of this study demonstrated their safety in the treatment of refractory perianal fistulas.

To evaluate the efficacy of mesenchymal stem cell-derived exosomes for the treatment of refractory perianal fistulas.

Nonrandomized, nonblinded single-center phase II clinical trial.

Tertiary university hospital.

Twenty-three patients were enrolled, 20 of whom completed the study. Refractory perianal fistula was defined as resistance to at least 1 course of treatment with anti-tumor necrosis factor-α therapy.

After clinical assessment and MRI, the patients received general anesthesia, and 5 mL of exosome solution was injected directly into the fistula tracts. The injections were repeated 3 times at 2-month intervals, and patients were followed monthly for 6 months after the last injection. Tissue samples from the tracts were obtained before each injection and subjected to immunohistopathological assessment. MRI data were obtained before and 6 months after the last injection.

The primary outcome of this study was fistula tract closure on clinical examination and MRI. The secondary outcome was an improvement in the discharge from the tracts.

Fistula tracts were fully closed in 12 patients (60%). Four patients showed clinical improvement, with some tracts remaining open, and 4 patients were completely resistant to treatment. A total of 43 fistula tracts were treated during the trial, 30 of which (69.7%) showed complete closure. Histopathological analysis revealed substantial reductions in local inflammation and signs of enhanced tissue regeneration. Immunohistochemical analysis of CD68, CD20, and CD31 reaffirmed these results.

Mesenchymal stem cell-derived exosomes are safe and effective for treating refractory perianal fistulas in patients with Crohn's disease. See Video Abstract .

ANTECEDENTES:Las fístulas perianales de la enfermedad de Crohn a menudo son resistentes a las terapias anti-TNF-α estándares. Los exosomas derivados de células madre mesenquimales (MSC) son vesículas extracelulares que tienen efectos antiinflamatorios muy potentes, y la fase anterior de este estudio demostró su seguridad en el tratamiento de fístulas perianales refractarias.OBJETIVO:Evaluar la eficacia de los exosomas derivados de MSC para el tratamiento de fístulas perianales refractarias.DISEÑO:Ensayo clínico de fase II, no aleatorizado y no ciego, unicéntrico.LUGARES:Hospital universitario terciario.PACIENTES:Se inscribieron veintitrés pacientes, 20 de los cuales completaron el estudio. La fístula perianal refractaria se definió como la resistencia a al menos un ciclo de tratamiento con terapia anti-TNF-α.INTERVENCIONES:Después de la evaluación clínica y la resonancia magnética, los pacientes fueron sometidos a anestesia general y se inyectaron 5 ml de solución de exosoma directamente en los trayectos de la fístula. Las inyecciones se repitieron tres veces a intervalos de 2 meses y los pacientes fueron seguidos mensualmente durante 6 meses después de la última inyección. Se obtuvieron muestras de tejido de los tractos antes de cada inyección y se sometieron a evaluación inmunohistopatológica. Los datos de imágenes de resonancia magnética se obtuvieron antes y seis meses después de la última inyección.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario de este estudio fue el cierre del trayecto de la fístula en el examen clínico y la imagen de resonancia magnética. El resultado secundario fue una mejora en la descarga de los tractos.RESULTADOS:Los trayectos de la fístula se cerraron completamente en 12 (60%) de los pacientes. Cuatro pacientes mostraron mejoría clínica, algunos tractos permanecieron abiertos y cuatro pacientes fueron completamente resistentes al tratamiento. Durante el ensayo se trataron un total de 43 trayectos fistulosos, 30 (69,7%) de los cuales mostraron un cierre completo. El análisis histopatológico reveló reducciones sustanciales en la inflamación local y signos de una mayor regeneración tisular. El análisis inmunohistoquímico del grupo de diferenciación 68, 20 y 31 reafirmó estos resultados.CONCLUSIONES:Los exosomas derivados de MSC son seguros y eficaces para el tratamiento de fístulas perianales refractarias en pacientes con enfermedad de Crohn. (Traducción-Dr. Aurian Garcia Gonzalez ).

Exosomes have garnered attention for use in bone regeneration, but their low activity, rapid degradation, and inaccurate delivery have been obstacles to their use in clinical applications. As such, there exists a need for an exosome-integrated delivery platform. Calcium silicate (Ca-Si) is considered one of the most promising bioceramics for bone regeneration because of its remarkable ability to promote hydroxyapatite formation, osteoblast proliferation, and differentiation. However, Ca-Si has limitations, such as a high degradation rate leading to high pH values. Here, we propose a bone regeneration platform: three-dimensional-fabricated Ca-Si scaffolds immersed in polycaprolactone (PCL) coated with exosomes. This setup enhanced porosity, mechanical strength, and natural hydroxyapatite formation. Ca-Si incorporation increased the quantity of attached exosomes on the scaffold and enabled more sustainable control of their release compared to bare PCL. The exosome-coated scaffold exhibited excellent cell attachment and osteogenic differentiation, significantly increasing biocompatibility and the in situ recruitment of stem cells when transplanted into the subcutaneous tissue of mice. The bone regenerating efficacy of the exosome-attached scaffold was confirmed using a mouse calvarial bone defect animal model. These findings suggest a potential application of exosome-coated Ca-Si/PCL scaffolds as an osteogenic platform for critical bone defects.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease in diabetes mellitus. It is also a significant contributor to cardiovascular morbidity and mortality in diabetic patients Thereby, Innovative therapeutic approaches are needed to retard the initiation and advancement of DN. Hyperglycemia can induce apoptosis, a regulated form of cell death, in multiple renal cell types, such as podocytes, mesangial cells, and proximal tubule epithelial cells, ultimately contributing to the pathogenesis of DN. Recent genome-wide investigations have revealed the widespread transcription of the human genome, resulting in the production of numerous regulatory non-protein-coding RNAs (ncRNAs), including microRNAs (miRNAs) and diverse categories of long non-coding RNAs (lncRNAs). They play a critical role in preserving physiological homeostasis, while their dysregulation has been implicated in a broad spectrum of disorders, including DN. Considering the established association between apoptotic processes and the expression of ncRNAs in DN, a thorough understanding of their intricate interplay is essential. Therefore, the current work thoroughly analyzes the intricate interplay among miRNAs, lncRNAs, and circular RNAs in the context of apoptosis within the pathogenesis of DN. Additionally, in the final section, we demonstrated that ncRNA-mediated modulation of apoptosis can be achieved through stem cell-derived exosomes and herbal medicines, presenting potential avenues for the treatment of DN.

The endometrium is essential to the development of embryos and pregnancy. Human umbilical cord mesenchymal stem cells (HUCMSCs) are promising stem cell sources. HUCMSCs self-renew quickly and are painless to collect. Spermidine is an inherent polyamine needed for cellular and molecular processes that regulate physiology and function. HUCMSCs and spermidine (SN) may heal intrauterine adhesions. HUCMSCs were investigated for endometrial repair in rats. Composite hydrogels are used for medical exosome implantation, including their materials, properties, and embedding procedures. This study examined whether bioengineered hydrogel-loaded exosomes from HUCMSCs and spermidine prenatally improved conception rates in mice with poor endometrial lining. The data show that HUCMSC and SN provide a good experimental base for HUCMSC safety and intrauterine treatment in rats. Western blots, exosome structural analysis, pregnancy outcomes, flow cytometry, H&E staining, immunohistochemistry, and immunofluorescence labelling found and recovered the aberrant area. HUCM-derived stem cells and spermidine-derived exosomes biophysically match. These traits strengthen and prolong endometrial function. Pregnant rats with HUCMSC and SN had thinner endometrium. Hydrogel-incorporated HEHUCMSC and SN exosomes may improve IUI in rats with thin endometrium.

Ischemia/reperfusion (I/R) injury is marked by the restriction and subsequent restoration of blood supply to an organ. This process can exacerbate the initial tissue damage, leading to further disorders, disability, and even death. Extracellular vesicles (EVs) are crucial in cell communication by releasing cargo that regulates the physiological state of recipient cells. The development of EVs presents a novel avenue for delivering therapeutic agents in I/R therapy. The therapeutic potential of EVs derived from stem cells, endothelial cells, and plasma in I/R injury has been actively investigated. Therefore, this review aims to provide an overview of the pathological process of I/R injury and the biophysical properties of EVs. We noted that EVs serve as nontoxic, flexible, and multifunctional carriers for delivering therapeutic agents capable of intervening in I/R injury progression. The therapeutic efficacy of EVs can be enhanced through various engineering strategies. Improving the tropism of EVs via surface modification and modulating their contents via preconditioning are widely investigated in preclinical studies. Finally, we summarize the challenges in the production and delivery of EV-based therapy in I/R injury and discuss how it can advance. This review will encourage further exploration in developing efficient EV-based delivery systems for I/R treatment.

Osteoarthritis (OA) is a joint disorder caused by wear and tear of the cartilage that cushions the joints. It is a progressive condition that can cause significant pain and disability. Currently, there is no cure for OA, though there are treatments available to manage symptoms and slow the progression of the disease. A chondral defect is a common and devastating lesion that is challenging to treat due to its avascular and aneural nature. However, there are conventional therapies available, ranging from microfracture to cell-based therapy. Anyhow, its efficiency in cartilage defects is limited due to unclear cell viability. Exosomes have emerged as a potent therapeutic tool for chondral defects because they are a complicated complex containing cargo of proteins, DNA, and RNA as well as the ability to target cells due to their phospholipidic composition and the altering exosomal contents that boost regeneration potential. Exosomes are used in a variety of applications, including tissue healing and anti-inflammatory therapy. As in recent years, biomaterials-based bio fabrication has gained popularity among the many printable polymer-based hydrogels, tissue-specific decellularized extracellular matrix might boost the effects rather than an extracellular matrix imitating environment, a short note has been discussed. Exosomes are believed to be the greatest alternative option for current cell-based therapy, and future progress in exosome-based therapy could have a greater influence in the field of orthopaedics. The review focuses extensively on the insights of exosome use and scientific breakthroughs centered OA.

Traditional methods for treating diabetic wounds are limited in effectiveness because of their long healing times, the risk of immune rejection, and susceptibility to infection. Suppressing neutrophil extracellular traps (NETs) is an effective strategy for reducing persistent inflammation in diabetic wounds. Although disulfiram (DSF) can inhibit the significant increase of NETs in diabetic wounds, oral DSF suffers from rapid and harmful metabolism in the liver. To address these challenges, we developed a nanomedicine formulation in which DSF was incorporated into the hydrogel.

In this study, we developed a DSF-laden sodium alginate hydrogel wound dressing, DEP@SA, and characterized its composition, properties, and performance. We examined the effects of DEP@SA on inflammatory phase-related markers such as NETs and their pathway proteins, inflammatory factors, and macrophage phenotypes in a high-glucose environment in vivo and in vitro. In addition, the effects of DEP@SA on tissue regenerative capacity such as epidermal proliferative migration and angiogenesis, were also assessed.

The results showed that by utilizing extracellular vesicles as a drug delivery system, we effectively mitigated the degradation of DSF via direct contact with aqueous solutions and ensured the stability of DSF@SA, which could then be applied to diabetic wounds. The inflammatory phase-related indicators revealed that DSF@SA effectively reduced inflammation levels, decreased NETs formation, suppressed the Caspase-1/GSDMD pathway in neutrophils, and promoted the polarization of M2 macrophages. Moreover, the hydrogel accelerated wound healing by promoting angiogenesis and re-epithelialization, thereby shortening the diabetic wound healing time.

This study confirmed that the DSF@SA composite dressing has the potential to enhance diabetic wound repair and offers a novel approach for drug reutilization.

Dry eye disease (DED), a multifactorial disease of the lacrimal system, manifests itself in patients with various symptoms such as itching, inflammation, discomfort and visual impairment. In its most severe forms, it results in the breakdown of the vital tissues of lacrimal functional unit and carries the risk of vision loss. Despite the frequency of occurrence of the disease, there are no effective curative treatment options available to date. Treatment using stem cells and its secreted factors could be a promising approach in the regeneration of damaged tissues of ocular surface. The treatment using secreted factors as well as extracellular vesicles has been demonstrated beneficial effects in various ocular surface diseases. This review provides insights on the usage of stem cell derived exosomes as a promising therapy against LG dysfunction induced ADDE for ocular surface repair.

In order to gain an overview of the existing research in this field, literature search was carried out using the PubMed, Medline, Scopus and Web of Science databases. This review is based on 164 publications until June 2024 and the literature search was carried out using the key words "exosomes", "lacrimal gland regeneration", "exosomes in lacrimal dysfunction".

The literature and studies till date suggest that exosomes and other secreted factors from stem cells have demonstrated beneficial effects on damaged ocular tissues in various ocular surface diseases. Exosomal cargo plays a crucial role in regenerating tissues by promoting homeostasis in the lacrimal system, which is often compromised in severe cases of dry eye disease. Exosome therapy shows promise as a regenerative therapy, potentially addressing the lack of effective curative treatments available for patients with dry eye disease.

Stem cell-derived exosomes represent a promising, innovative approach as a new treatment option for ADDE. By targeting lacrimal gland dysfunction and enhancing ocular surface repair, exosome therapy offers potential for significant advances in dry eye disease management. Future research is needed to refine the application of this therapy, optimize delivery methods, and fully understand its long-term efficacy in restoring ocular health.

Chorionic mesenchymal stromal cells (CHO-MSCs) and their extracellular vesicles (EVs) are becoming increasingly popular, since chorion is ethically harmless and an easily accessible source of MSCs. However, until now there is only a limited number of studies with a thorough characterization of CHO-MSCs derived EVs and their miRNA profile. In this study, we monitored changes in the EV-miRNA profile between early and late passage of human CHO-MSCs. First, senescence of CHO-MSCs was induced by serial passaging and confirmed by morphological changes, shortened telomeres and changes in the expression of selected genes. The expression of MSCs-specific surface markers CD73, CD90, CD105 did not change with increasing passages. Next, EVs and their miRNA profiles were compared between early vs late passage cells. Number of EVs and their size were not significantly changed. Seven of the top 10 most expressed EV-miRNAs were common to both early and late passages. A differential expression study between early and late passages identified 37 significantly differentially expressed EV-miRNAs, out of which 23 were found to be associated with pathways of cellular senescence based on KEGG pathway analysis. A set of 9 miRNAs were identified as the most frequently associated with senescence and/or with the most altered expression between early and late passages, out of which miR-145-5p, miR-335-5p and miR-199b-3p were the most significant downregulated miRNAs in late passages. The most upregulated EV-miRNAs were miR-1307-3p, miR-3615 and miR320b. Targeting these miRNAs in future experiments may prolong the therapeutic potential of CHO-MSCs and their EVs.

Inflammatory mediators that infiltrate the corneal stroma after corneal infections, trauma or refractive surgery can trigger the transformation of corneal keratocytes into myofibroblasts, resulting in highly irregular collagen deposition and subsequently corneal scarring. Mesenchymal stem cells (MSCs) can be used as therapeutic agents to regenerate corneal and conjunctival tissue damage, regulate inflammation, and reduce the development of limbal stem cell failure. The use of MSC-derived exosomes as a cell-free therapeutic vector is a novel therapeutic approach. This study aimed to assess the effect of exosomes obtained from melatonin (Mel)-treated human limbal mesenchymal stem cells (hLMSCs) on naïve hLMSCs and to determine their influence on the antifibrotic and pro-regenerative pathways involved in corneal scarring. hLMSCs were treated with varying concentrations of Mel, followed by isolation and characterization of the procured exosomes (Mel-prExos). These exosomes were added to the cell culture media of naïve hLMSCs to examine their antifibrotic and pro-regenerative effects. The expression of miR-155, miR-29, TGFβ1, TGFβ3, PPARγ, and α-SMA miRNAs and genes were compared between Mel-treated hLMSCs and Mel-prExo-treated hLMSCs by using real-time PCR. We found that at 1 μM Mel and in the presence of Mel-prExos, TGFβ1 was expressed 0.001-fold, while TGFβ3 was expressed 0.6-fold. miR-29 expression was increased 38-fold in the control-Exo group compared to that in the control group. Changes in TGFβ1/β3 and α-SMA expression are associated with miR-29 and miR-155. This approach could prove beneficial for ocular surface tissue engineering applications.