Umbrella review of mesenchymal stem cell-derived extracellular vesicles in preclinical models: therapeutic efficacy across diverse conditions

Although there are challenges in treating traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have recently proven to be a promising non-cellular therapy. We comprehensively evaluated the efficacy of mesenchymal stem cell-derived extracellular vesicles in traumatic central nervous system diseases in this meta-analysis based on preclinical studies. Our meta-analysis was registered at PROSPERO (CRD42022327904, May 24, 2022). To fully retrieve the most relevant articles, the following databases were thoroughly searched: PubMed, Web of Science, The Cochrane Library, and Ovid-Embase (up to April 1, 2022). The included studies were preclinical studies of mesenchymal stem cell-derived extracellular vesicles for traumatic central nervous system diseases. The Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE)’s risk of bias tool was used to examine the risk of publication bias in animal studies. After screening 2347 studies, 60 studies were included in this study. A meta-analysis was conducted for spinal cord injury (n = 52) and traumatic brain injury (n = 8). The results indicated that mesenchymal stem cell-derived extracellular vesicles treatment prominently promoted motor function recovery in spinal cord injury animals, including rat Basso, Beattie and Bresnahan locomotor rating scale scores (standardized mean difference [SMD]: 2.36, 95% confidence interval [CI]: 1.96–2.76, P < 0.01, I2 = 71%) and mouse Basso Mouse Scale scores (SMD = 2.31, 95% CI: 1.57–3.04, P = 0.01, I2 = 60%) compared with controls. Further, mesenchymal stem cell-derived extracellular vesicles treatment significantly promoted neurological recovery in traumatic brain injury animals, including the modified Neurological Severity Score (SMD = –4.48, 95% CI: –6.12 to –2.84, P < 0.01, I2 = 79%) and Foot Fault Test (SMD = –3.26, 95% CI: –4.09 to –2.42, P = 0.28, I2 = 21%) compared with controls. Subgroup analyses showed that characteristics may be related to the therapeutic effect of mesenchymal stem cell-derived extracellular vesicles. For Basso, Beattie and Bresnahan locomotor rating scale scores, the efficacy of allogeneic mesenchymal stem cell-derived extracellular vesicles was higher than that of xenogeneic mesenchymal stem cell-derived extracellular vesicles (allogeneic: SMD = 2.54, 95% CI: 2.05–3.02, P = 0.0116, I2 = 65.5%; xenogeneic: SMD: 1.78, 95%CI: 1.1–2.45, P = 0.0116, I2 = 74.6%). Mesenchymal stem cell-derived extracellular vesicles separated by ultrafiltration centrifugation combined with density gradient ultracentrifugation (SMD = 3.58, 95% CI: 2.62–4.53, P < 0.0001, I2 = 31%) may be more effective than other EV isolation methods. For mouse Basso Mouse Scale scores, placenta-derived mesenchymal stem cell-derived extracellular vesicles worked better than bone mesenchymal stem cell-derived extracellular vesicles (placenta: SMD = 5.25, 95% CI: 2.45–8.06, P = 0.0421, I2 = 0%; bone marrow: SMD = 1.82, 95% CI: 1.23–2.41, P = 0.0421, I2 = 0%). For modified Neurological Severity Score, bone marrow-derived MSC-EVs worked better than adipose-derived MSC-EVs (bone marrow: SMD = –4.86, 95% CI: –6.66 to –3.06, P = 0.0306, I2 = 81%; adipose: SMD = –2.37, 95% CI: –3.73 to –1.01, P = 0.0306, I2 = 0%). Intravenous administration (SMD = –5.47, 95% CI: –6.98 to –3.97, P = 0.0002, I2 = 53.3%) and dose of administration equal to 100 μg (SMD = –5.47, 95% CI: –6.98 to –3.97, P < 0.0001, I2 = 53.3%) showed better results than other administration routes and doses. The heterogeneity of studies was small, and sensitivity analysis also indicated stable results. Last, the methodological quality of all trials was mostly satisfactory. In conclusion, in the treatment of traumatic central nervous system diseases, mesenchymal stem cell-derived extracellular vesicles may play a crucial role in promoting motor function recovery.

BackgroundMesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent an effective and promising strategy for periodontitis, although studies remain pre-clinical. Herein, a meta-analysis was conducted to assess the efficacy of MSC-EVs in animal models of periodontitis.MethodsThe PubMed, Web of Science, and Embase electronic databases were searched up to Dec 2022 to retrieve preclinical studies examining the use of MSC-EVs for periodontitis treatment. Meta-analyses and sub-group analyses were performed to assess the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) or the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) in pre-clinical animal models of periodontitis.Results11 studies published from Mar 2019 to Oct 2022 met the inclusion criteria. Overall, MSC-EVs contributed to periodontal bone regeneration in the inflammatory bone loss area due to periodontitis, as represented by a weighted mean difference (WMD) of 14.07% (95% CI = 6.73, 21.41%, p < 0.001) for BV/TV and a WMD of -0.12 mm (95% CI= -0.14, -0.11 mm, p < 0.001) for CEJ-ABC. However, sub-analysis suggested that there was no significant difference in CEJ-ABC between studies with bioactive scaffolds and studies without bioactive scaffolds (p = 0.60).ConclusionsThe present study suggests that MSC-EVs may represent an attractive therapy for the treatment of inflammatory bone loss within periodontitis.

Ultraviolet B (UVB) radiation is a major cause of aging in dermal fibroblasts. Human umbilical cord mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show antioxidant activity. In this study, the anti-aging effects of MSC-EVs on dermal fibroblast photoaging induced by UVB radiation were evaluated, and the effects of extracellular vesicles derived from dermal fibroblasts (Fb-EVs) were compared. Human umbilical cord mesenchymal stem cells and human dermal fibroblasts were cultured, and MSC-EVs and Fb-EVs were isolated and characterized. Human dermal fibroblasts were cultured in the absence or presence of different concentrations of EVs 24 hours prior to UVB radiation exposure. Cell proliferation and cell cycle were evaluated, and senescent cells and intracellular ROS were detected. The expressions of matrix metalloproteinase-1 (MMP-1), extracellular matrix protein collagen type 1 (Col-1), and antioxidant proteins such as glutathione peroxidase 1 (GPX-1), superoxide dismutase (SOD), and catalase were also analyzed. Pretreatment with MSC-EVs or Fb-EVs significantly inhibited the production of ROS induced by UVB radiation, increased dermal fibroblast proliferation, protected cells against UVB-induced cell death and cell cycle arrest, and remarkably decreased the percentage of aged cells. Pretreatment with MSC-EVs or Fb-EVs promoted the expressions of GPX-1 and Col-1 and decreased the expression of MMP-1. Both MSC-EVs and Fb-EVs protected dermal fibroblasts from UVB-induced photoaging, likely through their antioxidant activity.

ObjectiveThe treatment of osteoporosis is challenged by limited bone regeneration and side effects. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) have gained widespread attention as a potential therapeutic approach. This study aims to evaluate the effects of BMSC-EVs on bone density, trabecular microstructure, and biomechanical properties in animal models of osteoporosis, providing evidence to support clinical translation and mechanism exploration.MethodsA systematic search was conducted in the PubMed, Cochrane, Web of Science, and Embase (inception to January 2025) databases for preclinical studies on BMSC-EV intervention in osteoporosis models. A random-effects model was used to synthesize and analyze seven key parameters (BMD, BV/TV, Tb.N, Tb.Sp, Tb.Th, Ct.Th, and ultimate load-bearing capacity). Subgroup analysis was performed based on species (rats/mice), EVs engineering targets/methods, injection frequency, and treatment duration. The quality of the studies was assessed using SYRCLE’s risk of bias tool.ResultsThe meta-analysis of 10 studies (355 animals) showed that, compared to the control group, BMSC-EV treatment significantly increased BMD, BV/TV, Tb.N, Tb.Th, Ct.Th, and ultimate load-bearing capacity, while reducing Tb.Sp in the osteoporosis model. A publication bias was found in the summary analysis for Tb.N. However, sensitivity analysis confirmed that all summary results were relatively stable.ConclusionsCompared to the control group, BMSC-EV treatment demonstrated positive effects in increasing BMD, improving trabecular microstructure, cortical thickness, and biomechanical properties in the osteoporosis model. However, clinical translation still requires standardized EV characterization and preclinical safety assessments.

BackgroundWith the increasing research on extracellular vesicles (EVs), EVs have received widespread attention as biodiagnostic markers and therapeutic agents for a variety of diseases. Stem cell-derived EVs have also been recognized as a new viable therapy for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). To assess their efficacy, we conducted a meta-analysis of existing preclinical experimental animal models of EVs for ALI treatment.MethodsThe database was systematically interrogated for pertinent data encompassing the period from January 2010 to April 2022 concerning interventions involving extracellular vesicles (EVs) in animal models of acute lung injury (ALI). The lung injury score was selected as the primary outcome measure for statistical analysis. Meta-analyses were executed utilizing RevMan 5.3 and State15.1 software tools.ResultsThe meta-analyses comprised 31 studies, exclusively involving animal models of acute lung injury (ALI), categorized into two cohorts based on the presence or absence of extracellular vesicle (EV) intervention. The statistical outcomes from these two study groups revealed a significant reduction in lung injury scores with the administration of stem and progenitor cell-derived EVs (SMD = -3.63, 95% CI [-4.97, -2.30], P < 0.05). Conversely, non-stem cell-derived EVs were associated with an elevation in lung injury scores (SMD = -4.34, 95% CI [3.04, 5.63], P < 0.05). EVs originating from stem and progenitor cells demonstrated mitigating effects on alveolar neutrophil infiltration, white blood cell counts, total cell counts in bronchoalveolar lavage fluid (BALF), lung wet-to-dry weight ratios (W/D), and total protein in BALF. Furthermore, pro-inflammatory mediators exhibited down-regulation, while anti-inflammatory mediators demonstrated up-regulation. Conversely, non-stem cell-derived EVs exacerbated lung injury.ConclusionIn preclinical animal models of acute lung injury (ALI), the administration of extracellular vesicles (EVs) originating from stem and progenitor cells demonstrably enhances pulmonary function. This ameliorative effect is attributed to the mitigation of pulmonary vascular permeability and the modulation of immune homeostasis, collectively impeding the progression of inflammation. In stark contrast, the utilization of EVs derived from non-stem progenitor cells exacerbates the extent of lung injury. These findings substantiate the potential utility of EVs as a novel therapeutic avenue for addressing acute lung injury.

Extracellular vesicles: A promising therapy against SARS-CoV-2 infection

The treatment of osteoporosis is challenged by limited bone regeneration and side effects. Bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) have gained widespread attention as a potential therapeutic approach. This study aims to evaluate the effects of BMSC-EVs on bone density, trabecular microstructure, and biomechanical properties in animal models of osteoporosis, providing evidence to support clinical translation and mechanism exploration. A systematic search was conducted in the PubMed, Cochrane, Web of Science, and Embase (inception to January 2025) databases for preclinical studies on BMSC-EV intervention in osteoporosis models. A random-effects model was used to synthesize and analyze seven key parameters (BMD, BV/TV, Tb.N, Tb.Sp, Tb.Th, Ct.Th, and ultimate load-bearing capacity). Subgroup analysis was performed based on species (rats/mice), EVs engineering targets/methods, injection frequency, and treatment duration. The quality of the studies was assessed using SYRCLE's risk of bias tool. The meta-analysis of 10 studies (355 animals) showed that, compared to the control group, BMSC-EV treatment significantly increased BMD, BV/TV, Tb.N, Tb.Th, Ct.Th, and ultimate load-bearing capacity, while reducing Tb.Sp in the osteoporosis model. A publication bias was found in the summary analysis for Tb.N. However, sensitivity analysis confirmed that all summary results were relatively stable. Compared to the control group, BMSC-EV treatment demonstrated positive effects in increasing BMD, improving trabecular microstructure, cortical thickness, and biomechanical properties in the osteoporosis model. However, clinical translation still requires standardized EV characterization and preclinical safety assessments.

Purpose/Aim of the study There is still no evidence of which drug has the greatest therapeutic potential for post-traumatic arthrofibrosis. The aim of this study is to systematically review the literature for quality evidence and perform a meta-analysis about the pharmacological therapies of post-traumatic arthrofibrosis in preclinical models. Materials and Methods A comprehensive and systematic search strategy was performed in three databases (MEDLINE, EMBASE and Web of Science) retrieving studies on the effectiveness of pharmacological therapies in the management of post-traumatic arthrofibrosis using preclinical models in terms of biomechanical outcomes. Risk of bias assessment was performed using the SYRCLE’s risk of bias tool. A meta-analysis using a random-effects model was conducted if a minimum of three studies reported homogeneous outcomes for drugs with the same action mechanism. Results Forty-six studies were included in the systematic review and evaluated for risk of bias. Drugs from 6 different action mechanisms of 21 studies were included in the meta-analysis. Overall, the methodological quality of the studies was poor. Statistically significant overall effect in favor of reducing contracture was present for anti-histamines (Chi2 p = 0.75, I2 = 0%; SMD (Standardized Mean Difference) = –1.30, 95%CI: −1.64 to −0.95, p < 0.00001) and NSAIDs (Chi2 p = 0.01, I2 = 63%; SMD= −0.93, 95%CI: −1.58 to −0.28, p = 0.005). Conclusions Anti-histamines, particularly ketotifen, have the strongest evidence of efficacy for prevention of post-traumatic arthrofibrosis. Some studies suggest a potential role for NSAIDs, particularly celecoxib, although heterogeneity among the included studies is significant.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as key regulators of intercellular communication, orchestrating essential biological processes by delivering bioactive cargoes to target cells. Available evidence suggests that MSC-EVs can mimic the functions of their parental cells, exhibiting immunomodulatory, pro-regenerative, anti-apoptotic, and antifibrotic properties. Consequently, MSC-EVs represent a cell-free therapeutic option for patients with inflammatory bowel disease (IBD), overcoming the limitations associated with cell replacement therapy, including their non-immunogenic nature, lower risk of tumourigenicity, cargo specificity and ease of manipulation and storage. This review aims to provide a comprehensive examination of the therapeutic efficacy of MSC-EVs in IBD, with a focus on their mechanisms of action and potential impact on treatment outcomes. We examine the advantages of MSC-EVs over traditional therapies, discuss methods for their isolation and characterisation, and present mechanistic insights into their therapeutic effects through transcriptomic, proteomic and lipidomic analyses of MSC-EV cargoes. We also discuss available preclinical studies demonstrating that MSC-EVs reduce inflammation, promote tissue repair and restore intestinal homeostasis in IBD models, and compare these findings with those of clinical trials. Finally, we highlight the potential of MSC-EVs as a novel therapy for IBD and identify challenges and opportunities associated with their translation into clinical practice. The source of mesenchymal stem cells (MSCs) strongly influences the composition and function of MSC-derived extracellular vesicles (EVs), affecting their therapeutic potential. Adipose-derived MSC-EVs, known for their immunoregulatory properties and ease of isolation, show promise as a treatment for inflammatory bowel disease (IBD). MicroRNAs are consistently present in MSC-EVs across cell types and are involved in pathways that are dysregulated in IBD, making them potential therapeutic agents. For example, miR-let-7a is associated with inhibition of apoptosis, miR-100 supports cell survival, miR-125b helps suppress pro-inflammatory cytokines and miR-20 promotes anti-inflammatory M2 macrophage polarisation. Preclinical studies in IBD models have shown that MSC-EVs reduce intestinal inflammation by suppressing pro-inflammatory mediators (e.g., TNF-α, IL-1β, IL-6) and increasing anti-inflammatory factors (e.g., IL-4, IL-10). They also promote mucosal healing and strengthen the integrity of the gut barrier, suggesting their potential to address IBD pathology.

ObjectiveTraditional pharmacological treatments for osteoporosis face challenges due to various limitations, including long-term safety concerns and limited bone anabolic effects. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as a promising cell-free alternative therapy. However, their preclinical efficacy and the factors driving heterogeneity still require systematic evaluation.MethodsA systematic search was conducted in PubMed, EMBASE, Cochrane Library, and Web of Science (from inception to February 2025). Two independent authors performed literature screening, data extraction, and risk of bias assessment. A random-effects model was used to pool and analyze bone mineral density (BMD), bone volume fraction (BV/TV), trabecular/cortical structural parameters, and biomechanical test results. Publication bias was assessed using funnel plots and Egger’s test, while leave-one-out sensitivity analysis was performed to evaluate the stability of the results. Subgroup analyses were conducted based on animal type, EVs source, synthesis method, engineering approach, intervention route, frequency, and treatment duration.ResultsA total of 17 studies were included. The results demonstrated that, compared to the control group, MSC-EVs significantly increased BMD, BV/TV, trabecular number (Tb.N), trabecular thickness (Tb.Th), cortical thickness (Ct.Th), mineral apposition rate (MAR), and the ultimate load-bearing capacity of the femur, while reducing trabecular separation (Tb.Sp). Significant heterogeneity and publication bias were observed in all analyses. Sensitivity analysis confirmed the robustness of all results.ConclusionsMSC-EVs demonstrate significant improvements in preclinical osteoporosis models, highlighting its potential for clinical translation. However, further standardized studies are needed to evaluate the long-term efficacy and safety of MSC-EVs.

JOURNAL/nrgr/04.03/01300535-202602000-00050/figure1/v/2025-05-05T160104Z/r/image-tiff Our previous study demonstrated that combined transplantation of bone marrow mesenchymal stem cells and retinal progenitor cells in rats has therapeutic effects on retinal degeneration that are superior to transplantation of retinal progenitor cells alone. Bone marrow mesenchymal stem cells regulate and interact with various cells in the retinal microenvironment by secreting neurotrophic factors and extracellular vesicles. Small extracellular vesicles derived from bone marrow mesenchymal stem cells, which offer low immunogenicity, minimal tumorigenic risk, and ease of transportation, have been utilized in the treatment of various neurological diseases. These vesicles exhibit various activities, including anti-inflammatory actions, promotion of tissue repair, and immune regulation. Therefore, novel strategies using human retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles may represent an innovation in stem cell therapy for retinal degeneration. In this study, we developed such an approach utilizing retinal progenitor cells combined with bone marrow mesenchymal stem cell-derived small extracellular vesicles to treat retinal degeneration in Royal College of Surgeons rats, a genetic model of retinal degeneration. Our findings revealed that the combination of bone marrow mesenchymal stem cell-derived small extracellular vesicles and retinal progenitor cells significantly improved visual function in these rats. The addition of bone marrow mesenchymal stem cell-derived small extracellular vesicles as adjuvants to stem cell transplantation with retinal progenitor cells enhanced the survival, migration, and differentiation of the exogenous retinal progenitor cells. Concurrently, these small extracellular vesicles inhibited the activation of regional microglia, promoted the migration of transplanted retinal progenitor cells to the inner nuclear layer of the retina, and facilitated their differentiation into photoreceptors and bipolar cells. These findings suggest that bone marrow mesenchymal stem cell-derived small extracellular vesicles potentiate the therapeutic efficacy of retinal progenitor cells in retinal degeneration by promoting their survival and differentiation.

Aim Tendon and ligament injury pose an increasingly large burden to society. With surgical repair and grafting susceptible to failure, tissue engineering provides novel avenues for treatment. This systematic review explores evidence whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can facilitate tendon and ligament repair in animal models. Method A systematic search was performed on PubMed, Web of Science, Cochrane Library, Embase. Risk of bias was assessed using Systematic Review Centre for Laboratory animal Experimentation (SYRCLE). Studies administering EVs isolated from human or animal derived MSCs into in vivo models of tendon/ligament injury were included. In vitro, ex vivo, in silico studies were excluded. Data on isolation and characterisation of MSCs and EVs, and in vivo findings in animal models were extracted. Results Eleven case-control studies were included for analysis. Six studies utilised bone marrow derived MSCs. All studies characterised MSCs via flow cytometry, which expressed CD44 and CD90, and isolated EVs via ultracentrifugation (average diameter 125nm). Five studies utilised histological scoring systems, all of which reported a lower score with EV treatment, suggesting improved healing ability. Four studies reported increased anti-inflammatory cytokine expression (IL-10, TGF-β1); three studies reported decreased endogenous M1/M2 macrophage ratio with EV treatment. Eight studies reported increased maximum stiffness, breaking load, tensile strength in EV-treated tendons. Conclusions MSC-EVs are effective therapeutic agents for tendon/ligament pathologies, attenuating the initial inflammatory response, accelerating tendon matrix regeneration, however evidence linking biomechanical alterations to functional improvement was weak. Future randomised controlled trials are needed to definitely demonstrate MSC-EVs superiority in tendon/ligament injury management.

Aim Tendon and ligament injury pose an increasingly large burden to society. With surgical repair and grafting susceptible to failure, tissue engineering provides novel avenues for treatment. This systematic review explores evidence whether mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) can facilitate tendon and ligament repair in animal models. Method A systematic search was performed on PubMed, Web of Science, Cochrane Library, Embase. Risk of bias was assessed using SYstematic Review Center for Laboratory animal Experimentation (SYRCLE). Studies administering EVs isolated from human or animal-derived MSCs into in vivo models of tendon/ligament injury were included. In vitro, ex vivo, in silico studies were excluded. Data on isolation and characterisation of MSCs and EVs, and in vivo findings in animal models were extracted. Results Eleven case-control studies were included for analysis. Six studies utilised bone marrow-derived MSCs. All studies characterised MSCs via flow cytometry, which expressed CD44 and CD90, and isolated EVs via ultracentrifugation (average diameter 125nm). Five studies utilised histological scoring systems, all of which reported a lower score with EV treatment, suggesting improved healing ability. Four studies reported increased anti-inflammatory cytokine expression (IL-10, TGF-β1); three studies reported decreased endogenous M1/M2 macrophage ratio with EV treatment. Eight studies reported increased maximum stiffness, breaking load, tensile strength in EV-treated tendons. Conclusions MSC-EVs are effective therapeutic agents for tendon/ligament pathologies, attenuating the initial inflammatory response, accelerating tendon matrix regeneration, however evidence linking biomechanical alterations to functional improvement was weak. Future randomised controlled trials are needed to definitely demonstrate MSC-EVs superiority in tendon/ligament injury management.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have obvious advantages over MSC therapy. But the strong procoagulant properties of MSC-EVs pose a potential risk of thromboembolism, an issue that remains insufficiently explored. In this study, we systematically investigated the procoagulant activity of large EVs derived from human umbilical cord MSCs (UC-EVs) both in vitro and in vivo. UC-EVs were isolated from cell culture supernatants. Mice were injected with UC-EVs (0.125, 0.25, 0.5, 1, 2, 4 μg/g body weight) in 100 μL PBS via the tail vein. Behavior and mortality were monitored for 30 min after injection. We showed that these UC-EVs activated coagulation in a dose- and tissue factor-dependent manner. UC-EVs-induced coagulation in vitro could be inhibited by addition of tissue factor pathway inhibitor. Notably, intravenous administration of high doses of the UC-EVs (1 μg/g body weight or higher) led to rapid mortality due to multiple thrombus formations in lung tissue, platelets, and fibrinogen depletion, and prolonged prothrombin and activated partial thromboplastin times. Importantly, we demonstrated that pulmonary thromboembolism induced by the UC-EVs could be prevented by either reducing the infusion rate or by pre-injection of heparin, a known anticoagulant. In conclusion, this study elucidates the procoagulant characteristics and mechanisms of large UC-EVs, details the associated coagulation risk during intravenous delivery, sets a safe upper limit for intravenous dose, and offers effective strategies to prevent such mortal risks when high doses of large UC-EVs are needed for optimal therapeutic effects, with implications for the development and application of large UC-EV-based as well as other MSC-EV-based therapies.

ObjectiveIn recent years, stem cell-derived extracellular vesicles (SC-EVs) have garnered widespread attention for the treatment of osteoporosis. Based on all available data, we conducted a comprehensive evaluation of the efficacy of SC-EVs in preclinical studies, aiming to provide the latest evidence to support their clinical translation.MethodsA comprehensive search was conducted in PubMed, Cochrane, Embase, and Web of Science databases for preclinical studies on SC-EVs for the treatment of osteoporosis, with the search period ending on November 10, 2024. Data extraction focused on three main aspects: general bone analysis parameters, histological quantification, and serum bone turnover markers. Additionally, the reporting quality and risk of bias of the studies were rigorously assessed.ResultsA total of 21 studies met the inclusion criteria and were included in the final meta-analysis. The results showed that SC-EVs treatment, compared to placebo, significantly increased bone mineral density, bone volume fraction, trabecular number, and trabecular thickness, while reducing trabecular separation. Furthermore, SC-EVs treatment promoted an increase in osteoblast numbers, inhibited osteoclast numbers, and enhanced bone mineralization. Despite the presence of heterogeneity and publication bias, the results were relatively robust.ConclusionsCompared with placebo, SC-EV treatment increased bone mass and strength, improved bone microarchitecture, and enhanced biomechanical properties. These effects may be associated with the regulation of bone homeostasis through osteoblasts and osteoclasts within trabecular bone. In summary, SC-EVs demonstrate great potential in regulating bone homeostasis in osteoporosis. However, rigorous and standardized quality control in future studies is essential to facilitate the clinical translation of SC-EVs.