Stem cell-derived extracellular vesicles (EVs) play a crucial role in intercellular communication and reflect the functional characteristics of their parent cells. Despite the significant therapeutic potential of these EVs, the molecular features of EVs derived from different stem cells and their relationship with tissue specificity remain underexplored. In this study, we conducted integrated proteomic and transcriptomic analyses of EVs derived from six dental stem cells (DSCs) and three systemic stem cells (SSCs) to investigate the role of EVs in tissue-specific molecular transfer. This study found that although DSCs and SSCs share 92.1% of the core proteome, the EVs derived from each stem cell type displayed distinct molecular signatures. EVs from DSCs were enriched in signaling molecules, reflecting their parent cells' roles in local tissue repair, whereas EVs from SSCs carried mitochondrial and metabolic proteins, indicating their preferential involvement in metabolic regulation. Furthermore, we uncovered that the parent cells transferred 83% of the core proteins to their EVs in a tissue-specific pattern, ensuring that dental EVs retain prominent signaling functions. Thus, understanding the relationship between EVs and their parent stem cells with respect to tissue origin would be helpful to harness EVs as targeted therapeutic agents, particularly in oral regenerative medicine.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are emerging as promising treatments for immunomodulation and tissue regeneration. However, the scalable production of functionally enhanced EVs remains a critical challenge. This study introduces microgravity culture using a three-dimensional (3D) rotating cell culture system as a novel strategy to optimize MSC-EVs yield and bioactivity. We first investigated the effects of microgravity on the proliferation and stemness of human umbilical cord-derived MSCs (UCMSCs). The yield of microgravity-derived EVs (µg-EVs) was quantified by nanoparticle tracking analysis. The function of µg-EVs was analyzed by proteomic profiling and further assessed by macrophage polarization and osteogenic differentiation of periodontal ligament stem cells (PDLSCs). Proteomic analysis of UCMSCs was performed to further explore the underlying mechanisms of EVs biogenesis and functional activity under microgravity condition. Microgravity culture significantly enhanced UCMSCs proliferation and stemness. Compared with conventional static culture, EVs production increased by 7.7-fold under microgravity. Functionally, µg-EVs more effectively promoted macrophage polarization toward the anti-inflammatory M2 phenotype and significantly enhanced the osteogenic differentiation capacity of PDLSCs. Mechanistically, Rab27B upregulation in microgravity-cultured UCMSCs was associated with increased EVs secretion and enhanced therapeutic efficacy. This study identifies microgravity as an effective platform for the large-scale production of high-quality UCMSC-EVs, addressing key manufacturing barriers and accelerating the clinical translation of EVs-based therapies.

Neuronal apoptosis significantly contributes to brain damage in cerebral ischemia and reperfusion (I/R) injury, posing a serious threat to human health and lacking effective treatment. MicroRNA-15b-5p (miR-15b-5p) was previously reported to be significantly elevated in serum exosomes from ischemia patients and in freshly excised human stroke brain tissue. However, how miR-15b-5p regulates neuronal death in cerebral I/R injury remains elusive. In addition, we propose that encapsulating the miR-15b-5p inhibitor in TAT and RVG co-modified mesenchymal stem cell-derived exosomes (TAT RVG-Exo + miR-15b-5p inhibitor) could serve as an effective treatment for cerebral I/R injury. This study utilized a mouse model of intraluminal middle cerebral artery occlusion/reperfusion (MCAO/R) and HT22 hippocampal neuronal cells exposed to oxygen–glucose deprivation and reoxygenation (OGD/R) to simulate cerebral I/R injury. The impact of miR-15b-5p on neuronal death in cerebral I/R injury and its underlying mechanisms were investigated through bioinformatic analysis, qRT-PCR, Western blotting, immunofluorescent staining, flow cytometry, luciferase reporter assay, and RNA-Fluorescence in situ hybridization. Exosomes derived from MSCs were isolated and characterized using transmission electron microscopy and nanoparticle flow cytometer. Through surface modification and sonication, TAT-peptide and RVG-peptide co-decorated MSC-Exos carrying miR-15b-5p inhibitor (TAT RVG-Exo + miR-15b-5p inhibitor) were prepared. The protective effects of TAT RVG-Exo + miR-15b-5p inhibitor on cerebral I/R injury were evaluated using biodistribution imaging system, TTC staining, Western blotting and immunofluorescent staining. In cerebral I/R injury, both in vivo and in vitro, miR-15b-5p expression was significantly elevated, and its inhibition notably reduced neuronal apoptosis. Our findings indicate that miR-15b-5p enhances OGD/R-induced neuronal apoptosis through the HTR2C-ERK signaling pathway. TAT RVG-Exo + miR-15b-5p inhibitor demonstrated enhanced ability to traverse the BBB and target the peri-infarct region in cerebral I/R injured mice, exhibiting superior protective effects against cerebral I/R injury. TAT and RVG co-modified MSC-derived exosomes-mediated delivery of microRNA-15b-5p inhibitor alleviate cerebral I/R-induced neuronal apoptosis by promoting HTR2C-ERK signaling, which offers a potentially effective new treatment for cerebral I/R injury.

A bioactive constituent of P. chinensis Phochinenin I (PI), a dihydrophenanthrene-type monomer, has been isolated from the pseudobulb for more than 15 years, but its activity has not been reported. This study discovered its protective effects on the inflammatory response and oxidative stress for the very first time. The LPS/IFN-γ-induced RAW264.7 model and H2O2-induced zebrafish model were used to evaluate the regulatory effects of PI on oxidative stress, and RNA sequencing analysis was performed to explore its possible molecular mechanism. First, PI alleviated the pro-inflammatory response by decreasing tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels and reduced nitric oxide (NO) secretion by inhibiting inducible nitric oxide synthase (iNOS) expression. Next, PI might reduce reactive oxygen species (ROS) production by enhancing nuclear factor erythroid 2-related factor 2 (Nrf2) expression. Western blotting results showed that PI alleviated the cellular inflammatory response mainly by suppressing phosphorylation of signal transducer and activator of transcription 3 (STAT3) and downregulating c-Myc expression, accompanied by reducing autophagy markers LC3B and SQSTM1/p62 accumulation. c-Myc is a target connected with many anti-inflammatory and antioxidant pathways. RNA sequencing data highlighted phagosome pathway regulation and SQSTM1/p62-associated gene networks as key mediators of PI's immunomodulatory effects. In vivo, using H2O2-challenged zebrafish embryos, PI conferred significant protection against oxidative injury, manifested by ROS scavenging along with antioxidant enhancement, which included elevated superoxide dismutase (SOD) activity and upregulated expression of Mn-SOD, Cu/Zn-SOD, and NAD-(P)-H:quinone oxidoreductase 1 (NQO1) genes. PI can be used as a pharmaceutical chemistry derivative of anti-inflammatory lead compounds and as a new candidate for future adjuvant therapy.

Tissue interactions play a crucial role in tooth development. Notably, extracellular vesicle-mediated interactions between the mandible and tooth germ are considered essential. Here, we revealed that mandible extracellular vesicles could modulate the proliferation and differentiation of dental mesenchymal cells by regulating the histone demethylase KDM2B. Further investigation showed that mandible derived extracellular vesicles could deliver miR-206 to KDM2B, thereby regulating tooth development. An animal study demonstrated that the miR-206/KDM2B pathway affected tooth morphogenesis and mineralization after eight weeks of subcutaneous transplantation in nude mice. In conclusion, this study suggested that the mandible played a critical role in tooth morphogenesis and mineralization, which could be a potential therapeutic target for abnormal tooth development and an alternative model for tooth regeneration.

Objectives Ischemic stroke, marked by oxidative stress and neuroinflammation in the long-term injury process after reperfusion, remains a leading global cause of disability and mortality, urging the need for innovative diagnostic and therapeutic strategies. Extracellular vesicles derived from human exfoliated deciduous teeth stem cells (SHED-EVs) have been suggested to be competent therapeutic agents in neurological diseases, with the capability as biological carriers. This study aims to develop engineered SHED-EVs for integrated diagnostic imaging and therapeutic intervention in ischemic stroke. Methods Engineered SHED-EVs were constructed by loading fluorescent quantum dots and single-atom catalysts into native SHED-EVs. These EVs were nasally administered to middle cerebral artery occlusion (MCAO) mouse model to assess their biodistribution, blood-brain barrier (BBB) permeability, neuroprotective efficacy, functional recovery outcomes, and biocompatibility. Results Live imaging demonstrated preferential accumulation of engineered SHED-EVs at ischemic injury sites, correlating with dynamic BBB remodeling. Treatment significantly improved neurological function and reduced infarct volume in stroke models. Mechanistically, the engineered SHED-EVs effectively scavenged excess reactive oxygen species (ROS) and inhibited mRNA expression of proinflammation factors in oxygen-glucose deprivation (OGD)-treated brain microvessel endothelial cells (BMECs), which is critical for the restoration of BBB integrity and attenuation of neuroinflammation. Conclusions We developed the engineered SHED-EVs with dual diagnostic-therapeutic functionality, which offers a promising approach for addressing post-reperfusion pathologies in ischemic stroke, including oxidative damage and neuroinflammation. The integration of tracking capability with therapeutic efficacy represents a significant advancement over current monomodal interventions. Clinical significance This study introduces a personalized theragnostic approach that combines SHED-EVs with real-time imaging to enhance treatment precision and monitoring in ischemic stroke. Clinically, it holds promise for improving patient outcomes by enabling early intervention, dynamic therapy adjustment, and reduced secondary injury.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSC-EVs) are promising therapeutic agents for various diseases. However, current methods to improve MSC-EV production are insufficient to meet the clinical demands. Although various strategies have been investigated to enhance MSC-EV production, they are often hampered by limited scalability, loss of stemness, or suboptimal therapeutic outcomes. Our study identified three key stimulators that significantly boosted MSC-EV production: epidermal growth factor (EGF), tumor necrosis factor-α (TNF-α), and hypoxia. Employing an orthogonal design, we developed an optimized cell culture condition, subsequently referred to as ETH (EGF 10 ng/mL, TNF-α 50 ng/mL, and a hypoxic environment of 1% O2) preconditioning. This approach led to a remarkable 4- to 5-fold increase in MSC-EV yield while preserving the stemness of MSCs. Through proteomic analysis, we elucidated the underlying mechanisms of ETH preconditioning, providing insight into the complex processes driving enhanced MSC-EV production. Notably, MSC-EVs generated through ETH preconditioning demonstrated enhanced therapeutic potential including superior angiogenesis, collagen deposition, and regulation of inflammation. These findings present a scalable and effective strategy for elevating MSC-EV production, paving the way for its broader clinical application in regenerative medicine.

The revolutionary integration of biology and engineering has had a significant impact on the field of oral and maxillofacial medicine. Historically, oral and maxillofacial medicine predominantly centered on the biomolecular aspect, while neglecting the crucial biomechanical principles. This oversight limited our comprehensive understanding of the oral and maxillofacial system and its functions. However, the emergence of the bioengineering integration approach has filled this gap and opened up a new frontier for the oral and maxillofacial field, which has brought significant theoretical innovations, technological breakthroughs, and progress in basic research and clinical translation. This review consolidates the advancements in the application of biomechanics to the oral and maxillofacial system and presents an introduction to the field of oral and maxillofacial mechanomedicine. By tracing its development through key milestones, the present review aims to offer a comprehensive overview of this emerging discipline. Besides, the connotations of oral and maxillofacial mechanomedicine are systematically introduced, mainly including oral and maxillofacial biomechanics, which investigates the mechanical properties of tissues in both physiological and pathological conditions. Oral and maxillofacial mechanobiology, focusing on the mechanisms by which cells detect and respond to mechanical signals and their interplay with biological processes. Oral and maxillofacial mechanodiagnosis, aiming at improving the precision of disease identification and diagnosis. Oral and maxillofacial mechanotherapy, highlighting how biomechanical principles can optimize therapeutic strategies and enhance treatment effectiveness. Finally, we consider future directions for the development of oral and maxillofacial mechanomedicine, addressing in-depth exploration of multi-scale mechanical characteristics of tissues as theoretical advancements, and the utilization of artificial intelligence in disease detection, diagnosis and treatment prediction as potential clinical applications. This interdisciplinary approach not only enriches our understanding of the complex oral and maxillofacial system but also holds great promise for transforming the diagnosis and treatment of oral and maxillofacial diseases.

Alzheimer’s disease (AD) has emerged as a global health threat that demands early detection to seize the optimal intervention opportunity. Central nervous system (CNS)-derived extracellular vesicles (EVs), lipid-bilayer nanoparticles released by CNS cells, carry key biomolecules involved in AD pathology, positioning them as a promising source of biomarkers for early detection. Current breakthroughs in EV-based isolation and detection technologies have opened up the possibility of early, accurate AD diagnosis. This review summarizes their multifaceted roles in AD pathogenesis, including amyloid-β (Aβ) aggregation, tau propagation, neuroinflammation, and synaptic dysfunction, and highlights neuron- and glia-derived EV biomarkers with translational potential. We further outline recent advances in EV isolation techniques—including density-, size-, charge/dielectric-, immunoaffinity-, and acoustics-based approaches—and emerging detection platforms such as fluorescence, surface plasmon resonance (SPR), surface-enhanced Raman spectroscopy (SERS), electrochemical, and nanomechanical sensors for sensitive, multiplex AD diagnostics. Finally, we discuss key challenges, including standardization, sensitivity, and high-throughput adaptation, and explore future directions such as automated microfluidics and single-vesicle analysis. CNS-derived EVs hold significant promise as minimally invasive, next-generation tools for early AD detection and precision medicine.

Tooth eruption as a crucial part in tooth development and regeneration is accompanied by ongoing osteogenesis and osteoclast activity. The dental follicle (DF) surrounding the developing tooth harbors dental follicle stem cells (DFSCs) which play a crucial role in maintaining bone remodeling. However, the mechanisms through which they regulate the balance between osteogenesis and osteoclast activity during tooth eruption remain poorly understood. Notably, extracellular vesicles (EVs) in bone homeostasis are considered essential. Our study revealed that the DFSCs could modulate tooth eruption by inhibiting osteoclast differentiation via EVs. Further investigation showed that EVs from DFSCs could inhibit osteoclast differentiation through the ANXA1-PPARγ-CEBPα pathway. Animal experiments indicated that EVs from DFSCs and the cargo ANXA1 affected tooth eruption. In summary, this study suggests the critical role of the dental follicle in tooth eruption through EVs, which may provide therapeutic targets for abnormal tooth eruption and effective approaches for the eruption of regenerated teeth.

The role of m6A modification in the regulation of the immune microenvironment (IME) of ischemic stroke (IS) is barely known. Thus, we aim to investigate the impact of m6A modification on the IME of IS and its diagnostic value in IS. We comprehensively assessed the m6A modification patterns, the relationship between these modification patterns and the characteristics of the IME. The m6A modification patterns of individual IS sample were quantified by m6Ascore. The performance of m6A phenotype-related genes as potential biomarkers was evaluated by the area under the receiver operating characteristic curve. Experimental validation was also performed by qRT-PCR. Six dysregulated m6A regulators were identified and a classification model consisting of four key m6A regulators (METLL3, RBMX, RBM15B, YTDHF3) could distinguish IS and healthy control samples well. METTL3 and YTHDF3 are closely related to circulating neutrophil abundance. Two distinct m6A modification patterns were determined which differed in immunocyte abundance. We also identified six m6A phenotype-related genes (APOBEC3A, PTMA, FCGR3A, LOC440926, LOC649946, and FTH1L11), and further explored their biological function. Among them, APOBEC3A, FCGR3A, and FTH1L11 were positively associated with neutrophil abundance. APOBEC3A and FCGR3A were stable diagnostic m6A-associated genes in both the discovery and validation cohorts. This study reveals that m6A modification plays a non-negligible role in the formation of a diversified and complex IME in IS. The m6A phenotype-related genes could be diagnostic biomarkers of IS.

Only a minority of cancer patients benefit from immune checkpoint blockade therapy. Sophisticated cross-talk among different immune checkpoint pathways as well as interaction pattern of immune checkpoint molecules carried on circulating small extracellular vesicles (sEV) might contribute to the low response rate. Here we demonstrate that PD-1 and CD80 carried on immunocyte-derived sEVs (I-sEV) induce an adaptive redistribution of PD-L1 in tumour cells. The resulting decreased cell membrane PD-L1 expression and increased sEV PD-L1 secretion into the circulation contribute to systemic immunosuppression. PD-1/CD80+ I-sEVs also induce downregulation of adhesion- and antigen presentation-related molecules on tumour cells and impaired immune cell infiltration, thereby converting tumours to an immunologically cold phenotype. Moreover, synchronous analysis of multiple checkpoint molecules, including PD-1, CD80 and PD-L1, on circulating sEVs distinguishes clinical responders from those patients who poorly respond to anti-PD-1 treatment. Altogether, our study shows that sEVs carry multiple inhibitory immune checkpoints proteins, which form a potentially targetable adaptive loop to suppress antitumour immunity.

Autophagy plays an important role in determining stem-cell differentiation. During the osteogenic differentiation of mesenchymal stem cells (MSCs), autophagosome formation is upregulated but the reason is unknown. A long-standing quest in the autophagy field is to find the membrane origin of autophagosomes. In this study, cytoplasmic coat protein complex II (COPII) vesicles, endoplasmic reticulum-derived vesicles responsible for the transport of storage proteins to the Golgi, are demonstrated to be a critical source of osteoblastic autophagosomal membrane. A significant correlation between the number of COPII vesicle and the autophagy level is identified in the rat bone tissues. Disruption of COPII vesicles restrained osteogenesis and decreased the number and size of autophagosomes. SEC31a (an outer coat protein of COPII vesicle) is found to be vital to regulate COPII vesicle-dependent autophagosome formation via interacting with ATG9a of autophagosomal seed vesicles. The interference of Sec31a inhibited autophagosome formation and osteogenesis in vitro and in vivo. These results identified a novel mechanism of autophagosome formation in osteogenic differentiation of stem cells and identified SEC31a as a critical protein that mediates the interplay between COPII and ATG9a vesicles. These findings broaden the understanding of the regulatory mechanism in the osteogenic differentiation of MSCs.

Dental diseases such as caries and periodontitis have been common public health problems. Dental disease treatment can be achieved through stem cell-based dental regeneration. Biophysical cues determine the fate of stem cells and govern the success of dental regeneration. Some studies have manifested exosomes derived from stem cells could not only inherit biophysical signals in microenvironment but also evade some issues in the treatment with stem cells. Nowadays, biophysical cue-regulated exosomes become another promising therapy in dental regenerative medicine. However, methods to improve the efficacy of exosome therapy and the underlying mechanisms are still unresolved. In this review, the association between biophysical cues and dental diseases was summarized. We retrospected the role of exosomes regulated by biophysical cues in curing dental diseases and promoting dental regeneration. Our research also delved into the mechanisms by which biophysical cues control the biogenesis, release, and uptake of exosomes, as well as potential methods to enhance the effectiveness of exosomes. The aim of this review was to underscore the important place biophysical cue-regulated exosomes occupy in the realm of dentistry, and to explore novel targets for dental diseases.

Tooth morphogenesis is a critically ordered process manipulated by a range of signaling factors. Particularly, the involvement of fine-tuned signaling mediated by non-coding RNAs has been of longstanding interest. Here, we revealed a double-negative feedback loop acted by a long non-coding RNA (LOC102159588) and a microRNA (miR-133b) that modulated tooth morphogenesis of miniature swine. Mechanistically, miR-133b repressed the transcription of LOC102159588 through downstream target Sp1. Conversely, LOC102159588 not only inhibited the transport of pre-miR-133b from the nucleus to the cytoplasm by regulating exportin-5 but also served as a sponge in the cytoplasm, suppressing functional miR-133b. Together, the double-negative feedback loop maintained normal tooth morphogenesis by modulating endogenous apoptosis. Related disruptions would lead to an arrest of tooth development and may result in tooth malformations.

Colorectal cancer (CRC) is a typical and lethal digestive system malignancy. In this study, we investigated the effect of sirtuin 3 (SIRT3) expression, a fidelity mitochondrial protein, on the proliferation of CRC cells and the mechanisms involved. Using the University of Alabama at Birmingham Cancer Data Analysis Portal database and the Clinical Proteomic Tumour Analysis Consortium database, we discovered that low expression of SIRT3 in CRC was a negative factor for survival prognosis (P < .05). Meanwhile, SIRT3 expression was correlated with distant metastasis and tumour, node, metastasis stage of CRC patients (P < .05). Subsequently, we observed that CRC cells with stable SIRT3 expression exhibited a significant decrease in proliferative capacities both in vitro and in vivo, compared to their counterparts (P < .05). Further investigation using western blot, immunoprecipitation and TOPflash/FOPflash assay showed the mechanism of growth retardation of these cells was highly associated with the degradation of β-catenin in cytosol, and the localization of β-catenin/α-catenin complex in the nucleus. In conclusion, our findings suggest that the inhibition of CRC cell proliferation by SIRT3 is closely associated with the inactivation of the Wnt/β-catenin signalling pathway.

BackgroundContrast-enhanced high-resolution magnetic resonance imaging (CE-HR-MRI) is a useful imaging modality to assess vulnerable plaques in intracranial atherosclerotic stenosis (ICAS) patients. We studied the relationship between the fibrinogen-to-albumin ratio (FAR) and plaque enhancement in patients with ICAS. MethodsWe retrospectively enrolled consecutive ICAS patients who had undergone CE-HR-MRI. The degree of plaque enhancement on CE-HR-MRI was evaluated both qualitatively and quantitatively. Enrolled patients were classified into no enhancement, mild enhancement, and obvious enhancement groups. An independent association of the FAR with plaque enhancement was identified by multivariate logistic regression and receiver operating characteristic (ROC) curve analyses. ResultsOf the 69 enrolled patients, 40 (58%) were classified into the no/mild enhancement group, and 29 (42%) into the obvious enhancement group. The obvious enhancement group had a significantly higher FAR than the no/mild enhancement group (7.36 vs. 6.05, p = 0.001). After adjusting for potential confounders, the FAR was still significantly independently associated with obvious plaque enhancement in multiple regression analysis (odds ratio: 1.399, 95% confidence interval [CI]: 1.080-1.813; p = 0.011). ROC curve analysis revealed that FAR >6.37 predicted obvious plaque enhancement with 75.86% sensitivity and 67.50% specificity (area under the ROC curve = 0.726, 95% CI: 0.606-0.827, p < 0.001). ConclusionThe FAR can serve as an independent predictor of the degree of plaque enhancement on CE-HR-MRI in patients with ICAS. Also, as an inflammatory marker, the FAR has potential as a serological biomarker of intracranial atherosclerotic plaque vulnerability.

Contrast-induced encephalopathy (CIE) following angiography, though not often and reversible, can in some cases lead to permanent neurological dysfunction. To identify how neuroinflammation is involved in CIE, we investigated microglia responses to a bolus injection of ioversol in the internal carotid artery (ICA) in rats. MicroCT scanning indicated that the injected ioversol was cleared from the rat’s brain within 25 min. However, proinflammatory activated and significantly increased microglia were found in the rat occipital cortex at 1 day, and the number of blood vessel-associated microglia was still significantly higher at 3-day post-injection, compared with sham- and PBS-treated rats. Moreover, significantly upregulated malondialdehyde (MDA), downregulated superoxide dismutase (SOD) levels, and elevated proinflammatory cytokines were observed in the brain of rats treated with ioversol. Ioversol administration decreased cell viability of primarily cultured microglia and induced significant proinflammatory activation. Furthermore, ioversol remarkably upregulated astrocytic aquaporin (AQP) 4 expression in the rats brain, and transwell cultures showed significantly enhanced microglia migrating to ioversol-treated endothelial cells. Immediate injection of edaravone dexborneol, a novel antioxidative drug, after ioversol injection effectively rescued ioversol-induced neuroinflammation. Together, these findings suggest that ioversol induced neuroinflammation and oxidative stress in the brain via microglia activation in a direct and indirect manner, which might contribute to the pathogenesis of CIE.

Lacunar stroke is a cerebral small vessel disease that accounts for nearly 25％ of cases of ischemic stroke. As an age-related disease, the incidence of lacunar stroke increases with age. Generally, biological age is equal to chronological age. However, under the influence of a range of chronic diseases and circumstances, the biological age can accelerate, which may contribute to the variation in risk of illness and death between individuals.

Mesenchymal stem/stromal cell-derived extracellular vesicles (MSC-EVs) have been considered promising therapeutics for disease treatments. However, MSC-EVs harvested from different tissues present unique biological features reflective of their origins. The heterogeneity of MSC-EVs constitutes an important barrier to their precise application in clinical translation that may probably lead to uncertain therapeutic effects. To give hints for future clinical translation, five MSCs are employed, whose derived EVs are most intensively utilized, namely bone marrow mesenchymal stem/stromal cells (BMMSCs), umbilical cord stem/stromal cells (UCSCs), adipose-derived stem/stromal cells (ASCs), dermal stem/stromal cells (DSCs) and dental pulp stem/stromal cells (DPSCs) and the heterogeneity landscape of the corresponding MSC-EVs are documented. Overall, the basic parameters, stability, and biosafety of different MSC-EVs are indiscriminate. Strikingly, UCSC-EVs exhibit distinguishing productivity. UCSC-EVs as well as DPSC-EVs present better drug loading/delivery capacity. In addition, the heterogeneity of different MSC-EVs in cargo diversity, cellular affinity, organ biodistribution, and therapeutic effects may cue the rational selection in different disease treatments. Through a combined assessment, a rational strategy is combined for selecting MSC-EVs in future clinics. Offering a panoramic view of MSC-EVs harvested from different tissues, the current study may provide guidelines for the precise selection of MSC-EVs in next-generation therapeutics.