The systemic progression of lung cancer involves a complex interplay between local tumor microenvironment (TME) dynamics and host-level metabolic decline, culminating in cachexia. Extracellular vesicles (EVs), have emerged as critical mediators in this process. This review constructs a comprehensive model of the “EV-metabolic axis” in lung cancer, framing EVs as natural nanocarriers within a systemic communication network that orchestrates a dual pathological process. Locally, EVs remodel the TME to support tumor growth, metastasis, and therapeutic resistance by transferringdiverse metabolic cargoes. Systemically, they transmit catabolic signals to distant adipose and muscle tissues, driving the severe tissue wasting characteristic of cachexia. This integrated perspective reveals the EV-metabolic axis as a central, targetable node in lung cancer pathology. From a nanomedicine perspective, targeting EV biogenesis, cargo loading, or uptake offers a novel, multifaceted therapeutic strategy to simultaneously inhibit tumor growth and mitigate cachexia, heralding a paradigm shift in future lung cancer treatment Scheme 1. This schematic illustrates the tripartite “EV-Metabolic Axis” framework linking local tumor metabolism, systemic EV trafficking, and cachexia development in lung cancer. In the Local Metabolic Axis, primary tumors and stromal cells (CAFs, TAMs, BMSCs) secrete extracellular vesicles (EVs) that reprogram glucose, lipid, and amino acid metabolism via cargoes such as miRNAs, metabolic enzymes, and cytokines — promoting glycolysis, glutamine addiction, ferroptosis resistance, and epithelial-mesenchymal transition (EMT). In the Circulatory System EV Transport Axis, EVs (40–150 nm exosomes, 50–1000 nm ectosomes) traverse biological barriers via membrane fusion, receptor-mediated endocytosis, or ligand-receptor binding, acting as natural nano-carriers. In the Systemic Cachexia Axis, circulating EVs deliver catabolic signals (e.g., miR-21, IL-6, HSP70/90, TGF-β, PTHrP) to distant organs — triggering adipose tissue browning, lipolysis, myofibrillar atrophy, and mitochondrial dysfunction — culminating in cancer-associated cachexia. This integrated axis positions EVs as both biomarkers and therapeutic targets across the nano-bio interface.

Excessive or persistent inflammation intensifies skin tissue damage, leading to abnormal repair processes like scar hyperplasia, and potentially causing chronic wound non-healing or even malignant transformation. The effective enhancement of wound repair and regeneration is impeded by the challenge of precisely suppressing overactivated immune cells, repairing damaged skin cells, and rapidly reconstructing a stable local immune microenvironment. We engineered small extracellular vesicles (sEVs) co-overexpressing PDL1 and Siglec15 (PDL1-Siglec15-sEVs), these PDL1-Siglec15-sEVs were encapsulated within photocurable hydrogels to create a multifunctional hydrogel-based therapeutic system (PDL1-Siglec15-sEVs@NHT). This system continuously releases PDL1-Siglec15-sEVs into the surrounding microenvironment at physiological temperature. In vitro experiments demonstrated that PDL1-Siglec15-sEVs exert an immune reprogramming effect, significantly inhibiting PBMC proliferation and reducing the proportion of CD8+ T cells. Furthermore, they effectively suppressed ROS generation in HaCaT cells and diminished the expression of multiple inflammatory factors. This multifunctional hydrogel composite system accelerated wound closure and promoted re-epithelialization in a rat full-thickness skin defect model by stimulating skin cell proliferation, migration, and extracellular matrix deposition. Transcriptome sequencing revealed that PDL1-Siglec15-sEVs profoundly upregulated Krt32 expression in skin keratinocytes while inhibiting activation of the NF-κB mediated inflammatory signaling pathway. PDL1-Siglec15-sEVs significantly promote skin wound healing through multifaceted mechanisms, synergistically enhancing the immunosuppressive effect mediated by the PD1/PDL1 pathway, reducing keratinocyte inflammatory responses, and fostering the polarization of M2-type macrophages.

Alzheimer’s disease is an increasingly prevalent neurodegenerative disorder characterized by the accumulation of misfolded Aβ aggregates. The efficacy of upconversion nanomaterials in photodynamic therapy has been proven, yet their applicability is constrained by their inherent toxicity. In this study, exosomes derived from stem cells, combined with targeting molecules, were utilized to encapsulate upconversion nanoparticles for targeted removal of pathogenic amyloid aggregates in Alzheimer’s disease. Evidence from AFM and TEM imaging, fluorescence spectroscopy, and cell-based experiments demonstrates that the clearance efficiency of amyloid aggregates is enhanced, and the cytotoxicity induced by misfolded Aβ aggregates is significantly reduced in nerve cells. Notably, the viability of neural PC12 cells is partially restored even in the presence of toxic amyloid aggregates.

Gastric cancer poses a significant global health challenge, promoting ongoing updates and exploration of treatment strategies. In this study, we proposed the naïve human umbilical cord mesenchymal stem cell derived small extracellular vesicles (hucMSC-sEVs) effectively inhibit gastric cancer proliferation and migration, presenting a promising bioactive agent for gastric cancer therapy. To address the issues of shortage in circulation time, limited targeting efficiency, suboptimal therapeutic outcomes associated with hucMSC-sEVs, we engineered a membrane fusion between hucMSC-sEVs with human neutrophil membrane, creating Neu/MSC-sEVs. This modification enhanced tumor cell targeting, reduced clearance by the mononuclear macrophage system, prolonged circulation time, and improved therapeutic efficacy. Furthermore, inhibiting the tumor suppressor protein pentraxin 3 (PTX3) in hucMSC-sEVs attenuated their anti-tumor effects, indicating that enrichment with PTX3 enhances the tumor-inhibiting potential of hucMSC-sEVs. Overall, our findings shed light on the mechanism by which hucMSC-sEVs exert their therapeutic effects on gastric cancer and underscore the importance of vesicle modification in enhancing targeting precision and therapeutic outcomes. These findings provide new insights for clinical application of modified vesicles in cancer treatment.

Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEV) have recently garnered attention as a potential therapeutic approach for kidney diseases with anti-inflammatory effects. Infiltrated macrophages play an important role in facilitating tissue regeneration. However, the intricate regulatory effects of hucMSC-sEV on macrophages during cisplatin-induced acute kidney injury (AKI) remain unknown. In this study, we uncovered that hucMSC-sEV exhibited potent anti-inflammation and effectively inhibited the polarization of M1 phenotype macrophages. Mechanically, miRNA sequencing analysis and qRT-PCR indicated that a novel miRNA, named miR-13896, was enriched in hucMSC-sEV. When transfected with miR-13896 mimic, macrophages displayed M2 phenotype with elevated levels of Arg1 and IL-10, while miR-13896 inhibitor promoted M1 phenotype. Furthermore, we firstly established that miR-13896 repressed Tradd expression by targeting its 3' untranslated region and subsequently inhibited NF-κB signaling pathway in macrophages. Additionally, to improve therapeutic effects, hucMSC-sEV were engineered with elevated levels of miR-13896 through electroporation, which resulted in promoting M2 phenotype macrophages, inhibiting inflammatory factors, and enhancing kidney repair. Conclusively, our findings provide novel insights into the mechanisms underlying the effects of hucMSC-sEV on macrophages and AKI, while also highlighting electroporation as a promising strategy for treating cisplatin-induced AKI.

Graft-versus-host disease (GvHD) is a prevalent complication following allogeneic hematopoietic stem cell transplantation (HSCT) and is characterized by relatively high morbidity and mortality rates. GvHD can result in extensive systemic damage in patients following allogeneic HSCT (allo-HSCT), with the skin, gastrointestinal tract, and liver frequently being the primary target organs affected. The severe manifestations of acute intestinal GvHD often indicate a poor prognosis for patients after allo-HSCT. Endoscopy and histopathological evaluation remain employed to diagnose GvHD, and auxiliary examinations exclude differential diagnoses. Currently, reliable serum biomarkers for the diagnosis and differential diagnosis of GvHD are scarce. As an essential part of standard transplant protocols, early application of immunosuppressive drugs effectively prevents GvHD. Among them, steroids represent first-line therapeutic agents, and the JAK2 inhibitor ruxolitinib represents the second-line therapeutic agent. Currently, no efficacious treatment modality exists for steroid-resistant aGvHD. Therefore, the diagnosis and treatment of GvHD still face significant medical demands. Extracellular vesicles (EVs) are nanometer to micrometer-scale biomembrane vesicles containing various bioactive components, such as proteins, nucleotides, and metabolites. Distinctive changes in serum-derived EV components occur in patients after allo-HSCT; Hence, EVs are expected to be potential biomarkers for diagnosing and treating GvHD. Furthermore, cell-free therapeutics characterized by EVs derived from mesenchymal stem cells (MSCs) have manifested remarkable therapeutic efficacy in preclinical models and preclinical trials of GvHD. Customized engineered EVs with fewer toxic and side effects for the combined treatment of GvHD hold broad prospects for clinical translation. This review article examines the potential value of translating EVs into clinical applications for the diagnosis and treatment of GvHD. It summarizes the latest advancements and prospects of engineered EVs applying GvHD.

A large number of apoptotic vesicles (ApoVs) are released during apoptosis, and mesenchymal stem cells (MSCs)-derived ApoVs (MSC-ApoVs) have significant efficacy in the field of tissue regeneration. ApoVs extracted by density gradient centrifugation have a larger volume and wider diameter distribution, high yield and drug loading efficiency, and inherit the apoptotic traces of FasL, phosphatidylserine (PS), ICAM-3, and other parent cells and the ability to target cell membranes. MSC-ApoVs can significantly promote skin wound healing; however, whether they can promote wound healing in the early stages by playing an antibacterial role is unclear. In the present study, human umbilical cord MSC-derived ApoVs (hucMSC-ApoVs) were extracted and prepared. An in vitro antibacterial test confirmed that hucMSC-ApoVs effectively inhibited the growth of bacteria and sterilized bacteria. In vivo experiments revealed that hucMSC-ApoVs can accelerate the healing of infected wounds. Further exploration of the antibacterial mechanism revealed that hucMSC-ApoVs significantly interfered with bacterial catabolic processes. In gram-positive bacteria (MRSA), hucMSC-ApoVs affect the normal metabolic process of bacteria mainly by inhibiting the metabolism of purines, pyrimidines, and other nucleotides of MRSA and arginine biosynthesis, whereas in the gram-negative bacteria E. coli, they affect this process. HucMSC-ApoVs inhibit bacterial metabolic processes such as sulfur, fatty acid, arginine, and proline metabolism; in particular, hucMSC-ApoVs can interfere with the ethanolamine metabolic process in E.coli by regulating a series of ethanolamine genes (Eut) that encode ethanolamine degrading enzymes. These findings suggest that hucMSC-ApoVs are useful natural reagents for inhibiting wound bacterial infection and promoting wound healing.

Abnormal expression of zinc finger (ZNF) proteins is closely associated with tumor proliferation and metastasis. However, due to limited knowledge about ZNF83, we conducted a pan-cancer analysis to explore its shared and distinct roles across various human malignancies. Standardized TCGA pan-cancer data, encompassing clinical details and ZNF83 expression levels, were obtained for in-depth analysis. We assessed the expression landscape of ZNF83, explored its prognostic significance, and examined its relationship with tumor heterogeneity and cellular stemness. Furthermore, immunohistochemical analysis was performed on lung and kidney cancer tissues to support the bioinformatic findings. ZNF83 expression patterns vary markedly among tumor types, with transcriptomic analysis revealing upregulation in eight malignancies and significant downregulation in twenty-two, compared to adjacent non-cancerous tissues. Notably, ZNF83 levels exhibited robust associations with markers indicative of genomic instability and with indices of tumor stemness across multiple cancer types, suggesting a role in genome maintenance and cellular plasticity. Immunohistochemical staining further substantiated these findings, showing elevated ZNF83 protein levels in renal carcinoma samples, whereas reduced expression was observed in lung adenocarcinoma specimens. In renal cancer, higher ZNF83 expression correlated with poorer overall survival, reinforcing its prognostic value. Although the difference in lung adenocarcinoma was not statistically significant, the expression trend was consistent with transcriptomic observations from the TCGA database. ZNF83 is differentially expressed across cancers and predicts poor prognosis, particularly in renal cell carcinoma, highlighting its utility as a prognostic biomarker.

Diabetic wounds exhibit delayed and incomplete healing, usually due to vascular and nerve damage. Dysregulation of cellular Ca2+ homeostasis has recently been shown to be closely related to insulin resistance and type 2 diabetes mellitus. However, the involvement of this dysregulation in diabetic wound complications remains unknown. In this study, we found calcium dysregulation in patients with diabetic ulcers via tissue protein profiling. High glucose and glucometabolic toxicant stimulation considerably impaired the function of TRPC6, a pore subunit of transient receptor potential channels mediating Ca2+ influx, and mitochondria, which regulate calcium cycling and metabolism. Furthermore, we found that mesenchymal stem cell (MSC)-derived small extracellular vesicles (MSC-sEVs) could play a dual role in restoring the function of TRPC6 and mitochondria by delivering transcription factor SP2 and deubiquitinating enzyme USP9, respectively. MSC-sEVs could transfer SP2 that activated TRPC6 expression by binding to its specific promoter regions (-1519 to -1725 bp), thus recovering Ca2+ influx and downstream pathways. MSC-sEVs also promoted mitophagy to restore mitochondrial function by transporting USP9 that stabilized the expression of Parkin, a major player in mitophagy, thereby guaranteeing Ca2+ efflux and avoidance of Ca2+ overload. Targeting the regulation of calcium homeostasis provides a perspective for understanding diabetic wound healing, and the corresponding design of MSC-sEVs could be a potential therapeutic strategy.

Extracellular vesicles (EVs) are secreted by almost all cells and are widely found in biological fluids. EVs contain a variety of bioactive substances, such as proteins, lipids, nucleic acids, and metabolites. Mounting evidence indicates that EVs not only have immunological functions of antigen presentation and immune regulation but also regulate cell proliferation and apoptosis, blood vessel formation, and information transmission. Therefore, EVs play indispensable roles in the normal physiological and pathological conditions of the body. With the development of techniques and methods for analysis of EVs, more functions of EVs in the regulation of multiple organ systems are gradually being revealed.

Stem cells (SCs) have been used therapeutically for decades, yet their applications are limited by factors such as the risk of immune rejection and potential tumorigenicity. Extracellular vesicles (EVs), a key paracrine component of stem cell potency, overcome the drawbacks of stem cell applications as a cell-free therapeutic agent and play an important role in treating various diseases. However, EVs derived from two-dimensional (2D) planar culture of SCs have low yield and face challenges in large-scale production, which hinders the clinical translation of EVs. Three-dimensional (3D) culture, given its ability to more realistically simulate the in vivo environment, can not only expand SCs in large quantities, but also improve the yield and activity of EVs, changing the content of EVs and improving their therapeutic effects. In this review, we briefly describe the advantages of EVs and EV-related clinical applications, provide an overview of 3D cell culture, and finally focus on specific applications and future perspectives of EVs derived from 3D culture of different SCs.

Gastric cancer (GC) is the fourth most common cancer and the second leading cause of cancer-related deaths worldwide. Despite recent advancements, clinical outcomes for GC remain unsatisfactory. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have shown promise in inhibiting tumor progression, but their role in GC, specifically human umbilical cord MSC-derived small EVs (hucMSC-sEVs), is not well understood. This study investigates the therapeutic potential of hucMSC-sEVs in GC treatment. We found that hucMSC-sEVs are captured by GC cells, substantially inhibiting their proliferation and inducing apoptosis. MiRNA sequencing revealed that hucMSC-sEVs were enriched with miRNAs having anticancer properties. Among these, miR-13896, a new miRNA, was identified as a potent inhibitor of GC cell proliferation and a promoter of apoptosis. Mechanistic studies revealed that miR-13896 targets and down-regulates the ATG2A-mediated autophagy pathway, suppressing GC cell growth and metastasis. Furthermore, we enriched hucMSC-sEVs with miR-13896 through electroporation. These engineered EVs specifically targeted tumor sites and significantly reduced GC cell growth and migration in vitro and in vivo. MiR-13896 emerged as a promising therapeutic target for GC. The delivery of miR-13896 via hucMSC-sEVs represents a novel and effective strategy for GC treatment, highlighting the potential of EV-based therapies to combat this malignancy.

Ultraviolet (UV) radiation is the primary extrinsic factor in skin aging, contributing to skin photoaging, actinic keratosis (AK), and even squamous cell carcinoma (SCC). Currently, the beneficial role of mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) in cutaneous wound healing has been widely reported, but the field of photoaging remains to be explored. Our results suggested that human umbilical cord MSC-derived sEVs (hucMSC-sEVs) intervention could effectively alleviate skin photoaging phenotypes in vivo and in vitro, including ameliorating UV-induced histopathological changes in the skin and inhibiting oxidative stress and collagen degradation in dermal fibroblasts (DFs). Mechanistically, pretreatment with hucMSC-sEVs reversed UVA-induced down-regulation of pregnancy zone protein (PZP) in DFs, and achieved photoprotection by inhibiting matrix metalloproteinase-1 (MMP-1) expression and reducing DNA damage. Clinically, a significant decrease in PZP in AK and SCC in situ samples was observed, while a rebound appeared in the invasive SCC samples. Collectively, our findings reveal the effective role of hucMSC-sEVs in regulating PZP to combat photoaging and provide new pre-clinical evidence for the potential development of hucMSC-sEVs as an effective skin photoprotective agent.

Kidney diseases are characterized by their intricate nature and complexity, posing significant challenges in their treatment and diagnosis. Nanoparticles (NPs), which can be further classified as synthetic and biomimetic NPs, have emerged as promising candidates for treating various diseases. In recent years, the development of engineered nanotherapeutics has focused on targeting damaged tissues and serving as drug delivery vehicles. Additionally, these NPs have shown superior sensitivity and specificity in diagnosis and imaging, thus providing valuable insights for the early detection of diseases. This review aims to focus on the application of engineered synthetic and biomimetic NPs in kidney diseases in the aspects of treatment, diagnosis, and imaging. Notably, the current perspectives and challenges are evaluated, which provide inspiration for future research directions, and encourage the clinical application of NPs in this field.

Ageing is a universal and unavoidable phenomenon that significantly increases the risk of developing chronic kidney disease (CKD). It has been reported that ageing is associated with functional disruption and structural damage to the kidneys. Extracellular vesicles (EVs), which are nanoscale membranous vesicles containing lipids, proteins, and nucleic acids, are secreted by cells into the extracellular spaces. They have diverse functions such as repairing and regenerating different forms of ageing-related CKD and playing a crucial role in intercellular communication. This paper reviews the etiology of ageing in CKD, with particular attention paid to the roles of EVs as carriers of ageing signals and anti-ageing therapeutic strategies in CKD. In this regard, the double-edged role of EVs in ageing-related CKD is examined, along with the potential for their application in clinical settings.

Spinal cord injury (SCI) is a traumatic condition of the central nervous system that causes paralysis of the limbs. Micro electric fields (EF) have been implicated in a novel therapeutic approach for nerve injury repair and regeneration, but the effects of human umbilical cord mesenchymal stem cell-derived small extracellular vesicles that are induced by micro electric fields (EF-sEVs) stimulation on SCI remain unknown. The aim of the present study was to investigate whether EF-sEVs have therapeutic effects a rat model of SCI. EF-sEVs and normally conditioned human umbilical cord mesenchymal stem cells-derived small extracellular vesicles (CON-sEVs) were collected and injected intralesionally into SCI model rats to evaluate the therapeutic effects. We detect the expression of candidate long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA-MALAT1) in EF-sEVs and CON-sEVs. The targets and downstream effectors of lncRNA-MALAT1 were investigated using luciferase reporter assays. Using both in vivo and in vitro experiments, we demonstrated that EF-sEVs increased autophagy and decreased apoptosis after SCI, which promoted the recovery of motor function. We further confirmed that the neuroprotective effects of EF-sEVs in vitro and in vivo correlated with the presence of encapsulated lncRNA-MALAT1 in sEVs. lncRNA-MALAT1 targeted miR-22-3p via sponging, reducing miR-22-3p’s suppressive effects on its target, SIRT1, and this translated into AMPK phosphorylation and increased levels of the antiapoptotic protein Bcl-2. Collectively, the present study identified that the lncRNA-MALAT1 in EF-sEVs plays a neuroprotective role via the miRNA-22-3p/SIRT1/AMPK axis and offers a fresh perspective and a potential therapeutic approach using sEVs to improve SCI.

小细胞外囊泡(small extracellular vesicles,sEVs)是近几年纳米医学界的新星,它有着独特的形态结构和理化性质,可以充当细胞间信息传递的介质,并作为疾病发生发展过程中的生物学标志物.现今人们越来越关注皮肤光老化问题,有关sEVs延缓和改善皮肤光老化的研究也逐渐成为热点.来源于间充质干细胞的sEVs不仅在皮肤光老化中有减轻炎症反应和减弱氧化损伤等的作用,而且对于其他皮肤疾病(例如皮肤创伤、斑块状银屑病、系统性红斑狼疮以及皮肤肿瘤等)也有着显著的作用.此外,由于sEVs的囊泡性质,sEVs正在成为一种新的药物递送系统.然而在将干细胞源性sEVs作为一种新的治疗方法时,仍需重视其安全性和毒性问题.

Mesenchymal stem cell small extracellular vesicles (MSC-sEVs) are a priority for researchers because of their role in tissue regeneration. sEVs act as paracrine factors and carry various cargos, revealing the state of the parent cells and contributing to cell–cell communication during both physiological and pathological circumstances. Hepatic diseases are mainly characterized by inflammatory cell infiltration and hepatocyte necrosis and fibrosis, bringing the focus onto immune regulation and other regulatory mechanisms of MSCs/MSC-sEVs. Increasing evidence suggests that MSCs and their sEVs protect against acute and chronic liver injury by inducing macrophages (MΦ) to transform into the M2 subtype, accelerating regulatory T/B (Treg/Breg) cell activation and promoting immunosuppression. MSCs/MSC-sEVs also prevent the proliferation and differentiation of T cells, B cells, dendritic cells (DCs), and natural killer (NK) cells. This review summarizes the potential roles for MSCs/MSC-sEVs, including immunomodulation and tissue regeneration, in various liver diseases. There is also a specific focus on the use of MSC-sEVs for targeted drug delivery to treat hepatitis.

外泌体可由多种细胞分泌，磷脂双分子层包裹多种生物活性分子如蛋白质、核苷酸、脂质及代谢产物等。外泌体在生理、病理过程中发挥重要作用，与多种疾病的发生和进展密切相关。外泌体相关的标志物在肿瘤、神经系统疾病、心血管疾病、传染性疾病等多种疾病的诊断及预后判断中起着重要的作用。该文概述了近年来外泌体标志物及其临床应用研究的进展。

Increasing evidences show that unmodified extracellular vesicles (EVs) derived from various cells can effectively inhibit the malignant progression of different types of tumors by delivering the bioactive molecules. Therefore, EVs are expected to be developed as emerging anticancer drugs. Meanwhile, unmodified EVs as an advanced and promising nanocarrier that is frequently used in targeted delivery therapeutic cargos and personalized reagents for the treatment and diagnosis of cancer. To improve the efficacy of EV-based treatments, researchers are trying to engineering EVs as an emerging nanomedicine translational therapy platform through biological, physical and chemical approaches, which can be broaden and altered to enhance their therapeutic capability. EVs loaded with therapeutic components such as tumor suppressor drugs, siRNAs, proteins, peptides, and conjugates exhibit significantly enhanced anti-tumor effects. Moreover, the design and preparation of tumor-targeted modified EVs greatly enhance the specificity and effectiveness of tumor therapy, and these strategies are expected to become novel ideas for tumor precision medicine. This review will focus on reviewing the latest research progress of functionalized EVs, clarifying the superior biological functions and powerful therapeutic potential of EVs, for researchers to explore new design concepts based on EVs and build next-generation nanomedicine therapeutic platforms.