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.

Currently, chronic diabetic wound healing is one of the urgent clinical challenges. Choosing appropriate dressings loaded with stem cell-derived exosomes (exo) and traditional Chinese medicine extracts that promote healing is an effective method to accelerate skin healing in diabetes. Paeonol (Pae), possessing anti-inflammatory properties and vascular enhancement functions, can serve as a therapeutic herbal extract for treating diabetic wounds.

Exo were extracted from mesenchymal stem cells and loaded them with Pae (Pae/exo). The effects of Pae/exo on human skin fibroblasts (HSF) and human umbilical vein endothelial cells (HUVEC) were evaluated using CCK-8, migration, and transwell assays. Western blotting, qPCR, and immunofluorescence experiments were conducted to analysis the regulation of associated genes and proteins. Mimics and inhibitors of miR-424-5p were synthesized to further investigate its role in HUVEC and HSF. Additionally, diabetic mice models were constructed with the knockout of miR-322 (a homologous miRNA of miR-424) to validate the impact of miR-424-5p knockout on diabetic skin healing in vivo. To better simulate clinical application, thermosensitive hydrogel Pluronic® F-127 (PF-127) was used as a carrier for Pae/exo, and the effect of Pae/exo@PF-127 on wound healing in diabetic mice was investigated.

This study confirmed that Pae/exo increased the proliferation and migration of HSF and HUVEC by promoting epithelial-mesenchymal transition (EMT) and angiogenesis. The expression of miR-424-5p was significantly upregulated upon treatment with Pae/exo, which correlated with the induction of EMT and angiogenesis. In vivo experiments demonstrated that the wound healing rate was significantly lower in miR-322-knockout diabetic mice compared to wild-type diabetic mice; vascular production and epithelialization rate were also reduced in the knockout mice. Pae/exo@PF-127 significantly improved wound healing efficiency in diabetic mice by enhancing EMT and promoting blood vessel formation. The integration of pae, MSC-exo, and PF-127 harnesses their synergistic effects to significantly enhance wound healing and prolong the interval between dressing changes, thereby alleviating patient discomfort.

Pae/exo@PF-127 promotes EMT and angiogenesis by upregulating miR-424-5p expression, thereby facilitating diabetic wound healing.

This paper investigated the effects of three glycosides-astragaloside IV, amygdalin, and paeoniflorin (AAP)-derived from Buyang Huanwu Decoction combined with endothelial progenitor cell-derived exosomes (EPC-Exo), on vascular endothelial repair in rats following balloon-induced injury, with specific focus on the PI3K/AKT signaling pathway.

Endothelial progenitor cells (EPC) were isolated, cultured, and identified using immunofluorescence, with EPC-Exo being validated through Western blotting (WB), transmission electron microscopy, and particle size analysis. A rat model of endothelial injury was established using a HFD and carotid artery balloon injury (CABI). The rats were subsequently treated with AAP and/or EPC-Exo. Vascular repair was evaluated using hematoxylin-eosin (H&E) staining, ELISA, immunofluorescence, and WB. In vitro, endothelial cell injury was induced, and treatment effects were analyzed using CCK-8, scratch assays, tube formation assays, immunofluorescence, and WB. The involvement of the PI3K/AKT pathway was verified using the PI3K inhibitor LY294002.

The combination of AAP and EPC-Exo significantly reduced intimal hyperplasia, improved endothelial function, and promoted angiogenesis. Network pharmacology and molecular docking analyses demonstrated strong interactions between AAP and PI3K/AKT-related proteins. By enhancing the uptake of EPC-Exo by vascular endothelial cells (VEC), AAP promoted proliferation, migration, and tube formation in vitro while reducing Cleaved-caspase 3 expression. This combination also increased activation of the PI3K/AKT signaling pathway. The PI3K inhibitor weakened these effects, verifying the pathway's involvement in vascular repair.

The combination of AAP and EPC-Exo synergistically promotes vascular endothelial repair and angiogenesis, partly by enhancing EPC-Exo uptake through activation of the PI3K/AKT signaling pathway.

Endometriosis (EMs) is a disease that adversely affects women's health. Immune imbalance is an important factor contributing to EMs, and exosomes (Exo) play an important role in immunomodulation. The purpose of this study was to investigate the effect of exosomes derived from the blood of patients with EMs on macrophage polarization and elucidate the underlying mechanisms. Exosomes were isolated from the serum of healthy controls (control exosomes) and patients with EMs (EMs exosomes). Macrophage polarization levels were detected using flow cytometry (FCM), RT-qPCR, and Western blot. Subsequently, we used RNA sequencing to analyze differential microRNAs (miRNA) and associated pathways. Electroporation techniques were used to modify the exosomes. The associated pathways were analyzed by Western blot. Finally, 12Z cells were co-cultured with macrophages of different polarizations, and the viability and metastasis of 12Z cells were calculated by cell counting kit-8 (CCK-8), scratch, and Transwell. EMs exosomes induced M2-type polarization in macrophages. RNA sequencing results showed that miR-196a-5p was dramatically decreased in EMs exosomes, whereas overexpression of miR-196a-5p in EMs exosomes could inhibit the M2-type polarization of macrophages and activate the Hippo pathway. In addition, M2-type macrophages promoted 12Z cell proliferation and metastasis. These findings suggest that serum-derived exosomes encapsulating miR-196a-5p alleviate endometriosis by promoting M1-type macrophage polarization via Hippo pathway activation.

With the ever-increasing burden of urological diseases, the need for developing novel imaging biomarkers and therapeutics to manage these disorders has never been greater. Extracellular vesicles (EVs) are natural membranous nanoparticles and widely applied in both diagnostics and therapeutics for many diseases. A growing body of research has demonstrated that EVs can be engineered to enhance their efficiency, specificity, and safety. We systematically examine the strategies for achieving targeted delivery of EVs as well as the techniques for engineering them in this review, with a particular emphasis on cargo loading and transportation. Additionally, this review highlights and summarizes the wide range of imaging biomarkers and therapeutic applications of engineered EVs in the context of urological diseases, emphasizing the potential applications in urological malignancy and kidney diseases.

Milk exosomes have also been widely used as emerging delivery vehicles for various therapeutic cargoes. Retinoblastoma (RB) is the most common primary intraocular malignancy of childhood. However, the therapeutic efficacy is severely hampered by the presence of blood-retinal barrier (BRB) and systemic side effects. Legumain (LGMN) can be used as a target for tumor microenvironment responsive delivery design and therapeutic applications. Here, a LGMN-sensitive peptide KC26-modified milk exosomes loaded with carboplatin (CBP-KC26-MExos). The system enables milk exosomes loaded with carboplatin (CBP) to reach the target cells by binding to LGMN, improves tumor targeting, enhances cellular uptake and apoptosis, inhibits cell proliferation, invasion and migration. Intravenous injection of CBP-KC26-MExos cross the BRB significantly inhibited intraocular tumor progression and reduced CBP toxicity. We have developed a 'drug-target-carrier' approach and proposed an enzyme sensitive peptide (KC26) modified milk exosomes loaded with CBP, providing a perspective for exploring targeted therapy of tumor cells and tumor microenvironment, and offering a promising clinical strategy for the treatment of retinoblastoma.

Exosomes are small extracellular vesicles with a diameter of 30-150 nm, secreted by a variety of cells and containing various active substances such as nucleic acids, proteins and lipids. The use of exosomes as drug carriers for targeted delivery of therapeutics has been studied for a long time. Ultrasound is recognized as a non-invasive diagnostic and therapeutic method for assisting drug loading and targeted delivery, cellular uptake and therapy. In this review, we summarize the applications of ultrasound in assisting drug loading into exosomes, targeted delivery of exosome-based drug formulations, cellular uptake, and therapy, and explore the prospects for the combined application of exosomes/exosome-based drug formulations and ultrasound.

In the cardiovascular system, different types of cardiovascular cells can secrete specific exosomes and participate in the maintenance of cardiovascular function and the occurrence and development of diseases. Exosomes carry biologically active substances such as proteins and nucleic acids from cells of origin and can be used as biomarkers for disease diagnosis and prognosis assessment. In addition, exosome-mediated intercellular communication plays a key role in the occurrence and development of cardiovascular diseases and has become a potential therapeutic target. This article emphasizes the importance of understanding the mechanism of exosomes in cardiovascular diseases and systematically details the current understanding of exosomes as regulators of intercellular communication in cardiomyocytes, providing a basis for future research and therapeutic intervention.

Integrins, a family of transmembrane cell adhesion receptors, mediate intercellular and cell-extracellular matrix crosstalk via outside-in and inside-out signaling pathways. Integrins, categorized into 24 distinct combinations of α and β subunits, exhibit tissue-specific expression and perform unique or overlapping roles in physiological and pathophysiological processes. These roles encompass embryonic angiogenesis, tissue repair, and the modulation of tumor cell angiogenesis, progression, invasion, and metastasis. Notably, integrins are significant contributors to tumor development, offering valuable insights into the potential of integrin-targeted diagnostics and therapeutics. Currently, there are various preclinical and clinical trials aiming to harness integrin antagonists that are safe, efficacious, and exhibit low toxicity. Owing to the functional redundancy across integrin types and the complexity of the mechanisms of integrin-mediated multiple key processes associated with tumor biology, challenges exist that impede advancements in integrin-targeted therapy. Nevertheless, innovative strategies focused on integrin modulation represent significant breakthroughs for improving patient care and promoting comprehensive insights into the underlying mechanisms of tumor biology. This review elucidates the impact of integrins on three distinct cell types in multiple key processes associated with tumor biology and explores the emerging integrin-targeted therapeutic approaches for the treatment of tumors, which will provide ideas for optimal therapeutic approaches in the future.

Adipose tissue-derived mesenchymal stem cells (ADSCs) are identified to be potential therapeutic candidates for diabetic nephropathy (DN) through secreting exosomes (Exos). Ubiquitin-specific protease 25 (USP25) has been reported to be involved in DN-induced renal injury. Herein, this study aimed to investigate whether ADSCs affected DN progression by Exo transfer of USP25. High glucose (HG)-induced mouse podocytes were used to mimic DN-induced injury for in vitro viability, inflammation, and apoptosis analyses. The db/db mice of DN were established for renal injury and function analysis in vivo. The deubiquitination effect of USP25 was analyzed by cellular ubiquitination and immunoprecipitation assays. ADSCs reversed HG-induced apoptosis and inflammation in podocytes, and these effects were achieved by Exo-mediated transfer of USP25. Mechanistically, USP25 interacted with SMAD7 protein and elevated its expression in podocytes via inducing SMAD7 deubiquitination. USP25 transferred via ADSC-Exos abolished HG-induced apoptosis and inflammation in podocytes by elevating SMAD7 protein levels. In vivo assay also confirmed that ADSC-Exo attenuated Type 2 Diabetes Mellitus-induced kidney injury and podocyte apoptosis and inflammation by releasing USP25. ADSCs attenuated T2DM-induced kidney injury, podocyte apoptosis, and inflammation via elevating SMAD7 stabilization through exosome transfer of USP25.

Exosomes are membrane-enclosed nanoparticles secreted by cells to mediate intercellular communication. Hence, functionalized exosomes are powerful tools in biology and medicine, and efficient methods to functionalize exosomes are highly desired. In this work, a novel approach is developed to modify and functionalize exosomes based on enzymatic engineering of their surface glycans. It employs a sialyltransferase and an azide-modified sialyl donor to enzymatically install azido-sialic acids onto exosomal glycans. The azide tags serve as universal molecular handles to attach various probes, e.g., biotin, protein, fluorophore, etc., by simple and biocompatible click chemistry. This approach is easy and effective, and the modified exosomes are readily retrieved from the plate, enabling the production of functional exosomes in practical scales for various studies and applications. The functionalized exosomes obtained are employed to profile exosomal glycans, disclosing the diverse glycosylation patterns of exosomes of different origins. They also facilitated comprehensive investigations on the cellular uptake of exosomes to disclose macropinocytosis as the main and general uptake route, while other endocytosis pathways are also partially involved in specific exosomes. Additionally, the new exosome functionalization approach has been demonstrated to be widely applicable to exosomes of different origins.

Exosomes, which carry bioactive RNAs, proteins, lipids, and metabolites, have emerged as novel diagnostic markers and therapeutic agents for heart failure (HF). This study aims to elucidate the trends, key contributors, and research hotspots of exosomes in HF.

We collected publications related to exosomes in HF from the Web of Science Core Collection. Using VOSviewer, CiteSpace, Excel, and SRplot software, we performed a visualization analysis of authors, countries, institutions, keywords, and references.

The publications on exosomes in the field of HF has grown rapidly. China ( N = 245, 42.683%) and the United States ( N = 170, 29.617%) are the leading contributors in this area. Wang L ( N = 14, 2.443%) is the most prolific author in the field. Key areas of exosome research in HF include mesenchymal stem cells (MSCs), angiogenesis, and microRNAs. Additionally, keywords and references analysis reveal that exosome research in HF is primarily focused on the role of exosomes in intercellular communication in HF, the value of miRNAs in exosomes as diagnostic markers, and the therapeutic mechanisms of MSC-derived exosomes.

Exosomes are receiving increasing attention in the field of HF. Mapping the development landscape of exosomes in HF will help researchers accelerate progress in this area.

Mesenchymal stem cells (MSCs) are currently being used in clinical trials for the treatment of a wide range of diseases and have a wide range of applications in the fields of tissue engineering and regeneration. Exosomes are extracellular vesicles containing a variety of components such as proteins, nucleic acids and lipids, which are widely present in biological fluids and have the functions of participating in intercellular information transfer, immune response and tissue repair, and can also be used as carriers to target and deliver tumors to improve therapeutic effects. Mesenchymal stem cell-derived Exosomes (MSC-Exos), which have the advantages of low immunogenicity and high tumor homing ability, have attracted much attention in targeted drug delivery. Here, we review the current knowledge on the involvement of MSC-Exos in tumor progression and their potential as drug delivery systems in targeted therapies. It also discusses the advantages and prospects of MSC-Exos as a drug carrier and the challenges that still need to be overcome.

Extracellular vesicles (EVs) have been actively explored for therapeutic applications in the context of cancer and other diseases. However, the poor tissue retention of EVs has limited the development of EV-based therapies. Here we report a facile approach to fabricating injectable EV hydrogels with tunable viscoelasticity and gelation temperature, by metabolically tagging EVs with azido groups and further crosslinking them with dibenzocyclooctyne-bearing polyethylene glycol via efficient click chemistry. One such EV gel has a gelation temperature of 39.4 °C, enabling in situ gelation of solution-form EVs upon injection into the body. The in situ formed gels are stable for over 4 weeks and can attract immune cells including dendritic cells over time in vivo. We further show that tumor EV hydrogels, upon subcutaneous injection, can serve as a long-term depot for EV-encased tumor antigens, providing an extended time for the modulation of dendritic cells and subsequent priming of tumor-specific CD8+ T cells. The tumor EV hydrogel also shows synergy with anti-PD-1 checkpoint blockade for tumor treatment, and is able to reprogram the tumor microenvironment. As a proof-of-concept, we also demonstrate that EV hydrogels can induce enhanced antibody responses than solution-form EVs over an extended time. Our study yields a facile and universal approach to fabricating injectable EV hydrogels with tunable mechanics and improving the therapeutic efficacy of EV-based therapies.

Nanotechnology and nanomaterials have emerged as promising tools for the delivery of anti-tumor drug cisplatin (CDDP). However, concerns exist regarding potential toxicity and cost-effectiveness, limiting their clinical applications. In contrast, plant-derived exosomes (PDEs), as natural nanovesicles, offer significant advantages as drug delivery carriers due to their large-scale production, biocompatibility, and ability to efficiently transport therapeutic drug across cellular barriers. In this work, we established a ginseng-derived exosome (G-Exo)-based CDDP delivery system (G-CDDP) and evaluated its anti-tumor efficacy both in vitro and in vivo. The results demonstrated that G-CDDP effectively targeted tumor site, inhibiting the proliferation and migration and promoting apoptosis in U-87MG tumor cells. Notably, the amount of CDDP in G-CDDP required for achieving the same cytotoxic effect on tumor cells was 12.66 times lower than that of free CDDP. In U-87MG tumor-bearing mice, G-CDDP effectively targeted tumor sites and exhibited significant therapeutic effect. Collectively, these findings highlight the potent anti-tumor activity of G-CDDP at reduced CDDP dosage, positioning it as a promising and efficient alternative to conventional drug treatments in clinical settings.

Extracellular vesicles (EVs) are small membrane-bound sacs released by cells that play crucial roles in intercellular communication. They transport biomolecules between cells and have both diagnostic and therapeutic potential. Artificial EVs, designed to mimic natural EVs, have been developed using various methods. In this study, Lactobacillus plantarum was used to create Lactobacillus-derived artificial EVs (LAEs) for skin rejuvenation and anti-aging. LAEs demonstrated monodispersity and effectively improved adverse gene expression and wound healing in fibroblasts. They also modulated aging-related genes and improved skin conditions in humans. Their simplicity, promptness, and lack of animal-derived sources make LAEs a promising alternative to natural EVs. LAEs have the potential to overcome the technical limitations of artificial EVs and advance EVs or exosome-based technologies for comprehensive skin rejuvenation.

Osteoarthritis (OA) is a cartilage-degenerative joint disease. Mitophagy impacts articular cartilage damage. tRNA-derived small RNAs (tsRNAs) are one of the contents of adipose mesenchymal stem cell (AMSC)-derived exosomes (AMSC-exos) and are involved in disease progression. However, whether tsRNAs regulate mitophagy and whether tsRNA-modified AMSC-exos improve OA via mitophagy remain unclear. We performed small RNA sequencing to identify OA-related tsRNAs, which were then loaded into AMSC-exos, exploring the function and mechanisms related to mitophagy in vitro and in vivo. Overall, 53 differentially expressed tsRNAs (DEtsRNAs) were identified between OA and normal cartilage tissues, among which 42 DEtsRNAs, including tsRNA-12391, were downregulated in the OA group. Target genes of tsRNA-12391 mainly participated in mitophagy-related pathways such as Rap1 signaling pathway. Compared to the control group, tsRNA-12391 mimics significantly promoted mitophagy, as shown by the upregulated expression of PINK1 and LC3 and the co-localization of Mito-Tracker Green and PINK1. Furthermore, tsRNA-12391 mimics effectively enhanced chondrogenesis in chondrocytes, as demonstrated by the elevated expression of collagen II and ACAN. AMSC-exos with tsRNA-12391 overexpression also facilitated mitophagy and chondrogenesis in vitro and in vivo. Mechanistically, tsRNA-12391 bound to ATAD3A restricted ATAD31 from degrading PINK1, leading to PINK1 accumulation. ATAD31 overexpression reversed the effects of tsRNA-12391 mimics on mitophagy and chondrogenesis. AMSC-exos loaded with tsRNA-12391 promoted mitophagy and chondrogenesis by interacting with ATAD31; this may be a novel therapeutic strategy for OA.

M2 macrophage-derived exosomes have been identified to modulate hepatocellular carcinoma (HCC) progression. E-twenty-six (ETS) variant transcription factor 4 (ETV4) shows protumoral effects in HCC. Here, we aimed to probe whether ETV4 performed oncogenic effects on HCC by macrophage-derived exosomes and its associated mechanism.

Exosomes were isolated from macrophages and co-cultured with HCC cells. qRT-PCR and western blotting were utilised for the detection of mRNA and protein. Cell survival was evaluated using EdU assay and flow cytometry. Glycolysis was determined by measuring the glucose uptake, lactate production, and ATP levels. Cell stemness was assessed by sphere formation and flow cytometry. The interaction between ETV4 and SULT2B1 (sulfotransferase family 2B member 1) was determined by a dual-luciferase reporter and chromatin immunoprecipitation assays. In vivo assay was performed by establishing mouse xenograft models.

ETV4 was highly expressed in the exosomes of M2 macrophages and could be internalised by HCC cells. ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness in vitro, and enhanced HCC growth in nude mice. Mechanistically, ETV4 interacted with SULT2B1 and promoted it transcription. SULT2B1 silencing suppressed HCC cell proliferation, glycolysis and stemness. In addition, exosomal ETV4 derived from M2 macrophage performed its effects by modulating SULT2B1.

ETV4 derived from M2 macrophage exosomes promoted HCC cell proliferation, glycolysis and stemness by interacting with SULT2B1, suggesting a novel insight into developing exosome-based therapy for HCC.

Malignant pleural effusion (MPE) is a common complication in patients with advanced lung cancer, significantly impacting their survival rates and quality of life. Effective tools for assessing the prognosis of these patients are urgently needed to enable early intervention. This study retrospectively analyzed patient data from the Affiliated Hospital of North Sichuan Medical College from 2013 to 2021, which served as the training cohort and internal testing cohort. Additionally, three external testing cohorts were introduced: data from Guang'an People's Hospital as cohort 1, data from Dazhou Central Hospital as cohort 2, and data from the Affiliated Hospital of North Sichuan Medical College from January 1, 2023, to December 31, 2023, constituting the temporal external testing cohort. Univariate logistic regression (LR) analysis of clinical variables (P < 0.05) was performed, followed by multivariate LR to identify independent predictors for inclusion in nine machine learning models: Decision Tree (DT), Random Forest (RF), Extreme Gradient Boosting (XGBoost), Elastic Net (Enet), Radial Support Vector Machine (rSVM), Multilayer Perceptron (MLP), LR, Light Gradient Boosting Machine (LightGBM), and K-Nearest Neighbors (KNN). The best-performing model was used to develop a nomogram for patient risk stratification. Three variables-treatment regimen, presence of pericardial effusion, and total pleural effusion volume-were identified as significant predictors in the study. The LR model demonstrated the best performance, achieving area under the curve (AUC) values of 0.885 in the training cohort, 0.954 in the internal testing cohort, and 0.920 in external testing cohort 1. To further validate the model's robustness, the nomogram developed from the LR model was evaluated in two additional validation cohorts: external testing cohort 2 and a temporal external testing cohort. The nomogram achieved AUCs of 0.962 in external testing cohort 2 and 0.949 in the temporal external testing cohort, demonstrating strong predictive accuracy. Calibration curves confirmed excellent model-reality concordance across all cohorts, and decision curve analysis (DCA) revealed superior clinical utility. The nomogram enabled individualized risk quantification and showed significant survival differences between high-risk/very high-risk groups and low-risk/medium-risk groups. This study evaluated nine machine learning models for prognostic prediction in lung cancer patients with MPE, finding that the LR-based model offered the best performance. A nomogram based on this model can effectively stratify patients for prognostic assessment and early intervention.

In this article, we revisit an article, which specifically focuses on the utilization of exosomes derived from human bone marrow mesenchymal stem cells (MSCs) for targeted delivery of gemcitabine in pancreatic cancer treatment. The experimental results demonstrated that the exosome-based drug delivery system derived from MSCs significantly augmented apoptosis in pancreatic cancer cells. The biocompatibility, targeting specificity, and low immunogenicity of exosomes render them as optimal carriers for drug delivery, enabling precise administration of therapeutics to diseased tissues while mitigating adverse effects, thereby achieving targeted treatment of cancer cells and significantly enhancing anti-tumor efficacy. However, the clinical application of exosome drug delivery platforms in oncology still presents challenges, necessitating further optimization to ensure their stability and efficacy. This study focuses on elucidating the advantages of exosomes as a drug delivery platform, exploring the utilization of MSC-derived exosomes in oncology therapy, and discussing their potential and future directions in cancer treatment.

The extracellular matrix (ECM) is a complex network of biomolecules with varying pore sizes, posing a challenge for the effective penetration of lipid nanoparticles. In contrast, cell-derived lipid nanoparticles, such as exosomes, have demonstrated the ability to travel to distant organs, indicating their capacity to penetrate the ECM. Here, we designed exosome-like vesicles (ELVs) inspired by exosomes' distinct transport phenomena. Specifically, we integrated three exosomal components (anionic lipid, cholesterol, and aquaporin-1) associated with transport into our ELVs to mimic the superior diffusion behavior of exosomes over synthetic lipid nanoparticles. Surprisingly, both bulk- and single-particle-diffusion studies revealed a more than 33 times increase in the effective diffusion coefficient within model ECM compared to conventional lipid nanoparticles. Furthermore, ELVs show an 80% increase in the effective diffusion coefficient within biological tissues. The excellent transport behavior of ELVs was further validated in vivo, where intratumoral injection showcased their superior transport. These findings provide insights into lipid nanoparticle design for improved tissue penetration.

Small extracellular vesicles (sEVs), including exosomes as a subtype, with a diameter typically less than 200 nm and originating from the endosomal system, are capable of transporting a diverse array of bioactive molecules, including proteins, nucleic acids, and lipids, thereby facilitating intercellular communication and modulating cellular functions. Vascular dementia (VaD) represents a form of cognitive impairment attributed to cerebrovascular disease, characterized by a complex and multifaceted pathophysiological mechanism. Currently, the therapeutic approach to VaD predominantly emphasizes symptom management, as no specific pharmacological treatment exists to cure the condition. Recent investigations have illuminated the significant role of sEVs in the pathogenesis of vascular dementia. This review seeks to provide a comprehensive analysis of the characteristics and functions of sEVs, with a particular focus on their involvement in vascular dementia and its underlying mechanisms. The objective is to advance the understanding of the interplays between sEVs and vascular dementia, thereby offering novel insights for future research and therapeutic strategies.

Exosomes are integral to the pathophysiology of osteoarthritis (OA) due to their roles in mediating intercellular communication and regulating inflammatory processes. Exosomes are integral to the transport of bioactive molecules, such as proteins, lipids and nucleic acids, which can influence chondrocyte behavior and joint homeostasis. Given their properties of regeneration and ability to target damaged tissues, exosomes represent a promising therapeutic avenue for OA treatment. Exosomes have potential in promoting cartilage repair, reducing inflammation and improving overall joint function. However, several challenges remain, including the need for standardized isolation and characterization methods, variability in exosomal content, and regulatory hurdles. The present review aims to provide a comprehensive overview of the current understanding of exosome mechanisms in OA and their therapeutic potential, while also addressing the ongoing challenges faced in translating these findings into clinical practice. By consolidating existing research, the present review aims to pave the way for future studies aimed at optimizing exosome‑based therapies for effective OA management.

Exosomes have become a potential field of nanotechnology for the treatment and identification of many disorders. However, the generation of exosomes is a difficult, time-consuming, and low-yielding procedure. At the same time, exosome mimetics (EM) resemble exosomes in their characteristics but have higher production yields. The aim of this study was to produce natural killer (NK) cell-derived EM (NKEM) loaded with sorafenib and test their killing ability against thyroid cancer cell lines.

Sorafenib was loaded into NKEM by mixing sorafenib with NK cells during NKEM production (NKEM-S). Then, these two types of nanoparticles were characterized with nanoparticle tracking analysis (NTA) to measure their sizes. In addition, the cellular uptake and in vitro killing effect of NKEM-S on thyroid cancer cell lines were investigated using confocal laser microscopy and bioluminescence imaging (BLI) techniques.

The uptake of NKEM and NKEM-S by the thyroid cancer cells was observed. Moreover, BLI confirmed the killing and anti-proliferation effect of NKEM-S on two thyroid cancer cell lines. Especially important, the NKEM-S demonstrated a desirable killing effect even for anaplastic thyroid cancer (ATC) cells.

Sorafenib-loaded NKEM showed the ability to kill thyroid cancer cells in vitro, even against ATC. This provides a new opportunity for drug delivery systems and thyroid cancer treatment.

This review explores the critical role of exosomes in promoting angiogenesis, a key factor in skin flap survival. Skin flaps are widely used in reconstructive surgery, and their survival depends heavily on the formation of new blood vessels. Exosomes, small extracellular vesicles secreted by various cells, have emerged as important mediators of intercellular communication and play a crucial role in biological processes such as angiogenesis. Compared to traditional methods of promoting angiogenesis, exosomes show more selective and targeted therapeutic potential as they naturally carry angiogenic factors and can precisely regulate the angiogenesis process. The review will delve into the molecular mechanisms by which exosomes facilitate angiogenesis, discuss their potential therapeutic applications in enhancing skin flap survival, and explore future research directions, particularly the challenges and prospects of exosomes in clinical translation. By highlighting the unique advantages of exosomes in skin flap survival, this review provides a new perspective in this field and opens up new research directions for future therapeutic strategies.

Traditional chemotherapy often encounters failure attributed to drug resistance mediated by tumor-repopulating cells (TRCs) and chemotherapy-triggered immune suppression. The effective inhibition of TRCs and the mitigation of drug-induced immune suppression are pivotal for the successful chemotherapy. Here, TRC-derived microparticles (3D-MPs), characterized by excellent tumor-targeting and high TRC uptake properties, are utilized to deliver metformin and the chemotherapeutic drug doxorubicin ((DOX+Met)@3D-MPs). (DOX+Met)@3D-MPs efficiently enhance tumor accumulation and are highly internalized in tumor cells and TRCs. Additionally, (DOX+Met)@3D-MPs significantly decrease the chemotherapy-triggered upregulation in P-glycoprotein expression to enhance intracellular doxorubicin retention, resulting in increased chemotherapy sensitivity and immunogenic cell death in tumor cells and TRCs for improved antitumor immunity. Importantly, (DOX+Met)@3D-MPs also remarkably reduce chemotherapy-induced PD-L1 expression, efficiently alleviating immune suppression facilitated by the PD-L1/PD-1 axis to further enhance immunological response against malignancy. These results underscore the (DOX+Met)@3D-MPs' potential as a viable platform for augmenting the efficacy of antitumor therapies.

Acute myelogenous leukemia (AML)-derived mesenchymal stem cells (MSCs) (AML-MSCs) have been identified to play a significant role in AML progression. The functions of MSCs mainly depend on their paracrine action. Here, we investigated whether AML-MSCs functioned in AML cells by transferring METTL14 (Methyltransferase 14) into AML cells via exosomes. Functional analyses were conducted using MTT assay, 5-ethynyl-2-deoxyuridine assay and flow cytometry. qRT-PCR and western blot analyses detected levels of mRNAs and proteins. Exosomes (exo) were isolated from AML-MSCs by ultracentrifugation. The m6A modification profile was determined by methylated RNA immunoprecipitation (MeRIP) assay. The interaction between Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) and Rho Kinase 1 (ROCK1) was validated using RIP assay. AML-MSCs incubation promoted the proliferation and radioresistance in AML cells. Moreover, AML-MSCs incubation led to increases in m6A levels and METTL14 levels in AML cells. METTL14 was transferred into AML cells by packaging into exosomes of AML-MSCs. The knockdown of METTL14 in AML-MSCs exosomes could reduce the proliferation and radioresistance in AML cells. Mechanistically, METTL14 induced ROCK1 m6A modification and stabilized its expression by an m6A-IGF2BP3-dependent mechanism. Rescue assay showed that ROCK1 overexpression reversed the inhibitory effects of METTL14 silencing in AML-MSCs exosomes on AML cell proliferation and radioresistance. Exosome-shuttled METTL14 from AML-MSCs promoted proliferation and conferred radioresistance in AML cells by stabilizing ROCK1 expression via an m6A-IGF2BP3-dependent mechanism.

The DNA damage response (DDR) is a crucial regulatory mechanism for the survival of organisms, and irregularity of DDR may contribute to the development of various diseases, including tumors, making it is a prominent topic in therapeutic research. Extracellular vesicles (EVs), as important mediators of intercellular communication, have been extensively studied in recent years. Notably, an increasing number of studies have revealed a strong connection between DDR and EVs. On one hand, DNA damage affects the release of EVs and their compositional content; on the other hand, EVs can dictate cell survival or death by modulating DDR in both the parental and the recipient cells. This review outlines current progress in the inter-regulatory relationship between EVs and DDR, with special emphasis on the effects of EVs derived from various sources on DDR in recipient cells. In addition, the potential applications of EVs in research and tumor therapy are discussed.

Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of all oral cancers, significantly impacting the survival and quality of life of patients. Exosomes, small extracellular vesicles released by cells, play a crucial role in intercellular communication in cancer. Nevertheless, their function and mechanism in OSCC remain elusive. Search Pubmed, Web of Science, and Cochrane Library using keywords OSCC, exome, diagnosis, and treatment to review the research progress of exome in OSCC. Based on these results, this review starting from the biosynthesis, structure, and contents of exosomes, elaborates on the research progress of exosomes in the diagnosis and treatment of OSCC. It explores the potential of exosomes in the diagnosis and treatment of OSCC, and briefly describes the challenges researchers currently face.

This review highlights recent progress in exosome-based drug delivery for cancer therapy, covering exosome biogenesis, cargo selection mechanisms, and their application across multiple cancer types. As small extracellular vesicles, exosomes exhibit high biocompatibility and low immunogenicity, making them ideal drug delivery vehicles capable of efficiently targeting cancer cells, minimizing off-target damage and side effects. This review aims to explore the potential of exosomes in cancer therapy, with a focus on applications in chemotherapy, gene therapy, and immunomodulation. Additionally, challenges related to exosome production and standardization are analyzed, highlighting the importance of addressing these issues for their clinical application. In conclusion, exosome-based drug delivery systems offer promising potential for future cancer therapies. Further research should aim to enhance production efficiency and facilitate clinical translation, paving the way for innovative cancer treatment strategies.

Oral squamous cell carcinoma (OSCC) is a tumor characterized by cellular redox imbalance, rendering it particularly sensitive to ferroptosis treatment. However, traditional ferroptosis inducers have a few drawbacks. In this study, ultrasmall AuMn nanoclusters (AMNCs) with a bovine serum albumin (BSA) ligand were synthesized and encapsulated in natural killer (NK) cell-derived exosomes to form an Exo-AMNCs composite for targeted ferroptosis therapy of OSCC. Unlike previously reported alloyed metal nanoclusters, not only do AMNCs react with intracellular H2O2 to produce reactive oxygen species (ROS) and induce ferroptosis but also the BSA ligand improves biocompatibility and water solubility. These properties render AMNCs ideal for fluorescence imaging in vivo. When combined with NK cell exosomes, the Exo-AMNCs composite exhibited strong targeted imaging and therapeutic effects on OSCC. Further investigation into the mechanistic details demonstrated that Exo-AMNCs downregulate the overexpression of fat mass and obesity-associated (FTO) in OSCC and regulate the key ferroptosis-related protein glutathione peroxidase 4 (GPX4).

Extracellular vesicles (EVs) present a promising modality for numerous biological and medical applications, including therapeutics. Developing facile methods to engineer EVs is essential to meeting the rapidly expanding demand for various functionalized EVs in these applications. Herein, we developed a technology that integrates enzymatic glycoengineering and microfluidics for effective EV functionalization. This method builds on a 3D nanostructured microfluidic device to streamline a multiple-step EV engineering process, which involves a step of enzymatic reaction to install azido-sialic acid residues to glycans on EVs using a sialyltransferase and an azide-tagged sialyl donor followed by the attachment of various functionalities, such as biotin and fluorescent labels, to the resulting azido-glycans on EVs through a biocompatible click reaction. Compared to traditional EV engineering methods, we show that our technology improves the efficiency of EV glycoengineering while simplifying and expediting the workflow. Furthermore, we demonstrated the applicability of this technology to EVs derived from the cell lines of different cancer types, including A549, PC3, and COLO-1 cells. Overall, this EV engineering technology could provide a potentially useful tool for broad applications.

Transfer RNA-derived small RNAs, a recently identified class of small noncoding RNAs, play a crucial role in regulating gene expression and are implicated in cerebrovascular diseases. However, the specific biological roles and mechanisms of transfer RNA-derived small RNAs in intracranial aneurysms (IAs) remain unclear. In this study, we identified that the transfer RNA-Asp-GTC derived fragment (tRF-AspGTC) is highly expressed in the IA tissues of both humans and mice. tRF-AspGTC promotes IA formation by facilitating the phenotypic switching of vascular smooth muscle cells, increasing of matrix metalloproteinase 9 expression, and inducing of oxidative stress and inflammatory responses. Mechanistically, tRF-AspGTC binds to galectin-3, inhibiting tripartite motif 29-mediated ubiquitination and stabilizing galectin-3. This stabilization activates the toll-like receptor 4/MyD88/nuclear factor kappa B pathway, further driving phenotypic switching and inflammation. Clinically, circulating exosomal tRF-AspGTC demonstrates strong diagnostic efficacy for IAs and is identified as an independent risk factor for IA occurrence. These findings highlight the potential of tRF-AspGTC as a promising diagnostic biomarker and therapeutic target for IAs.

Exosomes, extracellular vesicles originating from endosomes, were discovered in the late 1980s and their function in intercellular communication has since garnered considerable interest. Exosomes are lipid bilayer-coated vesicles that range in size from 30 to 150 nm and appear as sacs under the electron microscope. Exosome secretion is crucial for cell-to-cell contact in both normal physiology and the development and spread of tumors. Furthermore, cancer cells can secrete more exosomes than normal cells. Scientists believe that intercellular communication in the complex tissue environment of the human body is an important reason for cancer cell invasion and metastasis. For example, some particles containing regulatory molecules are secreted in the tumor microenvironment, including exosomes. Then the contents of exosomes can be released by donor cells into the environment and interact with recipient cells to promote the migration and invasion of tumor cells. Therefore, in this review, we summarized the biogenesis of exosome, as well as exosome cargo and related roles. More importantly, this review introduces and discusses the factors that have been reported to affect exosome secretion in tumors and highlights the important role of exosomes in tumors.

Messenger RNA (mRNA) therapeutics have garnered considerable attention due to their remarkable efficacy in the treatment of various diseases. The COVID-19 mRNA vaccine and RSV mRNA vaccine have been approved on the market. Due to the inherent nuclease-instability and negative charge of mRNA, delivery systems are developed to protect the mRNA from degradation and facilitate its crossing cell membrane to express functional proteins or peptides in the cytoplasm. However, the deficiency in transfection efficiency and targeted biological distribution are still the major challenges for the mRNA delivery systems. In this review, we first described the physiological barriers in the process of mRNA delivery and then discussed the design approach and recent advances in mRNA delivery systems with an emphasis on their tissue/cell-targeted abilities. Finally, we pointed out the existing challenges and future directions with deep insights into the design of efficient mRNA delivery systems. We believe that a high-precision targeted delivery system can greatly improve the therapeutic effects and bio-safety of mRNA therapeutics and accelerate their clinical transformations. This review may provide a new direction for the design of mRNA delivery systems and serve as a useful guide for researchers who are looking for a suitable mRNA delivery system.

The cancer cell marker poliovirus receptor-like protein 4 (PVRL4) has been shown to be highly expressed in many cancers, including lung cancer. Myeloid-derived suppressor cells (MDSCs) are a population of immature myeloid cells with immunosuppressive roles that can attenuate the anticancer response. Here, the precise functions and the relationship between PVRL4 and MDSCs in lung adenocarcinoma (LUAD) progression were investigated.

Detection of levels of mRNAs and proteins was conducted using qRT-PCR and western blotting. The CCK-8, colony formation, transwell, wound healing assays, and flow cytometry were used to explore cell growth, invasion, migration, and apoptosis, respectively. ELISA analysis detected TGF-β1 contents. LUAD mouse models were established for in vivo assay. Exosomes were isolated by ultracentrifugation. MDSCs were induced from peripheral blood mononuclear cells (PBMCs) by cytokine or co-culture with cancer cells.

LUAD tissues and cells showed high PVRL4 expression, and PVRL4 deficiency suppressed LUAD cell proliferation, invasion, migration, and induced cell apoptosis in vitro, and impeded LUAD growth in vivo. Thereafter, we found that PVRL4 was packaged into exosomes in LUAD cells, and could be transferred into PBMCs to promote MDSC induction and the expression of MDSC-secreted TGF-β1. Functionally, the silencing of exosomal PVRL4 impaired LUAD cell proliferation, invasion, migration, and evoked cell apoptosis, which could be reversed by the incubation of TGF-β1-overexpressed MDSCs.

Exosomal PVRL4 promoted LUAD progression by inducing the secretion of TGF-β1 in MDSCs, indicating a novel direction for LUAD immunotherapy.

Extracellular vesicles (EVs) are emerging as potential drug carriers in the fight against COVID-19. This study investigates the ability of EVs as drug carriers to target SARS-CoV-2-infected cells.

EVs were modified using Xstamp technology to carry the virus's RBD, enhancing targeting ability to hACE2+ cells and improving drug delivery efficiency. Characterization confirmed EVs' suitability as drug carriers. For in vitro tests, A549, Caco-2, and 4T1 cells were used to assess the targeting specificity of EVRs (EVs with membrane-surface enriched RBD). Moreover, we utilized an ex vivo lung tissue model overexpressing hACE2 as an ex vivo model to confirm the targeting capability of EVRs toward lung tissue. The study also evaluated drug loading efficiency and assessed the potential of the anti-inflammatory activity on A549 lung cancer cells exposed to lipopolysaccharide.

The results demonstrate the successful construction of RBD-fused EVRs on the membrane- surface. In both in vitro and ex vivo models, EVRs significantly enhance their targeting ability towards hACE2+ cells, rendering them a safe and efficient drug carrier. Furthermore, ultrasound loading efficiently incorporates IL-10 into EVRs, establishing an effective drug delivery system that ameliorates the pro-inflammatory response induced by LPS-stimulated A549 cells.

These findings indicate promising opportunities for engineered EVs as a novel nanomedicine carrier, offering valuable insights for therapeutic strategies against COVID-19 and other diseases.

Extracellular vesicles (EVs) have emerged as promising tools in diagnostics and therapy for chronic diseases, including cancer and Alzheimer's. Small EVs, also called exosomes, are lipid-bound particles (≈30-150 nm) that play a role in healthy and pathophysiological interactions, including intercellular communication, by transporting bioactive molecules, including proteins, lipids, and nucleic acids. Their ability to cross biological barriers, such as the blood-brain barrier, makes them ideal candidates for targeted therapeutic interventions. In the context of chronic diseases, exosomes can be engineered to deliver active agents, including small molecules and siRNAs to specific target cells, providing a novel approach to precision medicine. Moreover, exosomes show great promise as repositories for diagnostic biomarkers. Their cargo can reflect the physiological and pathological status of the parent cells, making them valuable indicators of disease progression and response to treatment. This paper presents a comprehensive review of the application of exosomes in four chronic diseases: cancer, cardiovascular disease, neurodegenerative disease, and orthopedic disease, which significantly impact global public health due to their high prevalence and associated morbidity and mortality rates. Furthermore, the potential of exosomes as valuable tools for theranostics and disease management is highlighted. Finally, the challenges associated with exosomes and their demonstrated potential for advancing future nanomedicine applications are discussed.