bims-engexo Biomed News
on Engineered exosomes
Issue of 2025–05–25
sixteen papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur



  1. Int J Surg. 2025 May 16.
      As pivotal mediators of intercellular communication, exosomes play a crucial role in transferring cellular cargo and regulating various biological functions. These extracellular vesicles encapsulate a diverse array of biomolecules, including nucleic acids, proteins, and lipids, which can serve as biomarkers for precise monitoring of physiological and pathological processes. Remarkably, exosomes derived from stem cells are densely packed with bioactive molecules that enable precise and selective intercellular communication, effectively dampen inflammatory responses, and actively drive tissue repair and regeneration. These attributes underscore their immense potential as a next-generation, cell-free therapeutic modality. Beyond their therapeutic potential, exosomes, characterized by their nanoscale size and excellent biocompatibility, serve as natural delivery vehicles for small molecules, proteins, and nucleic acids, making them highly suitable for targeted drug delivery and precision medicine applications. In this review, we provide a comprehensive analysis of the latest advancements in the clinical applications of exosomes, encompassing both diagnostic and therapeutic perspectives. Additionally, we critically assess the current limitations hindering their clinical translation and explore the potential of engineered exosomes in treating a wide range of diseases.
    Keywords:  clinical application; diagnostic and therapeutic; exosomes
    DOI:  https://doi.org/10.1097/JS9.0000000000002518
  2. Small. 2025 May 19. e2412170
      Spinal cord injury (SCI) is a severe central nervous system disorder characterized by a high rate of disability and limited axonal regeneration. Excessive post-injury inflammation often leads to further neuronal damage. Immune checkpoint (IC) genes, which regulate immune cell activity, play a critical role in modulating post-injury inflammation and thus influence neural repair and functional recovery. In this study, analysis of the GEO database reveals that the IC gene T cell immunoglobulin and mucin domain-containing protein 3 (Tim3) is highly expressed in microglia following SCI, contributing to an exacerbated inflammatory response. To address this, an RNAi-Tim3-Exo@SF hydrogel system is designed to deliver siRNA-Tim3 via exosomes, thereby regulating Tim3 expression after injury. Furthermore, miRNA sequencing indicates that the engineered exosomes (RNAi-Tim3-Exo) encapsulated within the hydrogel have the potential to promote axonal regeneration and modulate the spinal cord microenvironment. Preclinical studies demonstrate that the RNAi-Tim3-Exo@SF hydrogel could stabilize microtubules, promote damaged axon regeneration, stimulate angiogenesis, modulate the inflammatory environment, and ultimately improve motor function in SCI mouse models. Mechanistically, these reparative effects may be associated with miR-155-5p contained within the RNAi-Tim3-Exo. By integrating bioinformatics, biomedical science, and tissue engineering, this study presents a novel hydrogel-based therapeutic strategy with significant potential for the treatment of SCI.
    Keywords:  engineered exosomes; hydrogels; immune checkpoint blockade; spinal cord injury
    DOI:  https://doi.org/10.1002/smll.202412170
  3. Nano Lett. 2025 May 19.
      Exosomes, nanosized extracellular vesicles carrying proteins, lipids, and nucleic acids, hold great potential in therapeutic applications. Cryopreservation, a widely used method for their preservation and transport, often causes irreversible damage. Understanding the molecular mechanisms underlying biomembrane resistance to cryodamage is crucial for advancing cryopreservation techniques. In this study, we find that tetraspanin 4 (TSPAN4) and other tetraspanin family proteins play an essential role in protecting exosomes from cryodamage, likely due to their role in cholesterol binding and membrane microdomain formation. Furthermore, we engineered TSPAN4-loaded exosomes, which demonstrated enhanced cryoprotection while maintaining a similar protein composition and uptake efficiency compared to wild-type exosomes. Our novel cryopreservation strategy, which does not rely on external agents, offers a promising approach for advancing the clinical translation of exosomes as therapeutic agents.
    Keywords:  cryodamage resistance; cryopreservation; engineered exosomes; exosome; tetraspanin
    DOI:  https://doi.org/10.1021/acs.nanolett.5c00572
  4. J Transl Med. 2025 May 23. 23(1): 578
      The dysfunction of wound-healing processes can result in chronic non-healing wounds and pathological scar formation. Current treatment options often fall short, necessitating innovative approaches. Exosomes, extracellular vesicles secreted by various cells, have emerged as promising therapeutic agents serving as an intercellular communication system. By engineering exosomes, their cargo and surface properties can be tailored to enhance therapeutic efficacy and specificity. Engineered exosomes (eExo) are emerging as a favorable tool for treating non-healing wounds and pathological scars. In this review, we delve into the underlying mechanisms of non-healing wounds and pathological scars, outline the current state of engineering strategies, and explore the clinical potential of eExo based on preclinical and clinical studies. In addition, we address the current challenges and future research directions, including standardization, safety and efficacy assessments, and potential immune responses. In conclusion, eExo hold great promise as a novel therapeutic approach for non-healing wounds and non-healing wounds and pathological scars. Further research and clinical trials are warranted to translate preclinical findings into effective clinical treatments.
    Keywords:  Chronic non-healing wound; Engineered exosome; Pathological scar
    DOI:  https://doi.org/10.1186/s12967-025-06578-0
  5. Exploration (Beijing). 2025 Apr;5(2): 20240039
      The immunosuppressive microenvironment of glioblastoma multiforme (GBM) severely impacts the response to various treatments, including systemic chemotherapy. Targeted reprogramming of immunosuppressive GBM microenvironment using RNA interference (RNAi) is largely restricted by poor brain delivery efficiency and targeting specificity. Herein, an acid-cleavable transferrin (Tf) decorated engineering exosome-based brain-targeting delivery system (ACTE) was proposed to efficiently deliver small interference RNA towards transform growth factor-β (siTGF-β) and doxorubicin (DOX) to GBM site for combination chemo-immunotherapy. The siTGF-β and DOX co-loaded ACTE, termed as DOX&siTGF-β@ACTE (Ds@ACTE), is designed to specifically recognize the Tf receptor (TfR) on the blood-brain barrier (BBB). Subsequently, Ds@ACTE undergoes acid-responsive detachment of Tf within lysosome of brain capillary endothelial cells, leading to the separation of DOX&siTGF-β@Exo (Ds@Exo) from the Tf-TfR complex and enhanced BBB transcytosis. After crossing BBB, the separated Ds@Exo can further target GBM cells via the homing effect. In vivo studies validated that Ds@ACTE significantly downregulated the TGF-β expression to reprogram the immunosuppressive microenvironment, and thereby reinforce the chemotherapeutic effect of DOX and DOX-induced anti-tumor immune response. The effectiveness of this strategy not only can provide thinking for designing a more intelligent brain-targeting system based on engineered exosomes but also explore an effective treatment regimen for GBM.
    Keywords:  RNA interference; chemo‐resistance; engineered exosomes; glioblastoma; immunosuppressive microenvironment
    DOI:  https://doi.org/10.1002/EXP.20240039
  6. Nat Commun. 2025 May 23. 16(1): 4799
      Exosomes, as cell-derived lipid nanoparticles, are promising drug carriers because they can traverse challenging physiological barriers such as the blood-brain barrier (BBB). However, a major obstacle in utilizing exosomes as drug carriers is loading large therapeutic molecules without compromising the structural integrity of embedded biomolecules. Here, we introduce a membrane fusion method utilizing fusogenic lipid nanoparticles, cubosomes, to load large molecules into exosomes in a non-destructive manner. When the drug-loaded cubosome and exosome solutions are simply mixed, membrane fusion is completed in just 10 min. Our method effectively loads doxorubicin and immunoglobulin G into exosomes. Moreover, even the most challenging molecule-mRNA-is loaded with nearly 100% efficiency, demonstrating the versatility of our approach. In terms of biological behavior, the resulting hybrid exosomes preserve the functional behavior of exosomes in BBB uptake and penetration. Surprisingly, controlling exosome-to-cubosome ratios allows precise control over BBB uptake and transport. Furthermore, these hybrid exosomes retain cell-specific delivery properties, preserving the targeted delivery functions dictated by their exosomal origin. This study demonstrates the feasibility of a mix-and-load method for rapid and efficient drug loading into exosomes, with significant potential for the treatment of neurological diseases.
    DOI:  https://doi.org/10.1038/s41467-025-59489-5
  7. Anal Sci. 2025 May 23.
      In recent decades, advanced therapeutic modalities such as therapeutic cells, viral vectors, and extracellular vesicles (exosomes), have emerged as effective therapies for intractable diseases. These therapeutic modalities produced through bioprocesses must be purified from contaminants. Effective separation methods are essential for optimizing therapeutic modalities. This review highlights innovative temperature-modulated separation methods enabled by the thermoresponsive polymer poly(N-isopropylacrylamide) (PNIPAAm). The design of PNIPAAm-modified interfaces plays a pivotal role in ensuring precise and efficient separation. We summarize the recent advancements in the application of temperature-modulated separation methods for cells, viral vectors, and exosomes, with a focus on the design of PNIPAAm interfaces.
    Keywords:  Biomaterials; Polymer brush; Regenerative medicine; Temperature-responsive chromatography; Thermoresponsive interface; Thermoresponsive polymer
    DOI:  https://doi.org/10.1007/s44211-025-00785-x
  8. Cytokine. 2025 May 17. pii: S1043-4666(25)00108-5. [Epub ahead of print]192 156961
      Macrophages are key cells in the immune response, and their abnormal infiltration into the kidney is a common pathological feature in kidney diseases. Exosomes, acting as carriers for transporting essential proteins and genetic materials, can be derived from various cell types and are involved in a wide range of physiological and pathological processes in the kidney. As primary inflammatory immune cells, macrophages have garnered significant attention from scholars regarding the effects of their secreted exosomes on renal intrinsic cells in kidney diseases, as well as the interactive effects of exosomes derived from other cells on macrophages. This review delves into the detailed characteristics of macrophage-derived exosomes in kidney diseases, the mechanisms by which they promote damage to specific cells, and the signaling pathways involved. Additionally, it examines the reverse direction, elucidating the circulatory mechanisms of substances carried by exosomes from renal intrinsic cells that induce phenotypic transformation and inflammatory responses in macrophages, ultimately leading to further damage of renal intrinsic cells. The pathological role of exosome-macrophage interconnections in various renal diseases has received increasing attention, and understanding this mechanism can help unravel the microscopic immunoregulatory processes underlying kidney diseases. Moreover, the identification of therapeutic targets related to macrophage-related exosomes offers new strategies for the treatment of these conditions.
    Keywords:  Crosstalk; Exosome; Inflammation; Kidney disease; Macrophage
    DOI:  https://doi.org/10.1016/j.cyto.2025.156961
  9. Int Immunopharmacol. 2025 May 21. pii: S1567-5769(25)00882-3. [Epub ahead of print]159 114892
      Our previous studies have demonstrated that neutrophils play a key role in septic organ injury partly through the excessive formation of neutrophil extracellular traps (NETs) and that exosomes participate in the regulation of NET formation during sepsis. Therefore, this study aimed to determine whether neutrophil-derived exosomes promote the formation of NETs and induce multiple organ dysfunction during sepsis. Initially, polymorphonuclear neutrophil (PMN)-derived exosomes following in vitro stimulation with PBS or LPS (1 μg/mL) for 6 h. In vivo, PMN-derived exosomes were intravenously administered to wild-type C57BL/6 mice. Then, histopathological injury and NET formation in multiple organs were evaluated. In vitro, PMN-derived exosomes were cocultured with PMNs freshly isolated from healthy volunteers, and subsequently, NET formation and activation of associated molecular pathways were detected. Administration of LPS-stimulated PMN-derived exosomes in mice significantly enhanced NET formation, resulting in multi-organ inflammation and tissue injury. In vitro coculture experiments also demonstrated that exosomes from LPS-stimulated PMNs promote ROS-dependent NET formation. Proteomic analysis revealed enrichment of matrix metalloproteinase 9 (MMP9) expression in exosomes from LPS-stimulated PMNs, and further mechanistic investigations showed that exosomal MMP9 induced NET formation through the p38 MAPK pathway. Clinical data analysis suggests a close association between sepsis severity/prognosis and plasma-derived exosomal MMP9 expression levels. PMN-derived exosomes facilitate the excessive formation of NETs in sepsis, leading to the subsequent development of multiple organ dysfunction. This discovery reveals a novel role for PMN-derived exosomes in the pathogenesis of sepsis-related multiple organ dysfunction and suggests their potential as prognostic indicators for this condition.
    Keywords:  Exosomes; MMP9; NETs; Neutrophils; ROS; Sepsis-related multiple organ dysfunction
    DOI:  https://doi.org/10.1016/j.intimp.2025.114892
  10. Exp Gerontol. 2025 May 16. pii: S0531-5565(25)00115-9. [Epub ahead of print] 112786
      Mesenchymal stem cell (MSC)-derived exosomes have been intensively studied for their therapeutic effects on tissue repair and regeneration. However, the specific contributions of exosomes derived from endogenous bone marrow MSCs to the maintenance of bone tissue homeostasis remain unclear. In this study, we impaired MSC-derived exosome secretion by specifically deleting vascular protein sorting 33B (VPS33B). Mice deficient in VPS33B (VPS33B-cKO mice) exhibited premature bone loss and imbalanced bone remodeling processes, which were associated with a reduction in MSC number and an increase in bone marrow inflammation. MSCs derived from VPS33B-cKO mice exhibited impaired self-renewal, proliferation, osteoblastic differentiation, and increased cellular senescence. Incubation with exosomes (Y-Exo) derived from MSCs of wildtype young mice greatly ameliorated senescent phenotypes observed in VPS33B-deficient MSCs. We further demonstrated exosome autocrine pathway through a fluorescent-labeled uptake assay and observed a significant association between autocrinal exosomes and the senescence of MSCs. Mechanistically, miR-136-3p and miR-146a-5p were highly enriched in Y-Exo but not in exosomes from senescent MSCs, which promoted cell proliferation while inhibiting inflammation by targeting the PI3K-Akt and NF-κB pathway, respectively. Furthermore, intramedullary transplantation of Y-Exo successfully mitigated age-related MSC exhaustion and bone loss. Our findings indicate that endogenous MSC-derived exosomes play a crucial regulatory role in the maintenance of bone homeostasis, and propose the potential therapeutic application of young MSC-derived exosomes for the treatment of senile osteoporosis.
    Keywords:  Autocrine pathway; Exosome; MSC senescence; Senile osteoporosis; microRNA
    DOI:  https://doi.org/10.1016/j.exger.2025.112786
  11. Med Oncol. 2025 May 21. 42(6): 216
      Exosome roles in cellular cross-talking within tumor microenvironment (TME) is a critical event in tumorigenesis. Type 2 macrophages (M2), cancer-associated fibroblasts (CAFs) and cancer stem cells (CSCs) are the three most important cells in cancer progression and metastasis, and targeting their connectome route can be an effective anti-cancer strategy. Exosomes mediate bidirectional cross-talking between the three cell types in which exosomes secreted from CSCs promote polarization of M2 macrophages and CAFs, and that M2- and CAF-derived exosomes promote cancer stemness through activation of epithelial-mesenchymal transition (EMT)-related signaling including transforming growth factor (TGF)-β, WNT/β-catenin and epidermal growth factor (EGF). CSC-derived exosomal TGF-β is a key driver of CAF and M2 macrophage polarization, with the latter mediated through activation of signal transducer and activator of transcription 3 (STAT3). β-catenin activity also seems to take important role in exosomal cross-talk between CAFs and stemness state of cancer. Incubation of exosomes with inhibitors of signaling inter-connecting CSCs, M2 and CAFs is a key anti-cancer strategy and a promising supplementary to the routine immunotherapeutic approaches in cancer therapy.
    Keywords:  Cancer stem cell (CSC); Cancer-associated fibroblast (CAF); Epithelial-mesenchymal transition (EMT); Exosome; Transforming growth factor (TGF); Type 2 macrophage (M2)
    DOI:  https://doi.org/10.1007/s12032-025-02774-6
  12. Hereditas. 2025 May 16. 162(1): 79
       BACKGROUND: Exosomes are extracellular vesicles that carry various biological substances and have potential as functional mediators in cancers. However, little is known about special molecules in colorectal cancer (CRC) exosomes and their immunological functions.
    AIMS: Using genomic data from the TCGA-CRC cohort, we constructed a prognostic model based on exosome-related lncRNA for the first time, and the biological role of MIR4713HG in CRC was deeply analyzed.
    METHOD: In this study, we downloaded the gene expression data and clinical data of CRC from the TCGA database. The limma package, SVM-REF and univariate Cox analysis were used to screen out core ERG (CERG) in CRC. LASSO and multivariate Cox regression analyses were used to filter out CERG-related LncRNA and construct a risk score. We explored the distribution and expression levels of ERG in immune cell types by scRNA-seq data. xCell was used to calculate the infiltration levels of stromal cells and immune cells in CRC. KM plotter was used for immunotherapy evaluation of core ERG. Next, we further provide colony formation assay, Transwell assay and xenograft models to understand the carcinogenic effect of MIR4713HG.
    RESULT: First, 43 differentially expressed ERG and 7 CERG were obtained. We explored the expression and distribution levels of CERG in 9 types of cells by scRNA-seq data. In addition, two key exosome-associated LncRNA (MIR4713HG and ZEB1-AS1) were obtained, and a risk score (EALncRI) was constructed. EALncRI could accurately predict the prognosis of CRC. Based on the EALncRI, we constructed a nomogram that is easy to use in clinical practice, which can more accurately and stably predict the prognosis of CRC patients. Furthermore, EALncRI was significantly correlated with the expression of 5 HLA molecules and 13 immune checkpoint molecules. MIR4713HG showed a good predictive effect in the overall survival of patients with immunotherapy evaluation. Knocking down the expression of MIR4713HG significantly inhibited proliferation and migration, and also impaired subcutaneous tumor growth in nude mice.
    CONCLUSION: In this study, a variety of machine learning algorithms were used to construct the EALncRI based on ERG, which can effectively predict the prognosis and distinguish the immune landscape of CRC. More importantly, we conducted an in-depth study on MIR4713HG, which may become an important therapeutic target in CRC.
    Keywords:  Colorectal cancer; EALncRI; Immune; Integrating analysis; LncRNA; MIR4713HG; Oncogene; Prognosis
    DOI:  https://doi.org/10.1186/s41065-025-00445-0
  13. Nanoscale Adv. 2025 May 20.
      Cancer cells display the Warburg effect resulting in the production of excess pyruvate that is converted to acetyl-CoA in the mitochondria. Acetyl-CoA is further converted to citrate in the mitochondria. Meanwhile, in the cytosol, citrate is cleaved by ATP citrate lyase (ACLY) that regenerates acetyl-CoA and oxaloacetate. Recently, ACLY has been recognized as a potential target owing to its overexpression in several cancers, including non-small cell lung cancer. The aim of this study was to develop an ACLY-targeting exoformulation, where bovine milk-derived exosomes were surface-conjugated with folate and loaded with the natural ACLY inhibitor potassium hydroxycitrate. The therapeutic efficacy of potassium hydroxycitrate was enhanced by encapsulating it in bovine milk exosomes, and the anti-cancer potential of this exoformulation was evaluated in urethane-induced lung adenocarcinoma murine model. Potassium hydroxycitrate-loaded exosomes, which were surface-conjugated with folate (Exo-KH), exhibited a particle size of ∼183 nm and a practical loading efficiency of ∼16.8%. The exoformulation was found to be spherical in shape as characterized by scanning electron microscopy. Pharmacokinetic studies confirmed the continuous release of hydroxycitrate from the exoformulation, and Exo-KH administered mice showed inhibition of lung tumor growth. The mRNA expression levels of ACLY and other metabolic enzymes, such as FASN, HMGCR, SERBP1c, were also reduced in the exoformulation-treated group as compared with its free form-treated group. ACLY activity was also observed to be decreased in serum and tumor lysates of exoformulation-treated mice. This study demonstrates the potential of using bovine milk exosomes encapsulating potassium hydroxycitrate as a new chemotherapeutic option for non-small cell lung cancer.
    DOI:  https://doi.org/10.1039/d5na00094g
  14. Sci Rep. 2025 May 22. 15(1): 17876
      Angiogenesis is one of the hallmarks of solid tumors. Exosomes are extracellular vesicles, which are involved in multiple stages of tumor progression. The role of macrophage-derived exosomes in angiogenesis in oral squamous cell carcinoma (OSCC), where macrophages are crucial components of the tumor microenvironment (TME), remains to be explored. The M2 macrophages and microvessels in OSCC were stained by immunohistochemistry. M2 macrophages were induced in vitro and exosomes were extracted by gradient centrifugation using ultracentrifugation. Fluorescence confocal microscopy was used to observe the uptake of M2 macrophage-derived exosomes by human umbilical vein endothelial cells (HUVECs). CCK-8 proliferation assay, TRANSWELL migration assay and tube formation assay were used to detect the effects of M2 macrophage-derived exosomes on the proliferation, migration and tube formation of HUVECs. Immunohistochemical study showed that M2 macrophage infiltration was positively correlated with microvessel density in OSCC. We induced M2 macrophages in vitro and successfully extracted its exosomes. The cellular internalization of fluorescence-labeled exosomes by HUVECs was dynamically monitored via laser scanning confocal microscopy. The M2 macrophage-derived exosomes promoted the proliferation, migration, and tube-forming ability of HUVECs. The results showed that M2 macrophage-derived exosomes could promote the proliferation, migration and tubulation of HUVECs.
    DOI:  https://doi.org/10.1038/s41598-025-03113-5
  15. J Pharm Biomed Anal. 2025 May 14. pii: S0731-7085(25)00306-1. [Epub ahead of print]264 116965
      Autism spectrum disorder (ASD) has become a neurodevelopmental disorder that seriously endangers the health of infants and children. In order to explore the pathogenesis of the disease and search for early diagnostic biomarkers. In this study, plasma exosomes (PEs) and neural cell adhesion molecule L1 (L1CAM)-captured exosomes (LCEs) of ASD and controls were extracted and lysed to obtain proteins. Isobaric tags for relative and absolute quantitation (iTRAQ) proteomics were applied to investigate the differences in the expression of PEs and LCEs proteins between the two groups. Twenty-eight plasma exosomal differentially expressed proteins (DEPs) were identified, which were mainly associated with immunity, inflammation, complement and coagulation, and lipoprotein metabolism and transport. Twenty L1CAM-captured exosomal DEPs were identified, which were mainly involved in cytoskeleton, tight junctions, focal adhesion, and platelet-associated pathways. Meanwhile, our results suggested that processes or signaling pathways associated with the DEPs from plasma exosomes may be activated, whereas those associated with L1CAM-captured exosome may be inhibited. These processes or signaling pathways have been reported to be associated with ASD in previous studies. These DEPs have the potential to be diagnostic markers. This study provides new insights into disease mechanisms and diagnostic markers of ASD.
    Keywords:  Autism spectrum disorder; Biomarker; Exosomes; L1CAM-captured exosomes
    DOI:  https://doi.org/10.1016/j.jpba.2025.116965
  16. Life Sci. 2025 May 21. pii: S0024-3205(25)00387-X. [Epub ahead of print] 123752
      In recent years, exosomes versatility has prompted their study in the biomedical field for diagnostic, prognostic, and therapeutic applications. Exosomes are bi-lipid small extracellular vesicles (30-150 nm) secreted by various cell types, containing proteins, lipids, and DNA/RNA. They mediate intercellular communication and can influence multiple human physiological and pathological processes. So far, exosome analysis has revealed their role as promising diagnostic tools for human pathologies. Concurrently, artificial intelligence (AI) has revolutionised multiple sectors, including medicine, owing to its ability to analyse large datasets and identify complex patterns. The combination of exosome analysis with AI processing has displayed a novel diagnostic approach for cancer and other diseases. This review explores the current applications and prospects of the combined use of exosomes and AI in medicine. Firstly, we provide a biological overview of exosomes and their relevance in cancer biology. Then we explored exosome isolation techniques and Raman spectroscopy/SERS analysis. Finally, we present a summarised essential guide of AI methods for non-experts, emphasising the advancements made in AI applications for exosome characterisation and profiling in oncology research, as well as in other human diseases.
    DOI:  https://doi.org/10.1016/j.lfs.2025.123752