bims-engexo 2025-06-08 papers

bims-engexo

Biomed News

on Engineered exosomes

Issue of 2025–06–08
ten papers selected by
Ravindran Jaganathan, Universiti Kuala Lumpur

Engineered extracellular vesicles derived from pluripotent stem cells: a cell-free approach to regenerative medicine.
Therapeutic effect of mesenchymal stem cells and their derived exosomes in diseases.
Targeted delivery of apelin using a novel extracellular vesicle platform for pulmonary arterial hypertension treatment.
Versatile tethering system to control cell-specific targeting of bioengineered extracellular vesicles.
M2 macrophage-derived exosome facilitates aerobic glycolysis and osteogenic differentiation of hPDLSCs by regulating TRIM26-induced PKM ubiquitination.
The multifaceted roles of exosomes in corneal biology: elucidation of underlying mechanisms and therapeutic applications.
In vivo Targeted Delivery of Extracellular Vesicle‒Gold Nanorod Hybrids to Metastatic Melanoma Lung Tumors.
Endosome transcriptomics reveal trafficking of Cajal bodies into multivesicular bodies.
Exosomal small non-coding RNA profiling and the role of piRNA pathway genes in Lumpy skin disease virus-infected bovines.
Semiquantitative analysis of carbon quantum dot-labeled exosomes based on carrier ampholyte-free paper-based isoelectric focusing.

Burns Trauma. 2025 ;13 tkaf013

Engineered extracellular vesicles derived from pluripotent stem cells: a cell-free approach to regenerative medicine.

Aline Yen Ling Wang, Huang-Kai Kao, Yen-Yu Liu, Charles Yuen Yung Loh.

  The engineered extracellular vesicles (EVs) derived from pluripotent stem cells (PSCs) are a new concept in regenerative medicine. These vesicles are secreted from the embryonic stem cells as well as the induced PSCs (iPSCs) and are involved in the transfer of bioactive molecules required for cell signaling. This review describes the possibilities for their use in the modification of therapeutic approaches in regenerative medicine and targeted therapies. PSCs can differentiate into various cell types that can be useful for tissue engineering or to generate models of diseases in a dish. Compared to cell therapies, engineered EVs are characterized by lower immunogenicity, higher targetability, and improved stability. Some of the applications are angiogenic, tissue restorative, immunomodulatory, and gene therapies for the treatment of certain diseases. iPSC-derived engineered EVs find application in regenerative medicine, drug delivery systems, diagnostics of diseases, and hydrogel systems. In regenerative medicine, they can promote the restoration of cardiac, bone, cartilage, and corneal tissues. Engineered EVs are also employed in drug targeting to particular sites as well as in the diagnosis of diseases based on biomarkers and improving image contrast. Hydrogels that contain EVs provide a depot-based delivery system to slowly release drugs in a controlled manner that enhances tissue repair. Thus, the results described above demonstrate the potential of engineered PSC-EVs for various biomedical applications. Future work will be directed toward expanding the knowledge of engineered PSC-EVs and their possibilities to create new therapeutic approaches based on the functions of these vesicles.

Keywords:  Cell-free medicine; Engineered EVs; Extracellular vesicles; Pluripotent stem cells; Regenerative medicine

DOI:  https://doi.org/10.1093/burnst/tkaf013
Mol Biomed. 2025 Jun 04. 6(1): 34

Therapeutic effect of mesenchymal stem cells and their derived exosomes in diseases.

Yang Wang, Huanhui Wang, Jing Tan, Zhijie Cao, Qun Wang, Hongkun Wang, Shouwei Yue, Wei Li, Dong Wang.

  Mesenchymal stem cells (MSCs) are multipotent stem cells characterized by their robust proliferative capacity, homing ability, differentiation potential, and low immunogenicity in vitro. MSCs can be isolated from a variety of tissues, primarily including but not limited to bone marrow, adipose tissue, umbilical cord, placenta, and dental pulp. Although there have been a large number of clinical studies on the treatment of diseases by MSCs and MSCs-derived exosomes (MSCs-EXO), the large-scale clinical application of MSCs and MSCs-EXO have been limited due to the heterogeneity of the results among various studies. This review provides a detailed description of the classification and characterization of MSCs and MSCs-EXO, as well as their extraction methods. Furthermore, this review elaborates on three key mechanisms of MSCs and MSCs-EXO: paracrine mechanisms, immunomodulatory and anti-inflammatory effects, as well as their promotion of tissue regeneration. This review also examines the role of MSCs and MSCs-EXO in cardiovascular diseases, neurological disorders, autoimmune diseases, musculoskeletal disorders, and other systemic diseases over the past five years, while discussing the challenges and difficulties associated with their clinical application. Finally, we systematically summarized and analyzed the potential causes of the various heterogeneous results currently observed. Additionally, we provided an in-depth discussion on the challenges and opportunities associated with the clinical translation of disease treatment approaches based on MSCs, MSCs-EXO, and engineered exosomes.

Keywords:  Autoimmune diseases; Cardiovascular diseases; Exosome; Mesenchymal stem cell; Musculoskeletal disorders; Neurological disorders

DOI:  https://doi.org/10.1186/s43556-025-00277-4
Biomaterials. 2025 May 26. pii: S0142-9612(25)00357-6. [Epub ahead of print]323 123438

Targeted delivery of apelin using a novel extracellular vesicle platform for pulmonary arterial hypertension treatment.

Jihong Kim, Yong-Soon Choi, Jaehyun Kim, Riajul Wahab, Yeji Lee, Hyemin Joo, Seryoung Park, Inkyu Lee, Seong A Kim, Yeong Ha Hwang, Seongeon Cho, Jiyoong Goo, Cherlhyun Jeong, Seung-Yoon Park, Gi Beom Kim, Taslim A Al-Hilal, Gi-Hoon Nam, In-San Kim.

  Pulmonary arterial hypertension (PAH) is a severe disease characterized by endothelial dysfunction, vascular remodeling, and pulmonary artery occlusion, culminating in right ventricular hypertrophy and heart failure. While apelin peptides are promising therapeutic candidates due to their critical role in vascular homeostasis, their efficacy as agonists is limited by insufficient lesion-specific targeting and suboptimal in vivo stability. Here, we developed an engineered extracellular vesicle (EV) platform for precise apelin delivery to PAH lesions, maximizing therapeutic impact. Using interferon-induced transmembrane protein 3 (IFITM3), a type II transmembrane protein, we oriented the apelin peptide on the EV surface with its C-terminus fully exposed, preserving the critical binding interface for functional interaction with the apelin receptor. To further enhance targeting specificity, we integrated the PAH-targeting peptide CARSKNKDC (CAR), which selectively binds to heparan sulfate overexpressed on PAH endothelial cells, into the IFITM3-apelin scaffold, creating CAR-Apelin EVs. This dual-engineered EVs demonstrated exceptional targeting and therapeutic efficacy in PAH models. CAR-Apelin EVs significantly reversed pathological vascular remodeling and improved cardiac function, as evidenced by reduced right ventricular systolic pressure and hypertrophy. Our findings establish CAR-Apelin EVs as a transformative therapeutic strategy, providing a targeted and effective approach to meet critical unmet needs in PAH treatment.

Keywords:  Apelin; Engineered extracellular vesicle; Pulmonary arterial hypertension; Targeted delivery; Type II transmembrane protein scaffold

DOI:  https://doi.org/10.1016/j.biomaterials.2025.123438
Sci Rep. 2025 Jun 03. 15(1): 19454

Versatile tethering system to control cell-specific targeting of bioengineered extracellular vesicles.

Sheryl Bui, Jeanne Lainé, Maud Chevé, Stéphane Vassilopoulos, Gregory Lavieu.

  Extracellular Vesicles (EVs) are natural communication vectors involved in many physiological processes. Significant efforts have aimed to harness EVs for therapeutic delivery, with key challenges being control and enhancement of EV-mediated delivery steps. We and others have developed strategies to improve cargo loading and enhance EV content delivery using viral or non-viral fusogens. However, few targeting solutions have been proposed. Here, we present a versatile system for precise EV targeting to specific cell types, enabling quantitative assessment of targeting efficiency via luminescence and fluorescence. EVs are genetically engineered to express a chimeric adapter protein anchored by a glycosylphosphatidylinositol (GPI) anchor. This protein includes a fluorescent/luminescent domain for detection and a streptavidin domain recruit biotinylated antibodies or ligands specific to cell-surface antigens or receptors. We validated this platform with three different combinations of ligand/target cells, demonstrating up to 40-fold increase in EV uptake. This adaptable system promises to provide a comprehensive solution for targeted therapeutic delivery using EV-based vectors.

Keywords:  Bioengineering; Biotin; Drug delivery; Exosome; Extracellular vesicle; Streptavidin; Targeting

DOI:  https://doi.org/10.1038/s41598-025-04576-2
Free Radic Biol Med. 2025 May 29. pii: S0891-5849(25)00723-3. [Epub ahead of print]237 88-100

M2 macrophage-derived exosome facilitates aerobic glycolysis and osteogenic differentiation of hPDLSCs by regulating TRIM26-induced PKM ubiquitination.

Xianmin Liao, Zhenjin Yang, Yan Li, Yun Cui, Liya Ma, Cun Liang, Zheng Guan, Jiangtian Hu.

   BACKGROUND: Our previous findings revealed that exosomes derived from M2-polarized macrophages enhance the osteogenic differentiation of human periodontal ligament stem cells (hPDLSCs), and identified key microRNAs (miRNAs) using high-throughput miRNA sequencing. Therefore, the present study aimed to elucidate the role and underlying molecular mechanism by which exosomes derived from M2 macrophages mediate the osteogenic differentiation of hPDLSCs.
METHODS: Following lentiviral-mediated modulation of miR-6879-5p in both hPDLSCs and M2 macrophage-derived exosomes, RT-qPCR, western blotting, and Alizarin Red staining were applied to assess alterations in osteogenic markers, including ALP, OCN, Collagen I, and RUNX2, as well as mineralized nodule formation in hPDLSCs. Immunoprecipitation-mass spectrometry (IP-MS) was employed to identify proteins interacting with miR-6879-5p target genes in hPDLSCs.
RESULTS: Knockdown of miR-6879-5p in the exosomes reduced the expression of osteogenic markers and inhibited calcified nodule formation in hPDLSCs. Overexpression of TRIM26 attenuated the osteogenic differentiation of hPDLSCs, an effect that was reversed by miR-6879-5p overexpression. IP-MS identified 410 TRIM26-interacting proteins in hPDLSCs. These proteins were associated with ubiquitination, aerobic glycolysis, and amino acid metabolism. The hub proteins in the TRIM26-associated PPI network included RPL and RPS family proteins, as well as glycolysis-associated proteins. CO-IP confirmed an interaction between TRIM26 and PKM, and showed that TRIM26 increased PKM ubiquitination. Overexpression of PKM rescued TRIM26-mediated suppression of osteogenic marker expression and mineralized nodule formation in hPDLSCs.
CONCLUSION: miR-6879-5p carried by M2 macrophage-derived exosomes promotes osteogenic differentiation and aerobic glycolysis in hPDLSCs via modulating TRIM26-mediated ubiquitination of PKM.

Keywords:  Aerobic glycolysis; Exosome; Macrophage; Osteogenic differentiation; Periodontal ligament stem cells; Ubiquitination

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.425
Mol Biol Rep. 2025 May 31. 52(1): 527

The multifaceted roles of exosomes in corneal biology: elucidation of underlying mechanisms and therapeutic applications.

Samaneh Ahmadi, Sahar Gohari-Lasaki, Negin Jahangiri, Mahsa Ejlalidiz, Mohammadreza Saberiyan.

  The cornea, as the essential part of the eye with the duty of maintaining transparency and vision, is susceptible to various diseases and genetic abnormalities. Vision loss due to corneal disorders is a global concern, prompting research into innovative treatment approaches. The investigations have provided a significant role that exosomes play in maintaining corneal homeostasis and promoting intercellular communication. The cornea is made up of cellular and acellular components. The cellular components include the epithelial cells, stromal keratocytes, and endothelial cells, which secrete exosomes that contribute to preserving corneal transparency, immune privilege, and tissue repair. These nanosized vesicles contain molecules that regulate immune responses, promote cell proliferation and migration, and protect against stress-induced cell death. In this review, we try to survey the therapeutic potential and effects of exosomes in treating various corneal conditions, which can contribute to enhance corneal healing, reduce scarring, and improve visual outcomes.

Keywords:  Corneal disorders; Exosomes; Tissue repair; Vision loss

DOI:  https://doi.org/10.1007/s11033-025-10642-9
Int J Nanomedicine. 2025 ;20 6983-6998

In vivo Targeted Delivery of Extracellular Vesicle‒Gold Nanorod Hybrids to Metastatic Melanoma Lung Tumors.

Karen Bolaños, Daniela León, Pedro Jara-Guajardo, Pamela Contreras, David Silva Ancahuail, Ana Luisa Riveros, Yanay Montano, Damián Pérez, Eyleen Araya, Marcelo J Kogan, Andrew F G Quest.

   Background: Cutaneous melanoma is an aggressive type of cancer characterized by rapid progression, resistance to chemotherapy, and metastasis to the lung. Conventional chemotherapy and radiotherapy are the principal approaches for treating metastasizing tumors, but the lack of targeting results in severe side effects and low treatment efficacy. Nanoparticles reportedly increase selectivity, given that they can accumulate at specific locations owing to the enhanced permeation and retention (EPR) effect. In this respect, plasmonic nanoparticles, such as gold nanorods (AuNRs), are interesting because of their photothermal and optical properties, making them suitable for biomedical applications, such as drug delivery, tumor ablation, and theranostics. To increase the tumor accumulation of AuNRs, extracellular vesicles (with sizes ranging from 40-150 nm) have attracted attention because of their remarkable biocompatibility and natural cell-accumulation selectivity. To further increase the targeting properties of the nanosystem, we functionalized the AuNRs with methotrexate (MTX), which is known to interact with the overexpressed folate receptors in cancer cells. We combined the inherent homing properties of exosomes from B16F10 cells with the active targeting properties of MTX to increase the accumulation of AuNRs in metastatic lung melanoma tumors.
Methods: We obtained and exhaustively characterized B16F10 exosomes loaded with MTX-functionalized AuNRs (EXOS-AuNR-MTX). The safety of the complete nanosystem, as well as its specific and time-dependent accumulation in B16F10 cells, was determined using the mitochondrial MTS assay and fluorescence analysis, respectively.
Results: Surface functionalization with MTX in combination with B16F10 EXOS was used to promote the accumulation of AuNRs in metastatic lung nodules, with significantly greater amounts of gold in the tumors following EXOS-AuNR-MTX treatment than following only AuNR-MTX treatment, as was determined in vivo and ex vivo by quantitative gold measurements. Remarkably, 5.5% of the injected dose of the AuNRs was recovered at the tumor sites, whereas only 1% of the injected dose usually accumulated in tumors due to the EPR effect, as reported. We further confirmed the preferential accumulation of AuNRs from EXOS-AuNR-MTX rather than from AuNR-MTX in tumor vessels and tumor nodules rather than healthy tissues by histological analysis.
Conclusion: Our approach provides a valuable tool to improve the accumulation of gold nanoparticles in metastatic tumor nodules by combining the natural properties of exosomes to drive the targeting of AuNR-MTX.

Keywords:  drug delivery; exosomes; gold nanorods; metastasis; methotrexate; targeting

DOI:  https://doi.org/10.2147/IJN.S513628
bioRxiv. 2025 May 22. pii: 2025.05.22.655499. [Epub ahead of print]

Endosome transcriptomics reveal trafficking of Cajal bodies into multivesicular bodies.

Jasleen Singh, Justin Krish Williams, Quinn Elliott, Rohit Jhawar, Lucas Ferguson, Kathleen Collins, Randy Schekman.

All eukaryotic cells secrete exosomes, a type of extracellular vesicles (EVs) derived from the endocytic compartments known as multivesicular bodies (MVBs), or late endosomes (LEs). Exosomes contain a diverse range of cargo such as nucleic acids, proteins, lipids and small molecules but whether these contents have a biological function remains an area of intense investigation. Over the last decade, numerous studies have described the transcriptome of exosomes but very little is known about the RNA content of the MVBs, the source compartment for exosome biogenesis. Here we determine the small-RNA transcriptome of highly purified MVBs and report that various classes of nuclear small regulatory RNAs such as small-Cajal body associated RNAs (scaRNAs), small-nucleolar RNAs (snoRNAs) and small-nuclear RNAs (snRNAs) traffic to MVBs. We show that this RNA-trafficking requires the function of ESCRT machinery but is independent of canonical LC3 lipidation mediated selective autophagy. Furthermore, blocking the activity of a PI3K Class 3 enzyme, VPS34, required for recruitment of the ESCRT machinery to the endosome, prevents the turnover of these nuclear RNAs in MVBs. Our results provide a mechanism for targeting nuclear ribonucleoprotein complexes (RNPs), such as Cajal bodies, for degradation and turnover by the cytoplasmic endo-lysosomal pathway.
Significance Statement: Endosomes are cytoplasmic, membrane-bound subcellular organelles that are sites for biogenesis of exosomes, a class of extracellular vesicles, thought to mediate intercellular communication via their packaged cargo such as RNA. Previous studies have focused on the transcriptome of exosomes however very little is known about the identity of RNAs and mechanisms by which they are sorted into endosomes. Here we report a comprehensive endosome transcriptome and provide evidence that several nuclear RNA-protein complexes (RNPs) sort into endosomes, a previously unappreciated phenomenon. We show that this process requires the activity of endosomal sorting complexes and phospholipids characteristic of cellular endocytic compartments. Our study provides a mechanism for recycling and disposal of unwanted nuclear RNPs by the cytoplasmic endolysosomal pathway.

DOI: https://doi.org/10.1101/2025.05.22.655499
Anim Biosci. 2025 Jun 04.

Exosomal small non-coding RNA profiling and the role of piRNA pathway genes in Lumpy skin disease virus-infected bovines.

Anh Duc Truong, Ha Thi Thanh Tran, Thi Hoai Phan, Thi Hao Vu, Nhu Thi Chu, Hieu Minh Nguyen, Linh Phuong Nguyen, Lanh Phan, Chaeeun Kim, Hoang Vu Dang, Yeong Ho Hong.

   Objective: Lumpy skin disease (LSD) is a reemerging viral disease impacting cattle and buffaloes, posing substantial economic risks. However, the expression profile of non-coding RNAs (ncRNAs) in LSD virus (LSDV)-infected bovines has yet to be investigated. In this study, we employed small RNA sequencing (RNA-seq) to assess the expression of various ncRNAs in serum-derived exosomes from LSDV-infected bovines. We particularly focused on the bio-functional activity of piRNAs.
Methods: Cattle were infected with a 106.5 TCID50/mL LSDV Vietnam/HaTinh/CX01 (HT10) strain and ncRNAs expression in the serum of infected cattle was analyzed small RNA-seq.
Results: We identified 426 significantly differentially expressed (DE) piRNAs in serum-derived exosomes from LSDV-infected bovines compared to control groups, with 80 piRNAs being upregulated and 346 piRNA genes downregulated. Pathway analysis of DE piRNAs revealed their involvement in metabolism, cell signaling, and immune response pathways. Additionally, we identified a total of 35,170 tRNAs, 917 snoRNAs, 1,578 snRNAs, 17 Y-RNAs, five scRNAs, ten vault RNAs, 248 sRNAs, 1,064 piRNAs, and 1,011 miRNAs (not shown in this study) expressed in serum-derived exosomes from LSDV-infected bovines. Among these, 15,649 DE tRNAs, 476 DE snoRNAs, 861 DE snRNAs, 11 DE Y-RNAs, three DE scRNAs, three DE vault RNAs, and 134 DE sRNAs were identified when compared to the control group.
Conclusions: Our comprehensive analysis of small RNA-seq data revealed numerous DE ncRNAs in serum-derived exosomes from LSDV-infected bovines compared to controls. We propose that further elucidation and validation of the functions of these ncRNAs may be beneficial for the diagnosis, treatment, and prognosis of LSDV in bovines.

Keywords:  Lumpy skin disease; RNS-seq; bovine; non-coding RNA; piRNA

DOI:  https://doi.org/10.5713/ab.25.0217
Talanta. 2025 May 28. pii: S0039-9140(25)00902-6. [Epub ahead of print]296 128412

Semiquantitative analysis of carbon quantum dot-labeled exosomes based on carrier ampholyte-free paper-based isoelectric focusing.

Chenyu Liu, Haoran Yu, Lingyi Zhang, Weibing Zhang.

  In this paper, a semiquantitative analysis method based on carrier ampholyte-free paper-based isoelectric focusing (CAF-PAD-IEF) was developed for the isolation and detection of carbon quantum dots (CQDs) labeled exosomes. A stable pH gradient was established on the glass fiber paper by the migration of H+ and OH-. Three pH gradients of pH 3-9, 3-7 and 6-9 were established by changing the species and pH of anolytes and catholytes. The pH gradients were evaluated with phycocyanin (PC), ovalbumin and bovine hemoglobin (BHb) as standard proteins, and egg white was used as model sample too. The linear correlation coefficient (R2) of the pH gradient (pH 3-9) reached 0.9966. Exosomes obtained by ultracentrifugation from urine were used as the standard to realize the semiquantitative detection of exosomes. The urine exosomes were labeled with CQDs and then successfully focused based on their isoelectric points (pIs). The exosome concentration was determined semiquantitatively according to the fluorescence intensity of the focused bands. The standard curve was drawn based on the fluorescence intensity peak areas of the focused bands with the R2 value of 0.9881. This method was applied to the determination of exosome concentration in fetal bovine serum (FBS) and concentrated urine with the relative errors of -4.17 % and -8.70 % respectively compared with the values determined by nanoparticle tracking analysis (NTA), showing great potential in quick semiquantitative determination of exosomes in real samples.

Keywords:  Carbon quantum dots; Carrier electrolyte-free; Exosome; Paper-based isoelectric focusing

DOI:  https://doi.org/10.1016/j.talanta.2025.128412