bims-engexo 2025-05-11 papers

Neural Regen Res. 2026 Feb 01. 21(2): 478-490

Exosomes in neurodegenerative diseases: Therapeutic potential and modification methods.

Hongli Chen, Na Li, Yuanhao Cai, Chunyan Ma, Yutong Ye, Xinyu Shi, Jun Guo, Zhibo Han, Yi Liu, Xunbin Wei.

In recent years, exosomes have garnered extensive attention as therapeutic agents and early diagnostic markers in neurodegenerative disease research. Exosomes are small and can effectively cross the blood-brain barrier, allowing them to target deep brain lesions. Recent studies have demonstrated that exosomes derived from different cell types may exert therapeutic effects by regulating the expression of various inflammatory cytokines, mRNAs, and disease-related proteins, thereby halting the progression of neurodegenerative diseases and exhibiting beneficial effects. However, exosomes are composed of lipid bilayer membranes and lack the ability to recognize specific target cells. This limitation can lead to side effects and toxicity when they interact with non-specific cells. Growing evidence suggests that surface-modified exosomes have enhanced targeting capabilities and can be used as targeted drug-delivery vehicles that show promising results in the treatment of neurodegenerative diseases. In this review, we provide an up-to-date overview of existing research aimed at devising approaches to modify exosomes and elucidating their therapeutic potential in neurodegenerative diseases. Our findings indicate that exosomes can efficiently cross the blood-brain barrier to facilitate drug delivery and can also serve as early diagnostic markers for neurodegenerative diseases. We introduce the strategies being used to enhance exosome targeting, including genetic engineering, chemical modifications (both covalent, such as click chemistry and metabolic engineering, and non-covalent, such as polyvalent electrostatic and hydrophobic interactions, ligand-receptor binding, aptamer-based modifications, and the incorporation of CP05-anchored peptides), and nanomaterial modifications. Research into these strategies has confirmed that exosomes have significant therapeutic potential for neurodegenerative diseases. However, several challenges remain in the clinical application of exosomes. Improvements are needed in preparation, characterization, and optimization methods, as well as in reducing the adverse reactions associated with their use. Additionally, the range of applications and the safety of exosomes require further research and evaluation.

Keywords: Alzheimer’s disease; Parkinson’s disease; cell recognition; central nervous system diseases; enhanced targeting; exosome modification; exosome targeting; neurodegenerative disease; stem cell exosomes; stem cell therapy

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00720

Biochem Biophys Res Commun. 2025 Apr 30. pii: S0006-291X(25)00634-5. [Epub ahead of print]768 151920

Exosomes derived from human umbilical cord mesenchymal stem cells can reverse ventricular remodeling and improve long-term cardiac function after acute myocardial infarction.

Renjie Wang, Lulu Liu, Fusheng Han, Qian Ma, Hua He.

BACKGROUND: Acute myocardial infarction (AMI) is the most common ischemic heart disease with high morbidity and high mortality. Although the treatment of AMI is constantly developing, ischemia-reperfusion (I/R) injury remains a complex problem. In recent years, human umbilical cord-derived mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) have been shown to alleviate related damages. However, the long-term effects, safety, and mechanism of action have not yet been fully explored.
METHODS: We constructed human umbilical cord-derived mesenchymal stem cell-derived engineered exosomes. We compared the short-term and long-term protective abilities of engineered exosomes on myocardium during I/R in cardiomyocytes and rat models, and determined their long-term safety. At the same time, key pathways and genes were predicted through exosome sequencing.
RESULTS: hUC-MSC-EXO significantly reduced apoptosis, oxidative stress, and inflammation in both in vitro and in vivo models. In I/R rats, IMTP-EXO demonstrated superior cardioprotective effects, reducing myocardial fibrosis and improving left ventricular function compared to controls. Long-term studies showed enhanced ejection fraction (EF) and fractional shortening (FS) and reduced left ventricular end-diastolic dimensions (LVEDD). Fluorescence imaging revealed higher exosome accumulation in ischemic hearts. Genes related to cardiovascular diseases were obtained through cross-comparison of multiple databases. GO analysis revealed that protein binding was the most highly enriched term. KEGG analysis showed that these genes were primarily involved in apoptosis and the PI3K-Akt signaling pathways. The PPI network showed that TP53, TLR4, EGFR, MAPK3, and GJA1 are central genes of heart I/R injury. GJA1, HMGB1, and PTEN are considered to be key genes by comparing to the comparative toxicogenomic database (CTD).
CONCLUSIONS: This study demonstrates that hUC-MSC-derived exosomes, especially IMTP-EXO, are safe, feasible, and effective for reversing ventricular remodeling and improving cardiac function in rat MI models. GJA1, HMGB1, and PTEN may be the key genes associated with myocardial I/R injury. These findings provide critical insights for translating hUC-MSC-EXO into clinical applications for treating myocardial I/R injuries.

Keywords: Acute myocardial infarction; Exosomes; Mesenchymal stem cell

DOI: https://doi.org/10.1016/j.bbrc.2025.151920

Mater Today Bio. 2025 Jun;32 101790

CBD-conjugated BMP-inhibiting exosomes on collagen scaffold dual-target Achilles tendon repair: Synergistic regeneration and heterotopic ossification prevention.

Yan Xu, Jiaqiang Huang, Yingjie Mai, Zhiyuan Zhang, Siqi Li, Haofeng Lin, Fuxin Wei, Yang Chen.

Tendon injuries in the aging population are often complicated by heterotopic ossification (HO), hindering functional recovery. Exosomes from tendon stem/progenitor cells (TSPCs) promote regeneration but may also induce osteogenesis, contributing to HO. Preconditioning with the BMP inhibitor LDN193189 and modification with collagen-binding peptides (CBD) can enhance the tenogenic potential of exosomes while mitigating osteogenic effects. We evaluated the efficacy of a 3D-printed scaffold loaded with LDN-preconditioned, CBD-modified exosomes (3D-CBD@LDN/Exos) derived from CD26+ TSPCs in promoting Achilles tendon repair and preventing HO in aged Sprague-Dawley rats. CD26+ TSPCs were isolated from rat tendons, and exosomes were collected after LDN treatment and subsequently modified with CBD. A scaffold composed of PLGA and collagen I was fabricated via 3D printing and loaded with the exosomes. Rats (20 months old) with 6-mm Achilles tendon defects were randomly assigned to Control, 3D-Exos, 3D-LDN/Exos, or 3D-CBD@LDN/Exos groups, and tendon regeneration was evaluated at 4 and 12 weeks using histology, ECM quantification, micro-CT, and biomechanical testing. At 12 weeks, the 3D-CBD@LDN/Exos group exhibited near-normal histology, enhanced collagen and sGAG deposition, biomechanical properties comparable to native tendons, and significantly reduced HO, indicating that this dual-targeted strategy holds promise for tendon repair.

Keywords: 3D scaffold; Achilles tendon repair; BMP signaling; Heterotopic ossification; Tissue-engineered exosomes

DOI: https://doi.org/10.1016/j.mtbio.2025.101790

BMC Nephrol. 2025 May 08. 26(1): 230

Role of exosomes in pathogenesis, diagnosis, and treatment of diabetic nephropathy.

Shaimaa I Barr, Eman M Abd El-Azeem, Sahar S Bessa, Tarek M Mohamed.

Diabetic nephropathy (DN) is a serious microvascular complication that can progress to end-stage renal disease, with its prevalence and associated mortality increasing globally. However extensive research, the precise mechanisms underlying DN pathogenesis remain unclear, and the current treatment options for DN are limited to dialysis or renal replacement therapy, although several experimental approaches have shown potential, they remain investigational and lack clinical translation. Exosomes play a pivotal role in disease diagnosis and prognosis. Urinary exosomes, originating from various kidney cells, reflect the kidney's pathological condition and are involved in cell-to-cell communication through autocrine or paracrine signaling; therefore, they could contribute to the pathogenesis of DN and potential therapeutic approaches. Additionally, due to their diverse cargo, which depend on cellular origin and pathological state, exosomes may act as biomarkers for the early prediction of DN. This review presents a comprehensive overview of the latest findings on the role of exosomes in the diagnosis, pathogenesis, and treatment of DN.

Keywords: Biomarker; Diabetic nephropathy; Exosomes; Pathogenesis; Therapeutic strategies

DOI: https://doi.org/10.1186/s12882-025-04120-4

Se Pu. 2025 May;43(5): 518-528

[Isolation and proteomics analysis of cerebrospinal fluid exosome subtypes].

Xiao-Fei Chen, Wei Liu, Wen-Jia Zhang, Yan-Peng Li, Zhi-Hua Wang, Ming-Xia Gao, Xiang-Min Zhang.

Exosomes are small extracellular vesicles 30-200 nm in diameter that contain many bioactive macromolecules, including proteins, lipids, and nucleic acids; consequently, they play important roles in many physiological and pathological processes and are classified into various property-dependent subtypes. Research into exosome heterogeneity helps broaden our understanding of the physiological and pathological mechanisms associated with exosomes. Exosomes exist in many human biological fluids, with those derived from cerebrospinal fluid (CSF) regarded as potential disease biomarkers. Despite this, few studies have focused on their proteomics, and little research into CSF-derived exosome subtypes has been reported. Traumatic brain injury (TBI) is a major public health issue characterized by a large number of patients and complex pathological processes. While a comprehensive understanding of the pathophysiological processes that underpin TBI is essential for developing therapeutic interventions, proteomic studies into CSF-derived exosomes in patients with TBI are limited. Herein, we designed a tandem size-exclusion chromatography protocol for isolating and profiling the proteins of CSF-derived exosome subtypes from patients with TBI using nanoscale liquid chromatography and trapped-ion mobility spectrometry time-of-flight mass spectrometry (nanoLC-TIMS-TOF-MS). We first centrifuged the collected CSF to remove cells and cell debris, after which it was concentrated by ultrafiltration to increase the exosome concentration and remove small proteins and peptides. A mini-size exclusion chromatography (Mini-SEC) column was then used to separate the exosomes from large amounts of interfering proteins, after which high performance liquid-SEC (HPL-SEC) was used to further separate exosomes according to size. The entire extracellular-vesicle-subset separation and purification process takes approximately 1 h for a single CSF sample. Four differently sized exosome subtypes were successfully isolated and are referred to as S1, S2, S3, and S4 in order of descending size. The S1 subtype exhibited the highest exosome purity according to the particle-to-protein ratio. Multiple characterization methods, including transmission electron microscopy (TEM), Western blotting (WB), and nanoparticle tracking analysis (NTA), confirmed that the exosome subtypes had been successfully acquired. NanoLC-TIMS-TOF-MS, combined with database searching were then used to characterize the proteins. A total of 739 proteins were identified, of which 79% and 72% matched all proteins and the top 100 proteins in the Vesiclepedia database, respectively. Moreover, gene ontology analysis revealed that the identified proteins are mainly located in extracellular exosomes, and that the isolated exosome subtypes are closely related to multiple biological processes, including cell signaling, coagulation, and immune responses. Hierarchical cluster analysis revealed that samples from the same exosome subset are grouped first. Principal-component and Pearson's correlation coefficient analyses revealed that the proteins expressed in the CSF-derived exosome subtypes are heterogeneous. Interestingly, the proteins identified in the S1 subtype varied greatly between samples, highlighting the potential applicability of this subtype to formulating precise therapeutic regimens for different patients. We also analyzed the highly expressed proteins in the exosome subtypes, which revealed that the enrichment pathway of the S1 subtype involves Vitamin B12 metabolism and the regulation of protein catabolic processes, while the specific enrichment pathway of the S2 subtype includes binding and ligand uptake by scavenger receptors, heme scavenging from plasma, and an inflammatory response. In contrast, the unique enrichment pathway of the S3 subtype contains complementary and coagulation cascades and acute-phase responses, while that of the S4 subtype includes post-translational protein phosphorylation. Furthermore, STRING-based protein-association analysis predicted multiple interactions among proteins in the various exosome subtypes. In conclusion, the developed tandem size-exclusion chromatography method was used to isolate cerebrospinal fluid exosome subtypes. This study enriches knowledge regarding cerebrospinal fluid exosomes in patients with TBI based on proteomics.

Keywords: cerebrospinal fluid (CSF); exosome subtypes; exosomes; proteomics; traumatic brain injury (TBI)

DOI: https://doi.org/10.3724/SP.J.1123.2024.10014

Diabetes Res Clin Pract. 2025 May 03. pii: S0168-8227(25)00236-0. [Epub ahead of print]224 112222

Regulation of pancreatic β cells by exosomes from different sources.

Yuanyuan Gao, Qi Chen, Zhuoying Wu, Li Yuan.

Diabetes is a chronic metabolic disorder with rising global prevalence, particularly in developed and high-income regions. Central to its pathogenesis is the dysfunction of pancreatic β-cells, alongside impaired glucose and lipid metabolism in peripheral insulin-responsive tissues. Exosomes are nano-sized extracellular vesicles essential for intercellular communication and have emerged as pivotal regulators of metabolic homeostasis. Secreted by virtually all cell types, exosomes encapsulate bioactive cargo that reflects their cellular origin and physiological state, thereby exerting diverse functional effects. Recent evidence highlights the role of exosomes derived from the liver, gut, adipose tissue, skeletal muscle, and mesenchymal stem cells in modulating β-cell proliferation, insulin secretion, and survival. In peripheral tissues exosomes also influence insulin sensitivity by regulating glucose and lipid metabolism, ultimately shaping β-cell responses under hyperglycemic conditions. A more comprehensive understanding of exosome-mediated crosstalk between metabolic organs and pancreatic β-cells could pave the way for the development of exosome-based diagnostic tools and therapeutic strategies aimed at improving early detection, prevention, and treatment of the diabetes.

Keywords: Exosomes; Intercellular Communication; Pancreatic β-Cells; miRNA

DOI: https://doi.org/10.1016/j.diabres.2025.112222

Int J Cancer. 2025 May 02.

Exosomes, autophagy, and cancer: A complex triad.

María Guerra-Andrés, Álvaro F Fernández, Tania Fontanil.

Cancer remains one of the leading causes of death worldwide. Despite remarkable progress in prevention, diagnosis, and therapy, the incidence of certain types of cancer persists, urging the identification of clinically relevant biomarkers and the development of novel therapeutic strategies to improve clinical outcomes and overcome treatment resistance. Exosomes, small extracellular vesicles released by diverse types of cells, have attracted interest in biomedical research due to their potential as carriers for different treatments. Moreover, exosomes play a pivotal role in intercellular communication, modulating various cellular processes. One of those is autophagy, a pro-survival pathway that is essential for human cells. Even though autophagy is traditionally described as a catabolic route, its machinery is intricately involved in various cellular responses, including vesicle formation and secretion. In this regard, the link between autophagy and exosomes is complex, bidirectional, and highly dependent on the cellular context. Interestingly, both processes have been extensively implicated in cancer pathogenesis, highlighting their potential as therapeutic targets. This review updates our understanding of how exosomes can participate in cancer development and progression, with a specific focus on their influence on tumor growth, angiogenesis, and metastasis. Additionally, the interplay between these extracellular vesicles and autophagy is minutely reviewed and discussed, as we hypothesize that this crosstalk may hold valuable clues for biomarker discovery and the development of novel therapeutic strategies.

Keywords: angiogenesis; autophagy; cancer; exosomes; metastasis; tumor

DOI: https://doi.org/10.1002/ijc.35388