bims-evecad 2025-11-30 papers

bims-evecad

Biomed News

on Extracellular vesicles and cardiovascular disease

Issue of 2025–11–30
nine papers selected by
Cliff Dominy

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.
The impact of natural and engineered extracellular vesicles on post-myocardial infarction angiogenesis.
Investigating the mechanisms of small extracellular vesicles in cardiovascular disease using the living myocardial slice platform.
Extracellular Vesicles in Calcific Aortic Valve Disease: From Biomarkers to Drug Delivery Applications.
Cardiac Myofibroblast-Derived Small Extracellular Vesicles Moderate Fibrotic Responses via piRNA-62788/PIWIL2-Mediated SRF Silencing.
Extracellular vesicles in cardiac surgery: unlocking new frontiers in cardioprotection and patient outcomes.
Extracellular Vesicles as Therapeutic Strategy for Ischemic Stroke.
Extracellular vesicle R-Ras is a potential biomarker for human peripheral artery disease.
Nanoparticles Used for the Delivery of RNAi-Based Therapeutics.

Int J Mol Sci. 2025 Nov 15. pii: 11052. [Epub ahead of print]26(22):

Mitochondria-Enriched Extracellular Vesicles (EVs) for Cardiac Bioenergetics Restoration: A Scoping Review of Preclinical Mechanisms and Source-Specific Strategies.

Dhienda C Shahannaz, Tadahisa Sugiura, Taizo Yoshida.

  Mitochondrial dysfunction is a pivotal contributor to cardiac disease progression, making it a critical target in regenerative interventions. Extracellular vesicles (EVs) have recently emerged as powerful mediators of mitochondrial transfer and cardiomyocyte repair. This review highlights recent advancements in EV bioengineering and their applications in cardiac mitochondrial rescue, with a particular focus on EVs derived from induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Drawing upon a growing body of preclinical evidence, we examine the mechanisms of mitochondrial content delivery, EV uptake dynamics, and comparative bioenergetic restoration outcomes across EV sources. Special emphasis is placed on therapeutic outcomes such as adenosine triphosphate (ATP) restoration, reactive oxygen species (ROS) modulation, and improvements in contractility and infarct size. The convergence of mitochondrial biology, stem cell-derived EV platforms, and engineering innovations positions mitochondria-enriched EVs as a promising non-cellular regenerative modality for cardiovascular disease.

Keywords:  cardiac regenerative therapy; cardiomyocyte repair; extracellular vesicles (EVs); heart failure; induced pluripotent stem cell (iPSCs); mitochondrial dysfunction; mitochondrial transfer; regenerative medicine; stem cell-derived exosomes; targeted organelle delivery

DOI:  https://doi.org/10.3390/ijms262211052
Stem Cell Res Ther. 2025 Nov 25. 16(1): 658

The impact of natural and engineered extracellular vesicles on post-myocardial infarction angiogenesis.

Hongzhou Guo, Xiangpeng Kong, Dan Jiang, Jintong Jiang, Yingzhen Bu, Daopeng Wang, Chuan Lu, Xin Zhao.

  Myocardial infarction (MI) causes significant disintegration to the coronary microcirculation. Reperfusion following MI is essential to ensure the viability of cardiac tissue. Angiogenesis after MI involves interactions among various cell types, especially stem cells, which can be exploited as a promising therapeutic approach. Extracellular vesicles (EVs) transfer signaling molecules to adjacent cells in a paracrine manner, thereby playing a vital role in intercellular communication. This review summarizes the angiogenic regulating effects of EVs involved in the MI microenvironment and the therapeutic benefits of exogenous stem cell-derived EVs, and further clarifies the underlying mechanisms. We also discuss advanced methodologies to increase the yield and enhance the biological activities of engineered EVs to address major limitations preventing clinical applications to improve cardiac repair. Finally, highly efficient delivery systems are proposed to improve the efficacy of EVs for treatment of MI.

Keywords:  Angiogenesis; Exosomes; Extracellular vesicles; Myocardial infarction

DOI:  https://doi.org/10.1186/s13287-025-04785-6
Front Cardiovasc Med. 2025 ;12 1697099

Investigating the mechanisms of small extracellular vesicles in cardiovascular disease using the living myocardial slice platform.

Fani Koutentaki, Laura Nicastro, Richard J R Kelwick, Paul S Freemont, Cesare M Terracciano.

  Cardiovascular disease remains the leading cause of death worldwide. Extracellular vesicles (EVs) play a regulatory role in homeostasis, associated with their contribution to cell-cell communication. Recently, it has been confirmed that they also regulate the progression of cardiovascular disease. Specifically, myocardial injury induces an increase in the secretion of small extracellular vesicles (sEVs), both in the cardiac microenvironment and peripheral circulation. Small extracellular vesicles (sEVs) are lipid bilayer particles within the size range of 35-200 nm and are secreted by all cell types. Their high content of bioactive cargo-primarily miRNA-is altered in response to external stimuli, leading to behavioral changes of the recipient cells. In the context of cardiovascular disease, this change leads to acute and long term functional, structural, and biochemical effects on the myocardium. However, the mechanism behind the altered sEVs secretion and their changes in content in the context of cardiovascular disease is yet to be determined. That is partially due to the challenges associated with the isolation of cardiac-derived sEVs, which are essential for the investigation of the mechanisms behind cardiovascular disease progression. Living myocardial slices (LMS) provide an ideal platform for the isolation and investigation of sEVs function in the myocardium. Indeed, LMS not only maintain the cellular complexity and architecture of the native adult myocardium but can also be cultured over days/weeks without significant alterations in cardiac function, making them a reliable model for sEVs isolation and characterization at multiple timepoints. This review aims to summarize recent findings on the effect of sEVs on the onset and progression of cardiovascular disease and to discuss different methods for their isolation from LMSs and the investigation of their functional, structural, and biochemical effect on the myocardium.

Keywords:  cardiovascular disease; cell-cell crosstalk; extracellular vesicles; living myocardial slices; mechanisms; small extracellular vesicles

DOI:  https://doi.org/10.3389/fcvm.2025.1697099
Biomolecules. 2025 Nov 04. pii: 1548. [Epub ahead of print]15(11):

Extracellular Vesicles in Calcific Aortic Valve Disease: From Biomarkers to Drug Delivery Applications.

Alberto Cook-Calvete, Maria Delgado-Marin, Blanca Fernandez-Rodriguez, Carlos Zaragoza, Marta Saura.

  Calcific aortic valve disease (CAVD) is a progressive disorder where molecular alterations occur long before visible calcification, making early biomarkers essential. Extracellular vesicles (EVs) have gained attention as stable biomarkers due to their lipid bilayer, which protects proteins, lipids, and RNAs, ensuring reliable detection even in archived samples. This review highlights the role of EVs as biomarkers and delivery tools in CAVD. EVs derived from valvular endothelial, interstitial, and immune cells carry disease-specific signatures, including osteogenic proteins (BMP-2, Annexins), inflammatory miRNAs (miR-30b, miR-122-5p), and lipid mediators. These reflect early pathogenic processes before macroscopic calcification develops. Their presence in minimally invasive samples such as blood, urine, or saliva facilitates diagnosis, while their stability supports long-term monitoring of disease progression and therapeutic response. Advances in purification and single-EV analysis increase specificity, though challenges remain in standardizing methods and distinguishing CAVD-derived EVs from those in atherosclerosis. Beyond diagnostics, engineered EVs show promise as therapeutic carriers. Delivery of anti-calcific miRNAs or combined RNA cargos has reduced calcification and inflammation in preclinical models. Overall, EVs act as molecular mirrors of CAVD, enabling early diagnosis, risk stratification, and novel therapeutic strategies. Yet, clinical translation requires technical refinement and validation of the disease-specific signatures.

Keywords:  calcific aortic valve disease; cardiovascular calcification; drug delivery; extracellular vesicles; microRNAs; predictive biomarkers; therapeutic targets; valve remodeling

DOI:  https://doi.org/10.3390/biom15111548
J Extracell Vesicles. 2025 Dec;14(12): e70204

Cardiac Myofibroblast-Derived Small Extracellular Vesicles Moderate Fibrotic Responses via piRNA-62788/PIWIL2-Mediated SRF Silencing.

Shichao Li, Shuwen Su, Gaopeng Xian, Shunyi Li, Guoheng Zhong, Liming Wen, Dingli Xu, Qingchun Zeng.

  During fibrogenesis, certain negative feedback loops are elicited to restrain persistent and hyperactive fibrotic responses. Activated fibroblasts have been found to acquire anti-fibrotic phenotypes. However, the specific inhibitory modulators remain largely enigmatic. Thus, the present study aimed to examine the intrinsic autoregulatory mechanisms of fibroblasts. Here, we demonstrated that angiotensin II (AngII)-primed cardiac myofibroblast moderated subsequent profibrotic activation. More importantly, this suppressive action was dependent on small extracellular vesicles (sEVs). Strikingly, small RNA sequencing identified an abundant presence of Piwi-interacting RNAs (piRNAs) in sEVs. In cultured primary cardiac fibroblasts, piRNA-62788 was induced by AngII receptor type 2 (AT2R) stimulation and encapsulated into sEVs. Furthermore, fibrogenic responses were attenuated by piRNA-62788 overexpression, whereas aggravated by piRNA-62788 knockdown. In a mouse model of transverse aortic constriction, either piRNA-62788 agomir or circulating sEVs of patients with heart failure (HF) mitigated adverse cardiac remodelling, while piRNA-62788 inhibitor-containing sEVs accentuated myocardial fibrosis. Mechanistically, piRNA-62788 formed a functional complex with PIWI-like protein 2 (PIWIL2) and bound to the 3' untranslated region (UTR) region of serum response factor (Srf) mRNA transcripts, leading to inhibition of the SRF signalling. Additionally, plasma sEV-derived piRNA-62788 was significantly upregulated in HF patients and negatively correlated with left ventricular ejection fraction. Collectively, we uncovered a protective negative feedback circuit controlled by AngII/AT2R/sEVs axis. Understanding this endogenous anti-fibrotic pathway may hold therapeutic promise in HF.

Keywords:  Piwi‐interacting RNA; angiotensin II; cardiac remodelling; heart failure; serum response factor; small extracellular vesicles

DOI:  https://doi.org/10.1002/jev2.70204
Clin Exp Med. 2025 Nov 25. 26(1): 36

Extracellular vesicles in cardiac surgery: unlocking new frontiers in cardioprotection and patient outcomes.

Alessandro Carrozzo, Ilenia Pia Cappucci, Laura Basile, Elena Tremoli, Barbara Zavan, Letizia Ferroni.

  Cardiac surgery, while life-saving, induces profound physiological stress due to ischemia-reperfusion injury (IRI), systemic inflammation, and endothelial dysfunction, particularly in procedures involving cardiopulmonary bypass. In this complex setting, extracellular vesicles (EVs) have emerged as both biomarkers and potential mediators of cardiovascular injury and repair.This narrative review explores the multifaceted roles of EVs in cardiac surgery, with a focus on coronary artery bypass grafting (CABG) and valve repair or replacement. The review examines the diagnostic and therapeutic implications of circulating EVs and their role in graft patency, perioperative complications, myocardial protection, and vascular remodeling.We summarize current evidence regarding the biogenesis, classification, and engineering of EVs, highlighting their ability to transport bioactive molecules that modulate inflammation, coagulation, and apoptosis. In CABG, EVs have been linked to systemic inflammatory response, myocardial injury, and postoperative cognitive dysfunction. In valvular heart surgery and transcatheter procedures, endothelial- and platelet-derived EVs correlate with endothelial injury, shear stress, and postoperative outcomes. Preclinical studies indicate that stem cell-derived EVs exert cardioprotective effects by reducing apoptosis, promoting angiogenesis, and reprogramming macrophages.EVs represent a promising frontier in cardiac surgery, offering opportunities for risk stratification, real-time monitoring, and novel therapeutic strategies. Further translational research and standardized clinical protocols are needed to integrate EV profiling into perioperative care and to explore the full potential of EV-based therapies in cardioprotection and vascular healing.

Keywords:  Cardioprotection; Coronary artery bypass grafting; Extracellular vesicles; Ischemia–reperfusion injury; Myocardial infarction; Valve repair and replacement

DOI:  https://doi.org/10.1007/s10238-025-01945-z
J Neurochem. 2025 Nov;169(11): e70311

Extracellular Vesicles as Therapeutic Strategy for Ischemic Stroke.

Elisama Araújo da Silva, Júlio César Queiroz Figueiredo, Erik Aranha Rossi, Rachel Santana Cunha, Flávia Santos Sanches, Adne Vitória Rocha de Lima, Erick Correia Loiola, Zaquer Suzana Munhoz Costa-Ferro, Bruno Solano de Freitas Souza.

  Ischemic stroke remains one of the leading causes of death and long-term disability worldwide, with current treatments limited by narrow therapeutic windows and the risk of hemorrhagic transformation. In this context, extracellular vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate inflammation and support neuroregeneration. This review explores recent advances in the application of EVs in ischemic stroke therapy, highlighting their mechanisms of action, including the delivery of neuroprotective molecules such as microRNAs and proteins that promote angiogenesis, neurogenesis, and anti-apoptotic pathways. We summarize findings from preclinical models demonstrating the regenerative potential of EVs derived from mesenchymal stem cells, microglia, neural progenitor cells, and other cell types, as well as advances in bioengineered EVs for targeted delivery. Despite encouraging results, the clinical translation of EV-based therapies faces challenges, including large-scale production, content variability, and targeted delivery efficiency. Future efforts should focus on optimizing EV characterization and manufacturing processes to ensure therapeutic consistency and safety.

Keywords:  extracellular vesicles; immunomodulation; ischemic stroke; neural regeneration; therapeutic strategies

DOI:  https://doi.org/10.1111/jnc.70311
iScience. 2025 Nov 21. 28(11): 113859

Extracellular vesicle R-Ras is a potential biomarker for human peripheral artery disease.

Xiaochao Wei, Mohamed Zaghloul, Shahab Hafezi, Fumihiko Urano, Mohamed A Zayed, Clay F Semenkovich.

  Human peripheral artery disease (PAD) is common and associated with amputation, heart attack, stroke, and death. Treatment options are limited by inadequate understanding of disease pathophysiology and lack of early detection strategies. R-Ras, which regulates vascular integrity, undergoes reversible palmitoylation. In mice, disrupting this process by inhibiting the enzyme acyl-protein thioesterase 1 (APT1) impairs vascular function and promotes experimental PAD. In arteries from humans with PAD we found increased palmitoylated R-Ras, which correlated with age and hypertension. Extracellular vesicles (EVs) isolated from APT1-knockdown endothelial cells were enriched in R-Ras protein, suggesting that palmitoylation promotes incorporation of R-Ras into EVs. PAD patients compared to subjects without PAD had increased serum EV R-Ras content that was positively associated with age, smoking, hypertension, and PAD severity. These findings suggest that altered R-Ras palmitoylation impacts human PAD and that EV-associated R-Ras may be an accessible biomarker for human PAD.

Keywords:  cardiovascular medicine; cell biology

DOI:  https://doi.org/10.1016/j.isci.2025.113859
Pharmaceutics. 2025 Nov 20. pii: 1502. [Epub ahead of print]17(11):

Nanoparticles Used for the Delivery of RNAi-Based Therapeutics.

Tianrui Ren, Liang Ma, Ping Fu, Chuyue Zhang.

  RNA interference (RNAi) offers programmable, sequence-specific silencing via small interfering RNA (siRNA) and microRNA (miRNA), but clinical translation hinges on overcoming instability, immunogenicity, and inefficient endosomal escape. This review synthesizes advances in non-viral nanocarriers-liposomes, polymeric nanoparticles, and extracellular vesicles (EVs)-that stabilize nucleic acids, tune biodistribution, and enable organ- and cell-selective delivery. We highlight design levers that now define the field: ligand-guided targeting, stimuli-responsive release, biomimicry and endogenous carriers, and rational co-delivery with small molecules. Across major disease areas-cancer and cardiovascular, respiratory, and urological disorders-these platforms achieve tissue-selective uptake (e.g., macrophages, endothelium, and myocardium), traverse physiological barriers (including the blood-brain barrier and fibrotic stroma), and remodel hostile microenvironments or immune programs to enhance efficacy while maintaining favorable safety profiles. Early clinical studies reflect this diversity, spanning targeted nanoparticles, local drug depots, exosome and cellular carriers, and inhaled formulations, e.g., and converge on core phase-I endpoints (safety, maximum tolerated dose, pharmacokinetics/pharmacodynamics, and early activity). Looking ahead, priorities include good manufacturing practice scale, consistent manufacture-especially for EVs; more efficient loading and cargo control; improved endosomal escape and biodistribution; and rigorous, long-term safety evaluation with standardized, head-to-head benchmarking. Emerging directions such as in vivo EVs biogenesis, theragnostic integration, and data-driven formulation discovery are poised to accelerate translation. Collectively, nanoparticle-enabled RNAi has matured into a versatile, clinically relevant toolkit for precise gene silencing, positioning the field to deliver next-generation therapies across diverse indications.

Keywords:  exosomes; liposomes; miRNA; polymeric nanoparticles; siRNA

DOI:  https://doi.org/10.3390/pharmaceutics17111502