bims-evecad 2026-09-06 papers

bims-evecad

Biomed News

on Extracellular vesicles and cardiovascular disease

Issue of 2026–09–06
eight papers selected by
Cliff Dominy

Extracellular Vesicles in the Heart-Organ Axis: From Inter-Organ Communication to Precision Nanomedicine for Heart Diseases.
ALY688 Protects Against Myocardial Ischemia-Reperfusion Injury via Direct Effects and Rab8a-Dependent Extracellular Vesicles.
From Pathogenesis to Therapy: Extracellular Vesicles Orchestrate Cellular Crosstalk in Acetaminophen Hepatotoxicity.
Mesenchymal Stromal Cell Therapy in Cardiovascular Disease: Reconsidering Clinical Inconsistency Through the Mechanism-Endpoint Relationship.
Mesenchymal stem cell-derived small extracellular vesicles alleviate LPS-induced myocardial injury via the microRNA-23a-3p/BNIP3L pathway.
CD22+-apoptotic vesicles from cardiac fibroblasts provide endogenous cardioprotection against myocardial ischemia-reperfusion injury.
Aerobic Exercise Reduces Macrophage Inflammation and Lipid Accumulation in Atherosclerosis via Extracellular Vesicle-miR-203a-3p and miR-133b-3p.
Plasma Extracellular Vesicle Profiles After Heart Transplantation are Associated With the Type of Allograft Rejection.

Int J Nanomedicine. 2026 ;21 630176

Extracellular Vesicles in the Heart-Organ Axis: From Inter-Organ Communication to Precision Nanomedicine for Heart Diseases.

Shengwen Yang, Jianshi Du, Miao Hao.

   Background: Heart diseases, including myocardial infarction and heart failure, remain the leading causes of morbidity and mortality worldwide, underscoring an urgent need for innovative diagnostic and therapeutic strategies. In recent years, extracellular vesicles (EVs) have emerged as critical mediators of intercellular communication due to their nanoscale structure, intrinsic bioactivity, and ability to transport diverse molecular cargoes. Increasing evidence demonstrates that EVs are broadly distributed across tissues and organs, where they orchestrate complex inter-organ communication networks. However, the mechanisms by which EV-mediated heart-organ crosstalk regulates cardiovascular disease progression and repair remain incompletely understood. Importantly, EVs are not only endogenous regulators of disease progression but also promising nanocarriers for targeted therapeutic delivery. However, translational challenges remain, particularly in achieving efficient and specific delivery to cardiac tissue following systemic administration. Limited targeting specificity, rapid clearance, insufficient cardiac retention, and EV heterogeneity hinder clinical application, highlighting the need for advanced engineering strategies.
Methods: This review followed a systematic literature retrieval framework and searched PubMed, Web of Science, Scopus, and Embase databases from inception to January 2026 using keywords related to EVs, cardiovascular diseases, and interorgan communication. ClinicalTrials.gov was also searched to evaluate the translational progress of EV-based cardiovascular studies.
Results: The reviewed evidence demonstrates that EVs mediate bidirectional communication between the heart and peripheral organs, including brain, gut, liver, kidney, lung, skeletal muscle, bone marrow, spleen, and adipose tissue. Heart- and organ-derived EVs regulate inflammation, metabolism, vascular function, and remodeling through cargo transfer. Stem cell-derived and engineered EVs hold potential for myocardial repair, angiogenesis, immune modulation, and cardiovascular therapy.
Conclusion: EV-mediated heart-organ communication represents an active regulatory mechanism rather than a passive consequence of cardiac injury. Understanding and engineering this network may provide a paradigm for developing precision nanomedicine strategies that target cardiovascular diseases as systemic disorders.

Keywords:  bioengineering; drug delivery; extracellular vesicles; heart diseases; nanocarriers; targeted therapy

DOI:  https://doi.org/10.2147/IJN.S630176
J Extracell Vesicles. 2026 Sep;15(9): e70357

ALY688 Protects Against Myocardial Ischemia-Reperfusion Injury via Direct Effects and Rab8a-Dependent Extracellular Vesicles.

Hye Kyoung Sung, Jialing Tang, Yubin Lei, Khang Nguyen, Eddie Tam, Jun Wu, Ren-Ke Li, Vincent Richard, Christoph H Borchers, Lina Antounians, Dylan Burger, Augusto Zani, Gary Sweeney.

  Despite advances in percutaneous coronary intervention, ischemia-reperfusion (IR) injury remains a major cause of morbidity and mortality. Adiponectin confers broad cardioprotective effects, motivating the development of adiponectin receptor agonists. Here, we investigated the cardioprotective efficacy and mechanisms of ALY688, a synthetic adiponectin receptor agonist peptide, in myocardial IR injury. In a clinically translatable rat IR model, intravenous administration of ALY688 during ischemia together with subcutaneous dosing that continued for 28 days reduced troponin-I levels, cardiomyocyte death, and infarct size, while preserving cardiac function. ALY688 restored autophagic flux, mitigated reactive oxygen species accumulation, and suppressed apoptosis in both IR hearts and hypoxia-reoxygenation (HR)-treated cardiomyocytes. Proteomic profiling revealed that Rab8a, downregulated by IR, was maintained with ALY688 treatment. Notably, ALY688 increased extracellular vesicle (EV) abundance in myocardium and plasma, and EVs from treated animals displayed distinct proteomic signatures enriched in glycolytic and oxidative stress-related proteins. These EVs conferred protection against HR-induced injury in H9c2 and human iPSC-derived cardiomyocytes. CRISPR-mediated Rab8a knockout impaired ALY688-induced EV biogenesis and attenuated the cytoprotective effects of these EVs. Collectively, these findings identify ALY688 as a promising therapeutic that mitigates IR injury via both direct myocardial protection and Rab8a-dependent EV-mediated cardioprotective signalling.

Keywords:  Rab8a; adiponectin; cardioprotective; extracellular vesicle; ischemia reperfusion injury; proteomics; translational

DOI:  https://doi.org/10.1002/jev2.70357
Eur J Pharmacol. 2026 Sep 03. pii: S0014-2999(26)00789-2. [Epub ahead of print] 179307

From Pathogenesis to Therapy: Extracellular Vesicles Orchestrate Cellular Crosstalk in Acetaminophen Hepatotoxicity.

Ankit P Laddha, Carolina Ghanem, Josè E Manautou.

  Drug-induced liver injury (DILI) is a major cause of acute liver failure, with acetaminophen (APAP) overdose representing the leading cause of intrinsic hepatotoxicity worldwide. Although the mechanisms of APAP-induced liver injury have been extensively characterized, recent evidence highlights a critical role for extracellular vesicles (EVs) in mediating intercellular communication during hepatic stress and injury. EVs are lipid bilayer-enclosed vesicles released by hepatocytes and non-parenchymal liver cells under physiological and pathological conditions, carrying diverse bioactive cargo, including microRNAs, mRNAs, proteins, and mitochondrial components. Following APAP exposure, EV release is rapidly increased, often preceding overt hepatocellular necrosis and elevations in conventional biomarkers such as alanine aminotransferase (ALT). EVs actively contribute to the progression of liver injury by transferring stress signals that promote oxidative stress, activate c-Jun N-terminal kinase (JNK) signaling, and stimulate innate immune responses, including neutrophil recruitment and cGAS-STING-mediated inflammation. EV-associated cargo, particularly liver-specific microRNAs such as miR-122, demonstrates greater stability and diagnostic sensitivity than traditional compared serum biomarkers, supporting its utility as an early and reliable biomarker of hepatocellular injury. Beyond their diagnostic potential, EVs also exhibit therapeutic potential. Mesenchymal stromal cell-derived EVs have been shown to attenuate APAP-induced liver injury by delivering regulatory microRNAs, such as miR-186-5p, which suppresses chemokine signaling and reduces inflammatory cell infiltration. Collectively, EV function as dynamic mediators of liver injury, serving as biomarkers and intercellular communicators, while also showing potential as therapeutic agents. A better understanding of EV biology may facilitate the development of novel diagnostic and therapeutic strategies for APAP-induced liver injury.

Keywords:  APAP; Exosomes; Extracellular Vesicles; Liver

DOI:  https://doi.org/10.1016/j.ejphar.2026.179307
Rev Cardiovasc Med. 2026 Aug;27(8): 52521

Mesenchymal Stromal Cell Therapy in Cardiovascular Disease: Reconsidering Clinical Inconsistency Through the Mechanism-Endpoint Relationship.

Luca Bonanni, Nicola Ferri.

  Mesenchymal stromal cell (MSC) therapy has been investigated for more than two decades as a regenerative approach in cardiovascular disease. Preclinical studies have shown reproducible biological activity; however, clinical translation has been less convincing. Trials in acute myocardial infarction (AMI) and heart failure (HF) have established feasibility and an acceptable safety profile; however, effects on functional and imaging parameters remain modest, and a consistent impact on mortality, hospitalization, and other hard clinical outcomes has not been demonstrated.

Keywords:  clinical trials as topic; endpoint determination; extracellular vesicles; heart failure; immunomodulation; mesenchymal stromal cells; myocardial infarction; paracrine communication; regenerative medicine; translational research

DOI:  https://doi.org/10.31083/RCM52521
Immunobiology. 2026 Aug 26. pii: S0171-2985(26)00081-1. [Epub ahead of print]231(5): 153235

Mesenchymal stem cell-derived small extracellular vesicles alleviate LPS-induced myocardial injury via the microRNA-23a-3p/BNIP3L pathway.

Yan Meng, Yayun Pan, Panpan Duan, Hui Ji, Chuan Peng, Zhijia Zhao, Liang Chen, Jiankui Du, Tao Yang.

  Sepsis-induced myocardial injury is a critical condition with limited therapeutic options. This study investigates the therapeutic potential of mesenchymal stem cell (MSC)-derived small extracellular vesicles (MEx) in lipopolysaccharide (LPS)-induced myocardial injury in rat model and explores the underlying molecular mechanisms. We established a sepsis model using LPS and treated it with Mex, which were isolated and loaded with microRNA-23a-3p mimics (MEx-miR-23a-3p). Our findings demonstrate that MEx-miR-23a-3p significantly reduces LPS-induced secretion of B-type natriuretic peptide (BNP), cardiac troponin T (cTnT), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in H9C2 cells and rat serum. Furthermore, MEx-miR-23a-3p attenuates LPS-mediated proliferation impairment, apoptosis, and fibrosis in cardiomyocytes, and enhances migration and tube formation capacity in LPS-injured rat vascular endothelial cells. Notably, the protective role of MEx-miR-23a-3p against LPS-induced cardiomyocyte dysfunction was abolished upon pretreatment with GW4869, an inhibitor of exosome biogenesis and release. Mechanistically, miR-23a-3p directly binds to the 3' untranslated region of BNIP3L mRNA, downregulating its expression. Silencing BNIP3L mimics these protective effects by reducing LPS-induced cardiomyocyte apoptosis. These results suggest that MEx may attenuate myocardial injury, inflammation, and apoptosis in septic rats, possibly through MEx-mediated delivery of miR-23a-3p and modulation of the BNIP3L signaling axis. These results provide preliminary evidence supporting the therapeutic potential of MEx as a candidate intervention for sepsis-induced cardiomyopathy.

Keywords:  BNIP3L; Cardiomyocyte injury; Exosomes; MEx; Sepsis; miR-23a-3p

DOI:  https://doi.org/10.1016/j.imbio.2026.153235
Sci China Life Sci. 2026 Aug 26.

CD22+-apoptotic vesicles from cardiac fibroblasts provide endogenous cardioprotection against myocardial ischemia-reperfusion injury.

Chan Zhang, Hao Hao, Nan Mu, Yishi Wang, Yin Yue, Lu Yu, Heng Ma.

  Apoptotic vesicles (ApoVs) facilitate intercellular communication. Cardiac fibroblasts (CFbs) undergo apoptosis during myocardial ischemia-reperfusion (MI/R), but their ApoVs' role in cardiomyocyte survival is unknown. Here, CFbs-ApoVs were isolated from fibroblast conditioned medium (FCM). Transmission electron microscopy, nanoparticle tracking analysis, and protein blotting were used to characterize the properties of CFbs-ApoVs. Bioinformatics screening and experimental validation identified the molecular markers of CFbs-ApoVs. Enriched CFbs-ApoVs were explored in their effects and mechanisms on cardiomyocytes in vitro and in vivo. This study identified and characterized the apoptotic CFbs-derived ApoVs subtypes: CD22+-CFbs-ApoVs. The results showed that CD22+-CFbs-ApoVs were efficiently homed to cardiomyocytes. Mechanistically, miR-1246, which is enriched in CD22+-CFbs-ApoVs, effectively inhibits p53 protein expression and the translocation of p53 from the nucleus to mitochondria in MI/R-injured cardiomyocytes, rescues mitochondrial damage, and suppresses cardiomyocyte apoptosis. Overexpression of miR-1246 or inhibition of p53 enhanced the protective effect of CD22+-CFbs-ApoVs on injured cardiomyocytes. We found that CD22+-CFbs-ApoVs are effective endogenous cardioprotective vectors that can target cardiomyocytes for fusion, and we also revealed the dual inhibitory effect on p53 mediated by miR-1246. This study revealed a previously unidentified cell-to-cell communication mechanism of apoptotic CFbs that serves to promote cardiomyocyte survival during MI/R, and it also implies the potential use of ApoVs for combating MI/R injury.

Keywords:  apoptotic vesicles; intercellular communication; mitochondrial translocation; myocardial ischemic reperfusion injury; p53

DOI:  https://doi.org/10.1007/s11427-025-3251-7
Am J Pathol. 2026 Sep 02. pii: S0002-9440(26)00253-1. [Epub ahead of print]

Aerobic Exercise Reduces Macrophage Inflammation and Lipid Accumulation in Atherosclerosis via Extracellular Vesicle-miR-203a-3p and miR-133b-3p.

Ying Wang, Houbin Chu, Yuxiang Liu, Chao Yang, Xinxin Xu, Chuanrong Zhao, Guixue Wang, Guohua Song.

  Aerobic exercise reduces cardiovascular disease risk, with atherosclerosis being a primary contributor. While circulating extracellular vesicles (EVs) mediate intercellular communication, their role in this process remains unclear. This study aimed to investigate the role of aerobic exercise-derived circulating EVs in mitigating macrophage inflammation and lipid accumulation in an atherosclerotic model. Circulating EVs were isolated from the plasma of exercise-trained and sedentary mice. miRNA profiling of EVs was performed using miRNA arrays and quantitative real-time PCR. Aortic atherosclerosis was assessed by Oil Red O staining, immunofluorescence, and ELISA. Functional validation of EV effects was carried out through EVs labeling, cell transfection, luciferase reporter assays, and flow cytometry. Aerobic exercise slowed the progression of atherosclerosis and altered the miRNA profile of circulating EVs, notably increasing miR-203a-3p and miR-133b-3p expression. EVs from exercise-trained mice inhibited macrophage-driven inflammation and lipid accumulation in vitro and in vivo. Treatment with miR-203a-3p and miR-133b-3p mimics reproduced the anti-atherosclerotic effects, while inhibitors of these miRNAs reversed the effects. Mechanistically, miR-203a-3p and miR-133b-3p reduced macrophage inflammation and lipid accumulation by targeting Tlr4 and Insr, respectively, thereby suppressing NF-κB/NLRP3 signaling. Notably, the increased expression of miR-203a-3p and miR-133b-3p was primarily derived from skeletal muscle. These findings highlight a novel mechanism linking aerobic exercise to atherosclerosis via EV-miRNAs, proposing potential therapeutic strategies for atherosclerosis based on exercise-induced circulating EVs-miR-203a-3p and miR-133b-3p.

Keywords:  Aerobic exercise; Atherosclerosis; Extracellular vesicles; Macrophage; MicroRNA

DOI:  https://doi.org/10.1016/j.ajpath.2026.07.015
Front Biosci (Landmark Ed). 2026 Aug 03. 31(8): 50478

Plasma Extracellular Vesicle Profiles After Heart Transplantation are Associated With the Type of Allograft Rejection.

Arthur Aquino, Lubov Korneva, Maria Osipova, Maria Bortsova, Maria Simonenko, Darina Sambur, Ivan Golovkin, Igor Kudryavtsev, Ekaterina Zaikova, Anna Kostareva, Olga Kalinina, Petr Fedotov, Alexey Golovkin.

   BACKGROUND: Heart transplantation (HT) remains the primary treatment for end-stage heart failure, but graft rejection-including acute cellular rejection (ACR), antibody-mediated rejection (AMR), and chronic rejection such as cardiac allograft vasculopathy (CAV)-significantly impacts long-term patient outcomes. This study investigates the role of circulating plasma extracellular vesicle profiles as potential biomarkers for distinguishing between different rejection types following HT.
METHODS: We enrolled 85 HT patients with post-transplant follow-up ranging from 2 to 140 months. The cohort included patients diagnosed with AMR (n = 23), ACR (n = 11), CAV (n = 20), and those without rejection (R0, n = 31). Extracellular vesicle profiles were analyzed using the MACSPlex Exosome Kit, and associated cytokine profiles were assessed using the MILLIPLEX Human Cytokine Panel A. Statistical analysis involved the Kruskal Wallis test followed by Dunn's post-hoc test for multiple comparisons and discriminant analysis.
RESULTS: Circulating plasma extracellular vesicle profiles demonstrated significant differences across post-transplantation time strata and varied according to the type of transplant rejection. During the first year post-HT, the main discriminant factors were extracellular vesicles (EVs) characterized by tetraspanins (CD9+, CD63+) and platelet markers (CD62P+, CD42a+). Five years post-transplantation, significant differences emerged in patients with AMR and ACR (both compared to each other and to the CAV/R0 groups). This difference corresponded with an increase in EV markers associated with immune cell activity (CD3+, CD4+, CD49e+, CD86+, CD20+, CD14+, CD209+, CD1c+, CD29+). Levels of prominent EV subpopulations correlated with IL‑22 in CAV patients, whereas in AMR patients, they correlated with IL‑17 and IL‑25.
CONCLUSIONS: These findings support the hypothesis that extracellular vesicles may participate in both direct and indirect antigen presentation and in the regulation of immune responses leading to allograft rejection after HT. Plasma extracellular vesicle profiles hold promise as non-invasive biomarkers for monitoring and differentiating rejection types in heart transplant recipients.

Keywords:  allografts; biomarkers; exosomes; extracellular vesicles; graft rejection; heart failure; heart transplantation; tetraspanins

DOI:  https://doi.org/10.31083/FBL50478