Heterogeneity and Clinical Translation of Cardiac-Derived Extracellular Vesicles in Heart Failure: From Mechanisms to Precision Therapeutics

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  Fig. 1.. Biogenesis, molecular composition, and regulatory mechanisms of EVs. EVs are membrane-bound nanoparticles secreted by cells, mainly categorized into exosomes, microvesicles (MVs), and apoptotic bodies according to their distinct biogenesis pathways. Specifically, exosomes form through the endosomal system, evolving from early endosomes to multivesicular bodies; MVs are generated by direct budding from the plasma membrane; and apoptotic bodies are produced in the late stages of apoptosis. Additionally, EVs can be transported between cells and carry core biomolecular components such as proteins, lipids, and nucleic acids. EVs, extracellular vesicles; ILVs, intraluminal vesicles; ESCRT, endosomal sorting complex required for transport; ALIX, ALG-2 interacting protein X; Vps4, vacuolar protein sorting 4; MVB, multivesicular body; v-SNARE, vesicle-soluble N-ethylmaleimide-sensitive factor attachment protein receptor; HSP70, heat shock protein 70; Hsc70, heat shock cognate 70; TSG, tumor susceptibility gene; CD9, cluster of differentiation 9; CD81, cluster of differentiation 81; CD63, cluster of differentiation 63; ARF1, ADP-ribosylation factor 1; ARF6, ADP-ribosylation factor 6.…

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  Fig. 2.. Bipartite functional roles of EVs from cardiomyocyte, fibroblast, endothelial, and immune cells in heart failure. EVs derived from specific cell types exert critical yet opposing functions in the progression of heart failure. This diagram summarizes the pathogenic and protective roles of vesicles released from four distinct cell sources, which are denoted by different background colors; areas sharing the same color represent the dual functions of vesicles originating from an identical cell type. (A–D) The upper section illustrates the pathological mechanisms through which these vesicles promote the initiation and progression of heart failure by targeting downstream signaling pathways. In contrast, the lower section demonstrates the protective effects mediated by extracellular vesicles, which attenuate heart failure through diverse molecular mechanisms. Akt, protein kinase B; CaMK2α, calcium/calmodulin-dependent protein kinase IIα; CF, cardiac fibroblast; CCL7, chemokine ligand 7; CMs, cardiomyocytes; EC, endothelial cell; cHF, chronic heart failure; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NOS, nitric oxide synthase; Nrf2, nuclear factor…

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  Fig. 3.. The separation, characterization, and large-scale application of EVs. The isolation and purification of EVs are first achieved through ultracentrifugation and ultrafiltration techniques, followed by characteristic analysis using Raman spectroscopy and transmission electron microscopy. Through direct loading or genetic engineering approaches for subsequent improvements, these vesicles show promise as an effective therapeutic approach for heart failure treatment, paving the way for their clinical application in the future. Created in BioRender (https://www.biorender.com/).