Extracellular Vesicle-Mediated Local and Systemic Communication in Metabolic Diseases.

Figure 1. Biogenesis and characteristics of extracellular vesicles and non-vesicular extracellular nanoparticles. Extracellular vesicles (EVs) are lipid bilayer-enclosed particles released from cells through distinct biogenesis pathways. Microvesicles and apoptotic bodies are generated by the direct outward budding and fission of the plasma membrane. Exosomes originate as intraluminal vesicles within endosome-derived multivesicular bodies (MVBs); these MVBs subsequently fuse with the plasma membrane to release their vesicular contents into the extracellular space. Migrasomes are generated on the retraction fibers of migrating cells. In parallel, cells also release non-vesicular nanoparticles (NVEPs) lacking a lipid bilayer, such as exomeres and supermeres. EVs transport diverse molecular cargo, including proteins, lipids, nucleic acids, and even mitochondrial components, and can be taken up by the recipient cell via (1) receptor-mediated uptake, (2) direct fusion, (3) macropinocytosis, (4) phagocytosis, (5) endocytosis mediated by caveolae, clathrin, or lipid rafts, and (6) receptor-mediated endocytosis. Upon internalization, most EV cargo is sequestered within endosomes. From there,…

Figure 2. Extracellular vesicle-mediated local and systemic communication in diabetes. The (left) panel illustrates EV-mediated local communication in the diabetic microenvironment, highlighting contributions from T cells, islet-resident macrophages, β-cells, and pancreatic stellate cells. For example, T cell-derived EVs promote both β-cell apoptosis and chemokine expression in β-cells. The (right) panel depicts systemic communication, in which EVs derived from adipocytes, adipose tissue macrophages, hepatocytes, and skeletal muscle regulate β-cell fate and function. The central box outlines the corresponding EV cargo. The text following the arrow or bar indicates the EV-mediated effects on target cells or organs. For example, adipocyte-derived sEVs containing insulinotropic proteins promote insulin secretion but inhibit glucose uptake in β-cells. In the schematic, a solid arrow “→” indicates promotion, while a dashed bar “˧” denotes inhibition. The lines representing EV effects are color-coded according to the corresponding parental cells/tissues. Figures were created with BioRender (https://biorender.com/).

Figure 3. Extracellular vesicle-mediated local and systemic communication in adipose tissue remodeling and obesity. The (left) panel details the local EV-mediated crosstalk within adipose tissue, involving whole adipose tissue, adipocytes, adipose tissue macrophages, adipose-derived stem cells, and adipose endothelial cells. For example, adipocyte tissue-derived EVs are involved in promoting lipid accumulation and M1/M2 polarization in macrophages. The (right) panel summarizes the systemic EV signals originating from pancreatic β-cells, hepatocytes (including lipotoxic hepatocytes), and skeletal muscle, which modulate adipose tissue remodeling and metabolism. The central box outlines the corresponding EV cargo. The text following the arrow or bar indicates the EV-mediated effects on target cells or organs. For example, pancreatic β-cell-derived EVs containing miR-26a were able to inhibit adipocyte hypertrophy and insulin resistance. In this schematic, a solid arrow “→” indicates promotion, whereas a dashed “˧” represents inhibition. The lines representing EV effects are color-coded according to the corresponding parental cells/tissues. Figures were created with BioRender…

Figure 4. Extracellular vesicle-mediated local and systemic communication in hepatic metabolism, local environment, and pathology of MASLD and MASH. The (left) panel depicts the local EV-mediated crosstalk within the liver, involving hepatocyte, hepatic stellate cell (HSC), hepatic macrophage (HM), Kupffer cell (KC), and liver sinusoidal endothelial cell (LSEC). For example, EVs derived from lipotoxic hepatocytes, when delivered to HSCs, promote HSC activation, senescence, proliferation, and mitochondrial dysfunction. The (right) panel summarizes the systemic EV signals originating from pancreatic β-cell, adipose tissue, adipocyte, adipose tissue macrophage, brown adipose tissue, and skeletal muscle, which modulate hepatic glucose and lipid metabolism as well as the pathology of MASLD/MASH. The central box outlines the corresponding EV cargo. The text following the arrow or bar indicates the EV-mediated effects on target cells or organs. For example, pancreatic β-cell-derived EVs containing miR-26a could inhibit liver insulin resistance and lipid accumulation. In the schematic, a solid “→” indicates promotion, while a dashed “˧” denotes inhibition. The lines representing EV effects are…

Figure 5. Schematic illustration of extracellular vesicle-based therapeutic strategies. (a) The onset and progression of diseases can be inhibited by: (1) inhibiting the loading of disease-associated cargo into EVs; (2) inhibiting the secretion of disease-associated EVs; (3) blocking the delivery of disease-associated EVs to recipient cells; (4) suppressing the target signaling pathways of disease-associated EV cargo in recipient cells. (b) EV sources. Parental cells of EVs or EVs can be collected from humans, animals, plants, milk, and bacteria. (c) Isolation and purification of benign EVs. (d) Drug-loaded EVs. After passive or active loading, engineered EVs carrying externally loaded cargo are suitable for delivery to the cell surface, while EVs loaded internally are suitable for cytoplasmic delivery [202]. In panel (a), blue arrows: 4 corresponding steps; in panels (b–d), blue arrows: steps following parental cell collection; white arrows: steps following EV collection. Figures were created with BioRender (https://biorender.com/).