Metabolic dysfunction-associated steatotic liver disease (MASLD) is a multisystem disorder driven by dysregulated inter-organ communication. The liver integrates signals from adipose tissue, skeletal muscle, gut, and pancreas. Conventional frameworks focused on soluble factors, but extracellular vesicle (EV)-encapsulated microRNAs (miRNAs) are now identified as critical epigenetic mediators. This review systematically explores how EV-encapsulated miRNAs mediate MASLD pathogenesis and metabolic restoration across four core regulatory axes. In the adipose-liver axis, obesity-impaired delivery of miR-141-3p induces hepatic insulin resistance via disrupting the phosphatase and tensin homolog (PTEN)/AKT serine/threonine kinase (AKT) pathway, while pathogenic exosomal miR-122-3p drives de novo lipogenesis by suppressing hepatic fibroblast growth factor receptor 4 (FGFR4); conversely, exercise-upregulated miR-324 exerts hepatoprotective effects by inhibiting Rho-associated coiled-coil-containing protein kinase 1 (ROCK1) signaling. In the muscle-liver axis, high-intensity interval training stimulates muscle secretion of EVs enriched with miR-133b, which suppresses Forkhead box protein O1 (FoxO1)-mediated hepatic gluconeogenesis to improve systemic glycemic control; remote ischemic conditioning also triggers muscle-derived miR-181d-5p to alleviate steatohepatitis via targeting NR4A3. In the gut-liver axis, dysbiosis-associated bacterial EVs breach the gut barrier to drive hepatic inflammation and lipid metabolic abnormalities, while commensal bacterial EVs exert homeostatic protective effects. In the pancreas-liver axis, dysregulated miRNA cargo in β-cell-derived EVs disrupts hepatic glucolipid metabolism, with the miR-802-5p-Psmd2 axis acting as an early pathogenic trigger. Furthermore, this review highlights the diagnostic potential of circulating EV-miRNA panels (represented by the plasma miR-122/miR-34a ratio) as precise non-invasive liquid biopsies for MASLD staging and fibrosis assessment, and discusses the therapeutic promise of engineered EVs (e.g., 223/F-EVs) that simultaneously target steatosis, sterile inflammation and fibrosis. By framing MASLD as a disorder of disrupted inter-organ crosstalk, we highlight EV-miRNA regulatory networks as novel tractable targets in precision metabolic medicine.

Exosomes are nanosized vesicles secreted by cells. By transporting cargo such as proteins, RNAs, and particularly miRNAs, they mediate intercellular and intertissue communication and play important roles in the pathogenesis of multiple diseases. Accordingly, the targeted inhibition of exosomal miRNAs has been explored as a therapeutic approach and has shown some therapeutic potential. However, this approach has considerable limitations. Some researchers have begun to elucidate the mechanisms underlying exosomal miRNA sorting. Based on an analysis of exosomal miRNA-sorting mechanisms, we classify exosomal miRNA sorting into two categories: constitutive sorting, which reflects a cell’s intrinsic, stimulus-independent miRNA-packaging preferences, and adaptive sorting, which is dynamically reconfigured in response to physiological or pathological stimuli. Crucially, both categories share a defining feature: abundance independence, meaning that the exosomal enrichment of a given miRNA is decoupled from its intracellular expression level. This classification reveals a striking gap: although the molecular mechanisms of constitutive sorting have been partially elucidated, those governing adaptive sorting remain almost entirely unknown, making adaptive sorting the most pressing frontier in the field. We hope this classification framework will guide future mechanistic studies more precisely, particularly toward the largely uncharted area of adaptive sorting, and ultimately deepen our understanding of disease pathogenesis and open new avenues for more targeted therapeutic strategies.