Extracellular vesicle-mediated immune-metabolic crosstalk: research advances in inflammatory regulation and the pathogenesis of metabolic diseases

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Extracellular vesicles (EVs)—lipid bilayer-enclosed nanoparticles secreted by virtually all cell types—have shifted from being viewed as passive cellular byproducts to active signaling nodes orchestrating inter-cellular and inter-organ communication. Yet the field has accumulated faster than it has integrated: hundreds of EV–cargo–phenotype associations exist as isolated edges of a network whose system-level architecture remains poorly defined. Here we propose the vesiculome as an operational framework for that network, resting on three falsifiable axioms: (i) the EV complement of an organism constitutes a network addressable by donor cell × target tissue × cargo class; (ii) cargo composition tracks donor-cell metabolic state in a quantitatively predictable way; and (iii) the integrated balance between pro-inflammatory and pro-resolving vesicle outputs — rather than any single edge — determines the organismal metabolic phenotype. Organized along the chain of EV generation, immune–metabolic interaction, disease mechanism, and translational application, the review synthesizes how this network sustains metabolic homeostasis and how its dysregulation drives metaflammation, the chronic low-grade inflammation underlying obesity, type 2 diabetes mellitus, metabolic dysfunction-associated steatotic liver disease, and atherosclerosis. We dissect two reciprocal arcs of this vesiculome. Polarization-specific EVs from M1/M2 macrophages, Th17 and regulatory T cells, dendritic cells, NK cells, and neutrophils deliver inflammatory or protective cargo to adipose tissue, liver, and pancreas. EVs from adipocytes, hepatocytes, skeletal myocytes, pancreatic β-cells, and intestinal epithelial cells reciprocally reshape the immune microenvironment. Disease arises as a network-level configuration of these arcs rather than as isolated edge failures. We apply a four-tier causality framework to every claim, distinguishing correlational evidence from cargo-depletion and physiological-dose validation. Only miR-155, miR-122, miR-690, and miR-33 currently satisfy the highest tier; most cargoes require systematic experimental escalation before therapeutic translation. We further separate preclinical from clinically validated evidence, and downgrade plant-derived nanovesicles to a methodological cautionary note given non-reproducible cross-kingdom claims. The translational arm evaluates EV-based liquid biopsy biomarkers, native and engineered therapeutic EVs, and mesenchymal stem cell-derived EVs against this framework. We close with a structured catalogue of foundational, causal, and translational knowledge gaps and a priority research agenda built on single-EV multi-omics, in vivo tracking, multi-organ organoid-on-chip platforms, and longitudinal human cohorts.