EV-encapsulated extracellular microRNAs as orchestrators of systemic communication in immunity and inflammation

Abstract The discovery of stable extracellular microRNAs (miRNAs) in biofluids overturned the dogma that RNA is inherently unstable in RNase-rich environments, establishing circulating miRNAs as a cornerstone of liquid biopsy. This review traces their evolution from stability biomarkers to active orchestrators of systemic communication and immune regulation. Encapsulated in extracellular vesicles (EVs), miRNAs undergo selective sorting and targeted delivery, forming the precise molecular postal system of a hidden language that coordinates inter-organ crosstalk in metabolism, tissue repair, and immune homeostasis. In contrast, non-vesicular miRNAs primarily serve as stable biomarkers or act locally via surface receptors such as Toll-like receptors (TLR). EV-associated miRNAs mediate sophisticated bidirectional dialogues between host and “non-self” (pathogens) or “aberrant self” (tumors), revealing the essential function of this hidden language in shaping immune evasion, innate-adaptive integration, and responses to immune checkpoint inhibitors. However, critical gaps in our fluency with this language—particularly in sorting codes, endosomal escape, and carrier heterogeneity—remain. Addressing these challenges through MISEV2023-compliant standardization and single-vesicle multi-omics will enable true mastery. With these advances, extracellular miRNAs are poised to transform precise immunodiagnostics and engineered EV-based immunotherapeutics in cancer and autoimmune diseases.