A comprehensive review led by Professors Chen-Yu Zhang and Xi Chen at the School of Life Sciences, Nanjing University, China, was published in Volume 2, article number 26 of the journal Immunity & Inflammation on May 27, 2026. The article provides a systematic summary of the discovery, mechanisms, and clinical translation of extracellular vesicle-encapsulated microRNAs (EV-miRNAs), offering a clear theoretical framework for the field and guidance for inflammation and immunology research as well as liquid biopsy applications.
For a long time, RNA was thought to be highly unstable in RNase-rich bodily fluids and incapable of mediating intercellular communication. In 2008, two landmark studies simultaneously demonstrated the stable existence of circulating miRNAs, opening a new era of miRNA as a biomarker for liquid biopsy. Subsequent research revealed that the long-distance, functional signaling ability of miRNAs is due to their encapsulation within EVs. Through active secretion and targeted delivery, EV-miRNAs form a precise communication network, essentially a "hidden language" for organ crosstalk.
The review first distinguishes EV-miRNAs from non-vesicle-associated miRNAs. Non-vesicle miRNAs (primarily bound to Ago2 or high-density lipoprotein) are largely passively released, serving as indicators of cellular states and functioning as stable biomarkers or local Toll-like receptor (TLR) ligands. In contrast, EV-miRNAs undergo active sorting mechanisms that enable stimulus-dependent secretion and cell type-specific delivery. Importantly, EV-miRNAs display organ tropism: surface integrins, ligand-receptor interactions (such as signal regulatory protein α-MCAM), and the phosphatidylserine-Tim4 axis together constitute a "postal code" system that directs EVs to precise target organs. After endocytosis, EV-miRNAs are released into the cytoplasm, exerting long-distance regulatory functions in metabolism, tissue repair, and immune modulation.
The review then explores the bidirectional roles of EV-miRNAs in immune regulation. In pathogen infection, viruses such as Epstein-Barr virus and parasites like Schistosoma use their own EV-miRNAs to suppress host immunity, while the host can secrete miRNAs that directly bind viral RNA (e.g., SARS-CoV-2) to resist infection. In cancer, tumor-derived EV-miRNAs (e.g., miR-214, miR-301a) promote regulatory T cell (Treg) expansion and M2 macrophage polarization. Some EV-miRNAs even activate TLR7/8 (e.g., miR-21, miR-29a) to create a pro-metastatic inflammatory microenvironment. Conversely, EV-miRNAs from natural killer cells and M1 macrophages (e.g., let-7b, miR-186, and miR-16-5p) directly inhibit tumor growth and restore anti-tumor immunity.
The review also summarizes EV-miRNA functions in fine-tuning immune networks: let-7d in Tregs suppresses Th1 responses, miR-155 in T follicular helper cells guides B cell affinity maturation, and EV-miRNAs contribute to trained immunity through metabolic reprogramming, establish self-reinforcing loops of "inflammamiRs" in inflammaging, and mediate gut microbiota-host dialogue.
Despite rapid progress, the field remains faced with significant challenges. The selective sorting rules for miRNA loading into EVs and the mechanisms of endosomal escape remain incompletely understood. In addition, EV heterogeneity, lack of standardized isolation protocols, and difficulties in large-scale production all hinder the clinical translation of EV-miRNAs.
The review outlines future directions. For basic research, single-EV multi-omics, CRISPR gene editing, and AI-driven predictive models are needed to clarify endosomal sorting and escape mechanisms. For clinical translation, strict adherence to MISEV2023 guidelines, establishment of automated GMP-grade isolation platforms, and longitudinal cohort studies to quantify dynamic changes in EV-miRNA expression levels and functions are essential. Looking ahead, “ as these barriers are overcome, EV-miRNAs are poised to become next-generation liquid biopsy biomarkers for predicting responses to immune checkpoint inhibitors and monitoring disease activity in autoimmune conditions, ” the authors predicted, “ engineered EVs delivering miRNA mimics or inhibitors may open new therapeutic avenues for reversing tumor immune suppression and restoring immune tolerance in autoimmunity. ”
Reference
Title of original paper: EV‑encapsulated extracellular microRNAs as orchestrators of systemic communication in immunity and inflammation
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00042-4
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Professor Chen-Yu Zhang from Nanjing University, China
Prof. Chen-Yu Zhang is Dean at the School of Life Sciences, Nanjing University. A recipient of the National High-Level Talent Program and member of the Academic Advisory Committee of the Chinese Academy of Medical Sciences, he pioneered the discovery of functional extracellular RNA and developed related diagnostic and therapeutic technologies. As primary awardee, he has received the Second Prize of the National Natural Science Award, two First Prizes of the Ministry of Education, and the Tan Jiazhen Life Science Award. His research focuses on RNA biomedicine and its engineering applications, as well as the physiology and pathophysiology of endocrine metabolism.
About Professor Xi Chen from Nanjing University, China
Prof. Xi Chen is Director of the Department of Biochemistry and Molecular Biology. He has been supported by the National Science Fund for Distinguished Young Scholars (Type B) and the Jiangsu Provincial Distinguished Young Scientists Fund. He has received the First Prize of the Higher Education Outstanding Scientific Research Output Award (Natural Sciences) and the First Prize of the Technology Invention Award. His research focuses on the biological functions and translational applications of miRNAs.
Funding information
This work was supported by grants from the CAMS Innovation Fund for Medical Sciences (2021-I2M-5-015) and the National Natural Science Foundation of China (32022015 and 31871295).
Immunity & Inflammation
Systematic review
Not applicable
EV‑encapsulated extracellular microRNAs as orchestrators of systemic communication in immunity and inflammation
27-May-2026
The authors declare no competing interests.