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

In a review published in Immunity & Inflammation, Prof. Chen-Yu Zhang from the State Key Laboratory of Pharmaceutical Biotechnology at Nanjing University has synthesized two decades of progress in extracellular RNA biology. Their article, titled “EV-encapsulated extracellular microRNAs as orchestrators of systemic communication in immunity and inflammation,” traces the remarkable evolution of circulating microRNAs (miRNAs) from stable biomarkers in biofluids to active orchestrators of long-range immune regulation and inter-organ crosstalk. The review positions EV-encapsulated miRNAs as a sophisticated “molecular postal system” and “hidden language” that coordinates systemic communication in metabolism, tissue repair, and immune homeostasis.

For decades, the prevailing dogma held that RNA is inherently unstable in RNase-rich extracellular environments, rendering it unsuitable for systemic signaling. This view was overturned in 2008 by two independent landmark studies—one from the Zhang laboratory and the other by Mitchell and colleagues—that demonstrated the remarkable stability of specific miRNAs in human blood and their disease-specific signatures. Subsequent research confirmed their ubiquitous yet fluid-specific presence across nearly all human biofluids. The true functional breakthrough, however, came with the discovery that a distinct subset of these miRNAs undergoes selective packaging into extracellular vesicles (EVs). Unlike non-vesicular miRNAs, which primarily serve as passive biomarkers or act locally via surface receptors such as Toll-like receptors (TLR7/8), EV-encapsulated miRNAs are actively sorted, loaded, and delivered, enabling precise long-distance communication between cells, tissues, and organs.

The review details how this “molecular postal system” functions through highly regulated mechanisms: sequence-specific sorting mediated by RNA-binding proteins (such as hnRNPA2B1 recognizing distinctive motifs), ESCRT machinery and lipid-raft pathways, organotropic homing via surface integrins and tetraspanins, and efficient cytosolic cargo release following endocytosis or membrane fusion. In the realm of immunity and inflammation, EV-miRNAs orchestrate sophisticated bidirectional dialogues between the host and “non-self” (pathogens), “aberrant self” (tumors), and the microbiome. They fine-tune innate-adaptive immune integration, macrophage polarization, Treg/Th17 balance, cytokine responses, and even sensitivity to immune checkpoint inhibitors.

The broader implications of these findings are threefold:

(1) Redefining Intercellular Communication in Immunity and Beyond. By integrating selective sorting, directed trafficking, and functional cytosolic delivery, EV-encapsulated miRNAs establish a high-information-density language that links distant organs and immune compartments. This framework elegantly explains classic examples of inter-organ crosstalk, including exercise-induced cardioprotection, adipose-liver metabolic regulation, and tumor-mediated immune evasion.

(2) Bridging Biomarker Discovery and Therapeutic Innovation. While most approved circulating miRNA diagnostics rely on total (predominantly non-vesicular) miRNA profiles, the review underscores the unique translational potential of EV-miRNAs for functional, long-range immune reprogramming. Key clinical-stage examples include the NMPA-approved YiAn^TM miRNA panel and miRNA7^TM 7-miRNA panel for cancer early screening, EV-miRNA signatures for predicting response to PD-1/PD-L1 inhibitors, and engineered EV-based miRNA delivery platforms currently in Phase I/II trials for fibrosis and malignant pleural mesothelioma.

(3) Charting the Path Toward Precision Immunotherapy. The review candidly identifies remaining challenges—such as the incomplete decoding of miRNA sorting codes, endosomal escape mechanisms, and EV heterogeneity—and calls for strict adherence to MISEV2023 guidelines combined with single-vesicle multi-omics approaches. Overcoming these hurdles will pave the way for next-generation EV-based immunodiagnostics and therapeutics, ushering in a new era of precision medicine for cancer and autoimmune diseases.

Reference:

Chen et al. EV-encapsulated extracellular microRNAs as orchestrators of systemic communication in immunity and inflammation. Immunity & Inflammation (2026) 2:26. https://doi.org/10.1007/s44466-026-00042-4

Author contact:

Dr. Chen-Yu Zhang  

State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University  

Email: cyzhang@nju.edu.cn

Author Information:

Jiehao Chen is a PhD student at Nanjing University;

Jing Li is an Associate Professor at Nanjing University;

Xin Yin is a Postdoctoral Fellow at the Affiliated Drum Tower Hospital of Nanjing University Medical School;

Zheng Fu is a Researcher at Nanjing University;

Xi Chen is a Professor at Nanjing University.