RNA immunity: An overlooked antiviral defense in mammals

Conventional immunology holds that the immune system is built primarily upon immune cells and protein effectors such as antibodies and cytokines. While both the rapid-response innate immune system and the highly specific adaptive immune system depend on protein molecules—such as antibodies and cytokines—to recognize and neutralize pathogens, RNA was traditionally seen as a passive intermediary. For many years, its role was believed to be confined within the cell, serving primarily as a transient messenger that helps translate DNA instructions into proteins. It wasn’t until 2008 that extracellular RNA was found to exist in a stable, functional form outside of cells—capable of being actively secreted, traveling between tissues and organs, and regulating gene expression at a distance.

This review consolidates emerging research that elucidates the involvement of extracellular RNAs in the antiviral defense process. It highlights how microRNAs (miRNAs), a class of small non-coding RNAs, can bind viral genomes via base-pairing interactions and inhibit their expression with remarkable specificity—sometimes surpassing the efficiency of classical immune mechanisms. During viral invasion, host-derived small RNAs, plant-derived exogenous RNAs, and even virus-encoded small RNAs have all been shown to modulate different aspects of the infection process, collectively forming a regulatory network the authors describe as “RNA immunity”.

Based on this emerging evidence, the authors propose that RNA immunity represents a distinct and complementary arm of the mammalian immune system—functionally independent of, but synergistic with, traditional protein-based defenses. The review underscores that this overlooked mechanism may reshape our understanding of host-virus interactions and open new avenues for antiviral strategies.

Key highlights of the review include:

(1) RNA immunity enables sequence-specific targeting of viral genomes with high precision and mutation tolerance

Conventional immune recognition largely relies on three-dimensional structural complementarity between protein molecules—for example, the interaction between antibodies and antigens. However, such structural recognition is often vulnerable to point mutations, which are frequent in viral evolution. In contrast, RNA immunity operates through base-pair complementarity, allowing small RNA molecules to selectively bind and silence viral RNA. This sequence-based recognition not only offers higher specificity but also enables multiple binding sites within a single viral gene, making it more difficult for viruses to fully evade detection through single-site mutations. This confers RNA immunity with robust anti-mutation capacity and multi-target synergy, especially valuable in the context of emerging and highly variable viral pathogens. Traditionally, such RNA-based antiviral mechanisms were thought to be restricted to “lower organisms” such as plants and invertebrates, and believed to be lost in mammals during evolution. However, emerging evidence suggests that mammals have not entirely discarded RNA immunity, but have retained and integrated it into their immune repertoire in a more regulated and concealed manner—possibly as an adaptive strategy shaped by co-evolution with viruses.

(2) A decentralized antiviral network independent of specialized immune organs

Unlike classical immune responses, which depend on highly specialized cells such as lymphocytes or macrophages, RNA immunity appears to be widely distributed and cell-autonomous. Nearly all types of somatic cells are capable of synthesizing and releasing functional small RNAs upon viral challenge. These RNAs not only function intracellularly but can also be transferred between cells via extracellular vesicles, facilitating coordinated responses across multiple tissues. This decentralized model resembles a distributed network—akin to a blockchain system—where no single node controls the system, and each unit contributes to a collective response. As a result, RNA immunity is more resilient to systemic failure and more difficult for viruses to completely circumvent. Compared to traditional immune responses, which require complex signaling cascades and mobilization of immune organs, RNA-based defense can be activated more rapidly and locally, providing a crucial window for early control of highly contagious infections.

(3) RNA immune effectors can be endogenously synthesized or acquired from external sources

Endogenous small RNAs with antiviral activity are more abundant in young and healthy individuals, but their levels decline with aging or underlying disease. Interestingly, recent studies have shown that physical exercise can upregulate the expression of antiviral miRNAs, suggesting that RNA immunity is dynamically modulated by physiological conditions. Remarkably, RNA immune effectors are not limited to those produced by the host. Certain dietary plant-derived small RNAs—such as MIR2911 found in honeysuckle decoction—can be absorbed through the gastrointestinal tract, enter the bloodstream, and be delivered to target tissues via extracellular vesicles. Once inside the host, these dietary RNAs can directly suppress viral replication, effectively complementing endogenous RNA defenses. Moreover, individual differences in the absorption efficiency of dietary RNAs appear to be influenced by genetic background, pointing to the future potential for personalized nutritional interventions or RNA-based therapeutics tailored to maximize RNA immunity.

The authors of this work include Zheng Fu, Liang Li, Yanbo Wang, Xin Yin, Xi Chen, Chao Yan, Chen-Yu Zhang of State Key Laboratory of Nanjing Drum Tower Hospital Center of Molecular Diagnostic and Therapy, State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, NJU Advanced Institute of Life Sciences (NAILS), School of Life Sciences, Nanjing University, Nanjing 210023, China; and Dangsheng Li of Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.

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