RNA immunity: A silent defender against viruses in mammals

Mammalian immunity has long been thought to rely solely on proteins and specialized immune cells. However, a newly proposed concept—RNA immunity—is reshaping this perspective. In a recent publication in Science Bulletin, the research team from Nanjing University presents that small RNA molecules play a direct and specific role in fighting viral infections in mammals, acting alongside and independent of conventional immune responses. In contrast to the protein-based innate and adaptive immune systems, which depend on pattern recognition receptors, antibodies, and immune memory, RNA immunity relies on the base-pairing precision of small RNA fragments, such as microRNAs (miRNAs), to recognize and suppress viral genetic material.  While such systems are well-documented in lower species, the new review challenges the notion that mammals have abandoned RNA-based antiviral mechanisms. The authors compile extensive experimental and computational findings indicating that both endogenous RNA molecules produced by human cells and exogenous small RNAs derived from plants can bind directly to viral RNA sequences and inhibit viral replication.

Key highlights of the review include:

(1) Dual Layer RNA Defenses: Endogenous and Dietary Small RNAs Against Viruses

Evidence for the RNA immunity system has emerged abundantly from recent studies on SARS-CoV-2. Endogenous human miRNAs have been shown to target and suppress the expression of viral genes, with measurable effects observed in both cell culture systems and clinical patient samples. These miRNAs are produced intrinsically by host cells and can be rapidly mobilized in response to viral infection, enabling a broad-spectrum and immediate antiviral response. In this sense, endogenous RNA immunity closely parallels innate immunity—it is pre-existing, fast-acting, and capable of recognizing a wide array of viral targets through sequence complementarity. Exogenous small RNAs, such as plant-derived MIR2911 from honeysuckle, can enter the bloodstream after oral intake, travel via extracellular vesicles, and directly suppress viral gene expression. Clinical studies have shown that MIR2911 lowers SARS-CoV-2 viral load in patients. This form of RNA-based defense, acquired from external sources, resembles adaptive immunity and complements the endogenous RNA system, together forming a multilayered antiviral network with promising therapeutic potential.

(2)Decentralized Defense: A Cellular Blockchain Against Infection

Unlike the protein-dominated arms of immunity, RNA immunity is not restricted to immune cells. Much like the decentralized structure of blockchain technology underlying Bitcoin, where every node in the network contributes to verifying and securing transactions, every mammalian cell has the capacity to generate and release small RNAs that participate in antiviral defense—either directly or by sending them out in extracellular vesicles. This distributed and autonomous response system ensures that immunity is not solely reliant on a central authority like specialized immune organs or cells, but rather mobilizes the entire cellular network to recognize and neutralize viral threats. This architectural flexibility allows RNA immunity to be faster, more resilient to system failures, and capable of scaling up quickly—offering strategic advantages in the early stages of infection: it can act earlier than traditional immunity, respond more flexibly to viral mutations, and minimize off-target effects thanks to the specificity of nucleotide pairing.

(3) The Viral Counterstrike: A Molecular Arms Race Unfolding

Furthermore, the dynamic nature of RNA immunity is underscored by the fact that some RNA viruses have evolved their own small RNAs and suppressor proteins to evade or inhibit host RNA-based defenses, highlighting a coevolutionary arms race similar to that seen in protein-based immunity. Notably, virus-derived small RNAs have been identified in patient tissues and circulation system even before clinical symptoms emerge, which may actively modulate host cellular pathways and immune responses, functioning as regulatory elements that resemble antigens in their ability to trigger specific host reactions. Their presence in circulation before symptom onset suggests they may play an early and strategic role in shaping the trajectory of infection.

By naming and characterizing RNA immunity, the review highlights a previously underappreciated layer of host defender—one that is ancient in origin yet active and adaptable in humans today. Understanding and harnessing this RNA-based system may open new avenues in antiviral therapy, vaccine design, and cross-kingdom communication research.

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.