️ 22: Immune Sensing Unveiled — Ribonuclease Control of Naked Extracellular RNA

️ Episode 22: Immune Sensing Unveiled — Ribonuclease Control of Naked Extracellular RNA In this episode of Base por Base, we explore a landmark study by Castellano et al. (2025) published in Cell Genomics that uncovers how extracellular ribonucleases regulate the immune detection and functional uptake of naked extracellular RNA (exRNA). Through strategic use of a broad-spectrum ribonuclease inhibitor, the authors demonstrate that, contrary to long-held assumptions, naked exRNAs can be spontaneously internalized by dendritic cells and macrophages, engage both endosomal Toll-like receptors and cytosolic RIG-I-like receptors, and even serve as templates for protein translation, thereby revealing a novel, nonvesicular pathway of intercellular RNA communication . Key Highlights: Naked extracellular RNA exhibits intrinsic bioactivity when extracellular RNases are inhibited or absent, triggering pro-inflammatory transcriptional programs via endosomal TLR13 in murine cells and RIG-I/MAVS-dependent pathways in human macrophages; these naked RNAs can escape endosomes to reach the cytosol, where they activate downstream antiviral and inflammatory signaling; in vitro-transcribed mRNAs delivered as naked exRNA are taken up and translated into functional reporter proteins in both primary immune cells and epithelial cell lines in an RNase-sensitive manner; and systemic administration of naked bacterial RNA or synthetic dsRNA with ribonuclease inhibition markedly amplifies immune cell activation in vivo, whereas the high RNase activity of blood normally prevents such systemic inflammation . Conclusion: Castellano et al. reveal that extracellular RNase activity serves as a critical barrier to the bioactivity of naked exRNAs, and that in low-RNase environments naked RNA can mediate immune communication and protein expression. These insights fundamentally challenge the prevailing view that vesicular encapsulation is required for functional RNA transfer and position extracellular RNases as key modulators of intercellular RNA signaling and immune homeostasis . Reference:Castellano, M., Blanco, V., Li Calzi, M., Costa, B., Witwer, K., Hill, M., Cayota, A., Segovia, M., & Tosar, J.P. (2025). Ribonuclease activity undermines immune sensing of naked extracellular RNA. Cell Genomics, 5, 100874. https://doi.org/10.1016/j.xgen.2025.100874 License: This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International (CC BY 4.0) license – https://creativecommons.org/licenses/by/4.0/

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