Small RNA-Guided Control of Viral Pathogenesis: Integrated Roles of Cell-Associated and Extracellular Small RNAs

Dear Colleagues,

Small RNAs—including microRNAs (miRNAs), small interfering RNAs (siRNAs), PIWI-interacting RNAs (piRNAs), transfer RNA (tRNA), tRNA-derived fragments (tRFs), and viral small RNAs—whether retained within cells or released into the extracellular milieu, have emerged as central regulators of virus–host interactions. Once viewed as housekeeping molecules that merely fine-tune gene expression, these RNAs are now recognized as potent modulators of viral entry, innate immune activation, replication efficiency, persistence, and the systemic manifestations of viral disease. Their specificity, rapid kinetics, and broad network reach position them as key determinants of infection outcomes across diverse viral families.

This Special Issue highlights the expanding and interconnected roles of cell-associated and extracellular small RNAs in shaping viral pathogenesis. Cell-associated small RNAs orchestrate intracellular responses that determine whether viruses are restricted, tolerated, or reactivated. They regulate antiviral signaling pathways, chromatin accessibility, metabolic states, stress responses, and RNA decay machinery. Viruses counter these defenses by encoding viral miRNAs, degrading host RNA processing enzymes, or repurposing RNA-binding proteins to favor replication and immune evasion. The intracellular small RNA landscape thus represents a dynamic molecular arena where host defenses and viral strategies continuously evolve.

In parallel, extracellular small RNAs—packaged within extracellular vesicles (EVs), extracellular condensates (ECs), ribonucleoprotein complexes, or other non-vesicular particles (NVEPs)—enable communication between infected and uninfected cells, tissues, and organ systems. These extracellular RNAs disseminate antiviral or proviral signals, modulate immune cell activation, influence tissue susceptibility, and contribute to systemic disease phenotypes. Viruses exploit extracellular RNA pathways to remodel the microenvironment, suppress immunity, and facilitate spread, whereas hosts use them to coordinate multicellular antiviral responses. The recognition that extracellular small RNAs—including extracellular tRFs—can act as long-range regulators of viral pathogenesis has fundamentally reshaped our understanding of infection biology.

Among these regulators, tRNAs and tRNA-derived fragments have recently gained prominence. Viral infections frequently induce site-specific tRNA cleavage, generating tRFs that modulate translation, stress granule formation, innate immune signaling, and viral gene expression. Some viruses selectively manipulate tRNA pools to optimize codon usage, while others exploit tRFs to suppress host antiviral responses or enhance replication. The discovery that tRFs act with specificity comparable to canonical small RNAs has opened new mechanistic and translational frontiers in RNA-guided control of infection.

Together, cell-associated and extracellular small RNAs form an integrated regulatory network that extends beyond individual cells and tissues. Their combined actions influence viral latency, persistence, neuroimmune communication, oncogenic transformation, and inflammatory sequelae. Advances in high-resolution sequencing, extracellular particle isolation, tRNA profiling, single-cell transcriptomics, and RNA targeting technologies have accelerated discoveries across these domains, revealing previously unrecognized layers of RNA-mediated control.

This Special Issue assembles cutting-edge research and authoritative reviews that illuminate these multifaceted roles. Contributions explore mechanistic RNA–protein interactions, host and viral small RNA networks, extracellular RNA signaling pathways, tRF biogenesis and function, and translational applications including RNA-based diagnostics, biomarkers, therapeutics, and vaccine strategies. By integrating perspectives on intracellular and extracellular small RNAs, this collection provides a comprehensive view of how RNA-guided regulation shapes viral infection biology.

We are pleased to present this Special Issue and hope it catalyzes new mechanistic insights, cross-disciplinary collaborations, and innovative RNA-based approaches to understanding and combating viral diseases.

Dr. Chioma M. Okeoma
Guest Editor

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