Non-coding RiboNucleic Acid (small or large ncRNA) are involved in epigenetic regulation directly silencing or activating chromatin at specific loci or through their integrated role into the machinery driving DNA methylation. Small RNAs, including short interfering RNAs (siRNAs) and microRNAs (miRNAs), mediate post-transcriptional gene silencing by RNA interference (RNAi) or have direct activity in the nucleosomes. These molecules are opening new avenues for therapeutic purposes or for assaying exogenous non-coding RNA acquisition on the immunity not only of the host, but also the putative consequences for generations on immunity, including allergic inflammation, cancer, or interactions with host microbiota. miRNA or siRNA are used as molecular therapies for environmental stress and metabolic diseases (obesity, Type-1, and 2 diabetes, metabolic syndrome). These molecules can also be supplied as exogenous molecules with various vectors manipulating host non-specific or specific immune response. Therefore, developing formulations that are suitable and can be applied to the oral delivery of miRNAs is in high demand. However, miRNA availability is highly challenging due to nucleic acid degradation in the gastric environment. Host bacteria can produce extracellular vesicles (EVs) containing non-coding RNAs that can mediate intercellular communication with epithelial and immune cells and potentially regulate the expression of genes involved in controlling the resistance to pathologies. On the other hand, host cells can also deliver non-coding RNAs to bacteria and similarly, regulate gene expression. We welcome the submission of Reviews, Mini-Reviews, and Original Research articles as well as Methods, Hypothesis and Theory, Perspective, Clinical Trial, Opinion, and Systematic Review articles. The following themes can be addressed in this Research Topic: (1) The use of miRNAs or siRNA in Molecular immunotherapy facing environmental stress and metabolic diseases (obesity, Type-1, and 2 diabetes, metabolic syndrome). For instance, delivering nc-RNA to engineer immune cells during autoimmune diseases, or using EVs to modulate inflammation. Studies manipulating the production by immune cells of pro and anti-inflammatory cytokines, T cell activation in autoimmune diseases, or the impact of the manipulation of RNA polymerase III subunits in autoimmune diseases and cancer are welcomed. (2) The role of non-coding RNA’s in immunotherapies manipulating the connection between gut and brain through investigating the glymphatic system or the brain-blood barrier. (3) The use of miRNA or si-RNA in cancer immunotherapy. The interactions between these RNA molecules and the regulatory effects on tumor immunity and the prognosis of patients. (4) Gut microbiota as a new player in regulating immune- and chemo-therapy efficacy through non-coding-RNA. Targeting immune cells from the gut to treat inflammatory diseases or infection with Extracellular vesicles or biomimetic nanovectors. The scope is implementing microRNA as a new immune-regulatory agent in breast milk, the sequence-non-specific effects of the miRNA delivered to cells with appropriate carriers or expressed in cells using suitable vectors often trigger both intended sequence-specific silencing effects and unintended sequence-non-specific immune responses. Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review. Non-coding RiboNucleic Acid (small or large ncRNA) are involved in epigenetic regulation directly silencing or activating chromatin at specific loci or through their integrated role into the machinery driving DNA methylation.