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Noncoding RNAs (ncRNAs) are increasingly recognized as promising therapeutic candidates. Here, we report the development of therapeutic Y RNA 1 (TY1), a synthetic ncRNA bioinspired by a naturally occurring human small Y RNA with immunomodulatory properties. TY1 up-regulates three-prime DNA exonuclease 1 (TREX1), an exonuclease that rapidly degrades cytosolic DNA. In preclinical models of myocardial infarction (MI) induced by ischemia-reperfusion, TY1 reduced scar size. The cardioprotective effect of TY1 was abrogated by prior depletion of macrophages and mimicked by adoptive transfer of macrophages exposed to either TY1 or Trex1 overexpression. Inhibition of Trex1 in macrophages blocked TY1 cardioprotection. Consistent with a central role for Trex1, TY1 attenuated DNA damage in the post-MI heart. The key beneficial effects appear to be mediated by extracellular vesicles secreted by TY1-conditioned macrophages. This previously undescribed mechanism-pharmacological up-regulation of Trex1 in macrophages-establishes TY1 as the prototype for a new class of ncRNA drugs with disease-modifying bioactivity. We refer to this potential new class of ncRNA drugs as exomers because of the identification of their parent molecules in extracellular vesicles.