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Med."],"published-print":{"date-parts":[[2025,12,3]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Trex1<\/jats:italic>\n                    overexpression. Inhibition of\n                    <jats:italic toggle=\"yes\">Trex1<\/jats:italic>\n                    in macrophages blocked TY1 cardioprotection. Consistent with a central role for\n                    <jats:italic toggle=\"yes\">Trex1<\/jats:italic>\n                    , 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\u2014pharmacological up-regulation of\n                    <jats:italic toggle=\"yes\">Trex1<\/jats:italic>\n                    in macrophages\u2014establishes 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.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adp1338","type":"journal-article","created":{"date-parts":[[2025,12,3]],"date-time":"2025-12-03T18:58:11Z","timestamp":1764788291000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["Augmentation of DNA exonuclease TREX1 in macrophages as a therapy for cardiac ischemic injury"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-7432","authenticated-orcid":true,"given":"Ahmed Gamal-Eldin","family":"Ibrahim","sequence":"first","affiliation":[{"name":"Cedars-Sinai Medical Center, Smidt Heart Institute, Los Angeles, CA 90048, 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