Abstract Body: We previously identified a small non-coding RNA derived from the 5’ half of a glutamate transfer RNA (tRNA), called tREX1, that has disease-modifying bioactivity in mice with myocardial infarction (MI) and Duchenne muscular dystrophy (DMD). DMD affects approximately 1 in 3,600 live-born males worldwide and results in increased wasting of cardiac and skeletal muscle, with no known cure. Native RNA can be unstable, potentially immunogenic, and have suboptimal potency. RNA stability can be improved by replacing the non-bridging oxygen atom of the phosphate backbone with a sulfur atom, creating a phosphorothioate (PS) nucleotide bond. Structure/activity relationship studies showed full replacement of tREX1’s phosphodiester bonds with PS bonds dramatically improves RNase resistance and potency by 10X. We call this chemically-modified tREX1 derivative TT1, a prototype of a new class of RNA drugs (exomers). We hypothesized that TT1 would have superior disease-modifying bioactivity due to its improved stability and potency in vitro. C57BL/6 mice (N=6) underwent 45 minutes of ischemia followed by 20 minutes reperfusion prior to oral administration of TT1/vehicle/scramble. Infarct size was measured after 48 hours. TT1 has improved disease modifying bioactivity compared to tREX1, dramatically reducing infarct size (from 26.7%±0.97 to 17.7%±1.5) even at a 10X lowered dose. We next gave TT1 orally twice-weekly for 4 weeks to aged mdx mice (N=7), a widely studied mouse model of DMD and its associated cardiomyopathy. At 10X lower dose, orally delivered TT1 improved exercise performance (by 127%±20), left ventricle ejection fraction (LVEF, by 16.6%±2.8) and myocardial fibrosis (from 23.2%±0.6 to 19.6%±0.9) compared to vehicle. However, we saw no benefits in skeletal muscle at this dose. We then administered a 10X higher dose (the effective tREX1 dose) twice-weekly for 4 weeks to aged mdx mice (N=8). TT1 improved exercise performance (by 64%±11), LVEF (by 21.7%±6.6), in-vivo tetanic torque (by 30.2%±6.8), and reduced interstitial fibrosis in heart (from 31.0%±1.5 to 25.2%±1.5) and skeletal muscle (from 32.9%±0.8 to 26.0%±1.5). TT1 shifts the cardiac macrophage profile towards an anti-inflammatory phenotype, regardless of dose, and is non-toxic. In conclusion, these data show TT1 has strong disease-modifying bioactivity in inflammatory cardiomyopathies like MI and DMD, and motivate further development of TT1 as a next-generation RNA drug with oral bioavailability.