Duchenne muscular dystrophy (DMD) affects approximately 1 in 3,600 live-born males worldwide and results in increased wasting of cardiac and skeletal muscle, and has no known cure. We have 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 mdx mice. In its natural state, RNA is inherently unstable, potentially immunogenic, and may 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. We call this chemically-modified tREX1 derivative TT1, a prototype of a new class of RNA drugs called exomers. When given orally twice a week for 4 weeks to aged mdx mice, TT1 improved: a) exercise performance, b) left ventricular ejection fraction, and c) peak isometric torque of the anterior crural muscles, compared to control. These functional benefits were associated with a significant reduction in interstitial fibrosis in heart and skeletal muscle. In summary, these data show TT1 has strong disease-modifying bioactivity in mdx mice with advanced-stage disease, and motivate further development of TT1 as a next-generation RNA drug with oral bioavailability.