Exon skipping antisense oligonucleotides (AOs) are promising treatments for muscle-related genetic ailments, including Duchenne muscular dystrophy (DMD), but clinical translation is unfortunately hampered by insufficient systemic delivery. Here, we describe how one can employ a glucose/fructose injection mixture to improve muscle uptake and functional outcomes of DMD AOs in energy-deficient peripheral muscles of mdx mice. The potentiating effect of glucose/fructose on AOs in energy-deficient muscles offers a simple and economical method for enhancing AO potency, reducing screening costs for researchers and accelerating the translation of nucleic acid-based therapeutics in DMD and other muscular dystrophies.