In vivo studies in the DMD mouse model, mdx, have shown that systemic delivery of naked phosphorodiamidate morpholino oligomers (PMO) 5 and 2′-O-methyl (2′OMe) 6 AOs are not capable of restoring significant dystrophin protein in cardiac muscle. Notably, even direct intra-cardiac injections of naked AOs resulted in very low exon skipping. 7 And although clinical trials with 2′OMe 8, 9 and PMO 10,11 chemistries have shown great promise, there is still a need for further optimization to improve AO delivery to all skeletal muscles and to the heart. This is critical as respiratory complications 12 and cardiac dysfunction 13 are the major causes of premature death in DMD patients. In particular the cardiomyopathy becomes clinically apparent at ~10 years of age, and is exhibited in all DMD patients by the age of 18. 13, 14 While some studies have shown that the restoration of dystrophin in respiratory muscles can improve cardiac function in the absence of restored dystrophin protein in the heart, 15, 16 there is concern that any improvement in skeletal muscle function in the absence of cardiac correction may worsen the cardiac disease progression due to increases in cardiac work load. [17] [18] [19] It is therefore highly desirable that future therapies endeavor to restore dystrophin in cardiac as well as in skeletal muscles.