Duchenne Muscular Dystrophy (DMD) is a severe monogenic disorder characterized by mutations in the DMD gene, which encodes the dystrophin protein responsible for muscle strength. Despite recent advances in gene therapy, nowadays there are no effective treatments to cure the disease. Among tested approaches, Adeno-Associated Viruses (AAVs) revealed to be promising vectors to deliver therapeutic genes directly into target cells. These are designed as gene replacement therapies. However, this strategy presents some limitations, such as the immune recognition of the vectors, that leads to a premature elimination. Thus, the need for innovative strategies to enhance the safety and efficacy of AAV-based therapies is an urgent need.