Transforming Duchenne muscular dystrophy therapy: The multifaceted role of extracellular vesicles and exosomes

Duchenne muscular dystrophy (DMD) remains a devastating X chromosome-linked disorder with restricted curative options. Additionally, the existing treatment approaches, such as growth-modulating agents, anti-inflammatory drugs, antisense oligonucleotides with exon-skipping capabilities, stop codon mutation suppressors, vector-mediated gene therapy, CRISPR/Cas9 gene editing, and exogenous cell transplantation, can delay disease progression but are not curative. Extracellular vesicles (EVs), especially exosomes, nanoscale vesicles involved in intercellular communication, have emerged as promising therapeutic tools for DMD due to their low immunogenicity, ability to deliver therapeutic cargos, and potential to modulate inflammation, oxidative stress, and fibrosis. This review explores the transformative role of EVs (including exosomes) as multifunctional tools in DMD management. Natural EVs, enriched with regenerative microRNAs (miRNAs) and anti-fibrotic proteins, modulate inflammation, oxidative stress, and muscle degeneration. Besides, innovative engineering approaches could improve EVs' cargo loading and targeting, assisting efficient delivery of oligonucleotides and CRISPR/Cas9 editing components. Furthermore, we address the capacity of these vesicles to restore dystrophin expression and attenuate pathogenic mechanisms. Lastly, challenges associated with EV isolation, stability, and scalability are critically evaluated to support the development of an integrated cell and gene therapy framework with significant potential to improve clinical outcomes in DMD patients.