This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation\'s unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation.

Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.