Unnatural Amino Acid‐Based Ionic Liquid Enables Oral Treatment of Nonsense Mutation Disease in Mice

Abstract 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.