%0 Journal Article
%T Unnatural Amino Acid-Based Ionic Liquid Enables Oral Treatment of Nonsense Mutation Disease in Mice.
%A Shi Y
%A Shi N
%A Yang Y
%A Zheng Z
%A Xia Q
%J Adv Sci (Weinh)
%V 11
%N 13
%D 2024 Apr 30
%M 38288517
%F 17.521
%R 10.1002/advs.202306792
%X 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.