Progress in peptide and protein therapeutics: Challenges and strategies

作者：Mengyang Liu, Darren Svirskis, Thomas Proft, Jacelyn M. S. Loh, Naibo Yin, Hao Li, Danhui Li, Yongzhi Zhou, Shuo Chen, Lizhuo Song, Guanyu Chen, Weiyue Lu, Zhiwen Zhang, Zhou Zhou, Lian Li, Yuan Huang, Craig R. Bunt, Guiju Sun, Paul W. R. Harris, Margaret A. Brimble, Jingyuan Wen · 发表于：Acta Pharmaceutica Sinica B · 年份：2025 · DOI：10.1016/j.apsb.2025.10.026 · 被引用次数：61 · 研究领域：RNA Interference and Gene Delivery、Monoclonal and Polyclonal Antibodies Research、Chemical Synthesis and Analysis

Peptide- and protein-based therapeutics offer realized and potential benefits to health, due to their potent bioactivity, high specificity, and favorable safety characteristics. However, their widespread clinical application is constrained by inherent limitations, including rapid enzymatic degradation, poor membrane permeability, and a reliance on parenteral administration, which reduces patient adherence. To overcome these challenges, extensive research has explored non-invasive delivery strategies, including topical, transdermal, and oral formulations. Despite promising advances in these delivery strategies, they are yet to overcome substantial biological and physicochemical barriers in peptide and protein therapeutics, such as enzymatic degradation in the gastrointestinal tract, limited epithelial transport, and inherently low systemic bioavailability. This review provides a comprehensive and up-to-date analysis of the structural and physiological barriers influencing peptide and protein bioavailability and therapeutic efficacy. It critically examines key challenges associated with various administration routes, including topical, transdermal, oral (including delivery targeting the brain), and others. Furthermore, it explores innovative strategies to enhance peptide and protein stability and bioavailability, including chemical modifications, enzyme inhibitors, penetration enhancers, physical delivery technologies, and advanced nanoparticulate formulations. Additionally, em...