In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization.
Ruo-Chen GuoXue-Hao ZhangPeng-Sheng FanBen-Li SongZhi-Xiang LiZhong-Yu DuanZeng-Ying QiaoHao WangPublished in: Angewandte Chemie (International ed. in English) (2021)
Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.