中科院国家纳米科学中心王浩团队开发了体内自组装诱导的细胞膜相分离改善肽药物内化策略。相关研究成果发表在2021年9月22日出版的《德国应用化学》。

治疗性肽因其良好的生物相容性而受到广泛关注，但其有效性因其不能穿透细胞膜而受到限制，是肽药物传递的关键瓶颈。

该文中，研究人员开发了一种体内自组装策略，以诱导细胞膜的相分离，从而提高肽药物的内部化和抗癌功效。合成了一种磷酸肽KYp，其包含抗癌肽[KLAKLAK]2（K）和磷酸化反应部分Y（Yp）。KYp与细胞膜上的碱性磷酸酶（ALP）相互作用后，可被去磷酸化并原位自组装，从而诱导ALP在细胞膜上聚集和蛋白脂相分离。碱性磷酸酶参与肽的组装，形成大聚集体并进入细胞，导致细胞膜通透性增强。因此，与非反应性肽纳米粒相比，肽药物的内化增强约2倍，KYp的IC50值比游离肽低约5倍。最后，KYp治疗的小鼠肿瘤得到有效抑制，在体内显示出可忽略的副作用。

因此，在细胞膜上的体内自组装诱导相分离有望成为一种提高肿瘤治疗药物传递效率的新策略。

附：英文原文

Title: In Vivo Self-Assembly Induced Cell Membrane Phase Separation for Improved Peptide Drug Internalization

Author: Hao Wang, Ruo-Chen Guo, Xue-Hao Zhang, Peng-Sheng Fan, Ben-Li Song, Zhi-Xiang Li, Zhong-Yu Duan, Zeng-Ying Qiao

Issue&Volume: 2021-09-22

Abstract: Therapeutic peptides have been widely concerned because of their good biocompatibility, 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 and anticancer efficacy. 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) on the cell membrane, KYp can be dephosphorylated and self-assembles  in situ  , which induces the aggregation of ALP and the protein-lipid phase separation on the cell membrane. ALP is involved in the assembly of peptides, forming the large aggregates and entering cells, which leads to the enhanced permeability of cell membrane. Consequently, the peptide drugs internalization is ~2-fold enhanced compared to non-responsive peptide nanoparticle, and IC  50  value of KYp is approximately ~5 times lower than that of free peptide. Finally, the tumor of mice treated with KYp is suppressed effectively, showing the negligible side effect  in vivo  . Therefore, the  in vivo  self-assembly induced phase separation on the cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.

DOI: 10.1002/anie.202111839

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202111839