Key Laboratory of Functional Polymer Materials, Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Institute of Polymer Chemistry, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Research Center for Analytical Sciences, College of Chemistry, Nankai University, 94 Weijin Road, Tianjin 300071, China.
J Am Chem Soc. 2022 Jun 1;144(21):9312-9323. doi: 10.1021/jacs.2c01025. Epub 2022 May 19.
Self-sorting is a common phenomenon in eukaryotic cells and represents one of the versatile strategies for the formation of advanced functional materials; however, developing artificial self-sorting assemblies within living cells remains challenging. Here, we report on the GSH-responsive self-sorting peptide assemblies within cancer cells for simultaneous organelle targeting to promote combinatorial organelle dysfunction and thereby cell death. The self-sorting system was created the design of two peptides E3C16E6 and EVM derived from lipid-inspired peptide interdigitating amphiphiles and peptide bola-amphiphiles, respectively. The distinct organization patterns of the two peptides facilitate their GSH-induced self-sorting into isolated nanofibrils as a result of cleavage of disulfide-connected hydrophilic domains or reduction of selenoxide groups. The GSH-responsive self-sorting in the peptide assemblies within HeLa cells was directly characterized by super-resolution structured illumination microscopy. Incorporation of the thiol and ER-targeting groups into the self-sorted assemblies endows their simultaneous targeting of endoplasmic reticulum and Golgi apparatus, thus leading to combinatorial organelle dysfunction and cell death. Our results demonstrate the establishment of the self-sorting peptide assemblies within living cells, thus providing a unique platform for drug targeting delivery and an alternative strategy for modulating biological processes in the future.
自组装是真核细胞中的一种常见现象，是形成先进功能材料的多种策略之一；然而，在活细胞内开发人工自组装仍具有挑战性。在这里，我们报告了在癌细胞内具有 GSH 响应性的自组装肽组装体，用于同时靶向细胞器以促进组合细胞器功能障碍，从而导致细胞死亡。该自组装系统是通过设计两种源自脂质启发的肽交错两亲物和肽双球两亲物的肽 E3C16E6 和 EVM 来创建的。这两种肽的不同组织模式有利于它们在 GSH 诱导下自组装成隔离的纳米纤维，这是由于二硫键连接的亲水结构域的断裂或硒氧化物基团的还原。通过超分辨率结构光照明显微镜直接表征了 HeLa 细胞内肽组装体的 GSH 响应性自组装。将巯基和 ER 靶向基团纳入自组装体中，赋予它们同时靶向内质网和高尔基体的能力，从而导致组合细胞器功能障碍和细胞死亡。我们的结果表明，在活细胞内建立了自组装肽组装体，从而为药物靶向递送提供了独特的平台，并为未来调节生物过程提供了替代策略。
