The intracellular or pericellular self-assembly of amphiphilic peptides is emerging as a potent cancer therapeutic strategy. Achieving the self-assembly of amphiphilic peptides inside a cell or cellular organelle is challenging due to the complex cellular environment, which consists of many amphiphilic biomolecules that may alter the self-assembling propensity of the synthetic peptides. Herein, we show that the hydrophobic–hydrophilic balance of the amphiphilic peptides determines the self-assembling propensity, thereby controlling the fate of the cell. A series of peptides were designed to target and self-assemble inside the mitochondria of cancer cells. The hydrophobicity of the peptides was tuned by varying their N-terminus capping. The analysis showed that the largest hydrophobic peptide was self-assembled before reaching the mitochondria and showed no selectivity toward cancer cells, whereas hydrophilic peptides could not self-assemble inside the mitochondria. Optimum balance between hydrophobicity and hydrophilicity is a critical factor for achieving self-assembly inside the mitochondria, thereby providing greater selectivity against cancer cells.

中文翻译：

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肽的时空自我组装决定了癌症的选择性毒性。

两亲性肽的细胞内或细胞周围自组装正在作为一种有效的癌症治疗策略出现。由于复杂的细胞环境，由许多两亲生物分子组成，可能会改变合成肽的自组装倾向，因此在细胞或细胞器内实现两亲肽的自组装是一项挑战。在这里，我们表明两亲性肽的疏水-亲水平衡决定了自组装倾向，从而控制了细胞的命运。设计了一系列肽以靶向并自组装在癌细胞的线粒体内。肽的疏水性通过改变其N端封端来调节。分析表明，最大的疏水性肽在到达线粒体之前是自组装的，对癌细胞没有选择性，而亲水性肽不能在线粒体内自组装。疏水性和亲水性之间的最佳平衡是实现线粒体内自组装的关键因素，从而提供了对癌细胞更大的选择性。