Nonviral vector–based gene therapy is a promising strategy for treating a myriad of diseases. Cell‐penetrating peptides are gaining increasing attention as vectors for nucleic acid delivery. However, most studies have focused more on the transfection efficiency of these vectors than on their specificity and toxicity. To obtain ideal vectors with high efficiency and safety, we constructed the vector stearyl‐TH by attaching a stearyl moiety to the N‐terminus of the acid‐activated cell penetrating peptide TH in this study. Under acidic conditions, stearyl‐TH could bind to and condense plasmids into nanoparticle complexes, which displayed significantly enhanced cellular uptake and transfection efficiencies. In contrast, stearyl‐TH lost the capacities of DNA binding and transfection at physiological pH. More importantly, stearyl‐TH and the complexes formed by stearyl‐TH and plasmids displayed no obvious toxicity at physiological pH. Consequently, the high transfection efficiency under acidic conditions and low toxicity make stearyl‐TH a potential nucleic acid delivery vector for gene therapy.

中文翻译：

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酸激活的非病毒肽载体，用于基因递送。

基于非病毒载体的基因治疗是治疗多种疾病的一种有前途的策略。细胞穿透肽作为核酸传递载体越来越受到关注。但是，大多数研究都集中在这些载体的转染效率上，而不是它们的特异性和毒性。为了获得高效，安全的理想载体，在本研究中，我们通过将硬脂基部分连接到酸活化细胞穿透肽TH的N末端，构建了硬脂基TH。在酸性条件下，硬脂基-TH可以与质粒结合并凝结成纳米颗粒复合物，从而显着提高细胞摄取和转染效率。相反，在生理pH值下，硬脂基TH失去了DNA结合和转染的能力。更重要的是，硬脂酸TH和硬脂酸TH与质粒形成的复合物在生理pH下没有明显的毒性。因此，在酸性条件下的高转染效率和低毒性使硬脂基TH成为基因治疗的潜在核酸传递载体。