有针对性且高效的基因传递系统通过对生物过程进行适当的修改，在改善癌症治疗方面具有巨大的潜力。在此，我们报告了一种新型阳离子二嵌段共聚肽的设计和合成，该肽结合了高精氨酸（HAG）和莽草酰（LSA）功能（HDA-b-PHAGm-b-PLSAn），专为增强癌细胞中的基因转染而定制。通过连续N-羧酸酐（NCA）开环聚合（ROP）技术合成了二嵌段共聚肽，并对其理化性质进行了表征，包括分子量、分散性、二级构象、尺寸、形态和表面电荷。与阳离子聚-L-高精氨酸相反，我们观察到由于包含莽草酰糖多肽嵌段，这种二嵌段共聚肽的细胞毒性作用显着降低，这也增加了内化特定细胞的选择性。这种二嵌段共聚肽通过甘露糖受体介导的内吞作用内化，这是通过甘露聚糖竞争性受体阻断来研究的。我们评估了共聚肽在 HEK 293T（非癌细胞）、MDA-MB-231（乳腺癌细胞）和 RAW 264.7（树突状细胞）中的转染效率，并将其与常用的转染剂（Lipofectamine）进行比较。我们的研究结果表明，高精氨酸和莽草酰功能化的阳离子二嵌段共聚肽表现出强大的基因转染能力，并且具有最小的细胞毒性作用，特别是在癌细胞中，而它对正常细胞无效，表明其作为癌细胞的有前途的平台的潜力。特定的基因传递系统。为了评估这一点，我们提供了一种针对 Hsp90 的人工设计的 miRNA 质粒 (amiR-Hsp90)，成功转染后，它会特异性地耗尽癌细胞中的 Hsp90（一种负责肿瘤生长的伴侣蛋白）水平并强制细胞凋亡。这种创新方法为开发靶向疗法提供了新途径，提高了癌症治疗的功效和安全性。

Targeted and efficient gene delivery systems hold tremendous potential for the improvement of cancer therapy by enabling appropriate modification of biological processes. Herein, we report the design and synthesis of a novel cationic di-block copolypeptide, incorporating homoarginine (HAG) and shikimoyl (LSA) functionalities (HDA-b-PHAGm-b-PLSAn), tailored for enhanced gene transfection specifically in cancer cells. The di-block copolypeptide was synthesized via sequential N-carboxyanhydride (NCA) ring-opening polymerization (ROP) techniques and its physicochemical properties were characterized, including molecular weight, dispersity, secondary conformation, size, morphology, and surface charge. In contrast to the cationic poly-L-homoarginine, we observed a significantly reduced cytotoxic effect of this di-block copolypeptide due to the inclusion of the shikimoyl glyco-polypeptide block, which also added selectivity in internalizing particular cells. This di-block copolypeptide was internalized via mannose-receptor-mediated endocytosis, which was investigated by competitive receptor blocking with mannan. We evaluated the transfection efficiency of the copolypeptide in HEK 293T (noncancerous cells), MDA-MB-231 (breast cancer cells), and RAW 264.7 (dendritic cells) and compared it with commonly employed transfection agents (Lipofectamine). Our findings demonstrate that the homoarginine and shikimoyl-functionalized cationic di-block copolypeptide exhibits potent gene transfection capabilities with minimal cytotoxic effects, particularly in cancer cells, while it is ineffective for normal cells, indicative of its potential as a promising platform for cancer cell-specific gene delivery systems. To evaluate this, we delivered an artificially designed miRNA-plasmid against Hsp90 (amiR-Hsp90) which upon successful transfection depleted the Hsp90 (a chaperone protein responsible for tumour growth) level specifically in cancerous cells and enforced apoptosis. This innovative approach offers a new avenue for the development of targeted therapeutics with an improved efficacy and safety profile in cancer treatment.