Synthetic gene delivery systems employ multiple functions to enable safe and effective transport of DNA to target cells. Here, we describe metabolite-based poly(l-lysine) (PLL) modifiers that improve transfection by imparting both pH buffering and nanoparticle stabilization functions within a single molecular unit. PLL modifiers were based on morpholine (M), morpholine and niacin (MN), or thiomorpholine (TM). PLL modification with (MN) or (TM) imparted buffering function over the pH range of 5–7 both in solution and live cells and enhanced the stability of PLL DNA nanoparticles, which exhibited higher resistance to polyanion exchange and prolonged blood circulation. These properties translated into increased transfection efficiency in vitro coupled with reduced toxicity compared to unmodified PLL and PLL(M). Furthermore, PEG-PLL(MN) DNA nanoparticles transfected muscle tissue in vivo for >45 days following intramuscular injection. These polymer modifiers demonstrate the successful design of multifunctional units that improve transfection of synthetic gene delivery systems while maintaining biocompatibility.

中文翻译：

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基于代谢物的聚（1-赖氨酸）修饰，用于改善基因传递。

合成基因传递系统具有多种功能，可以安全有效地将DNA转运至靶细胞。在这里，我们描述了基于代谢物的聚（1-赖氨酸）（PLL）改性剂，该改性剂通过在单个分子单元内赋予pH缓冲和纳米颗粒稳定功能来改善转染。PLL修饰剂基于吗啉（M），吗啉和烟酸（MN）或硫代吗啉（TM）。用（MN）或（TM）修饰的PLL在溶液和活细胞的pH范围为5-7时均具有缓冲功能，并增强了PLL DNA纳米颗粒的稳定性，从而表现出更高的抗聚阴离子交换能力和血液循环时间。这些特性可提高体外转染效率与未经修改的PLL和PLL（M）相比，毒性降低。此外，肌肉注射后PEG-PLL（MN）DNA纳米颗粒在体内转染肌肉组织> 45天。这些聚合物修饰剂证明了多功能单元的成功设计，该单元可改善合成基因传递系统的转染，同时保持生物相容性。