It is a great challenge to fabricate a gene carrier system containing multiple functional components to overcome the multiple bio-barriers during the gene delivery process. In this work, we developed a supramolecular approach to construct a versatile gene delivery system using two modules with specific functions. Through atom transfer radical polymerization (ATRP) and ring-opening reaction, we synthesized pH-sensitive and brush-shaped ethanolamine functionalized poly(glycidyl methacrylate) (PGEA) derivatives (PCD-acetal-PGEA) as a cationic host module, which contains poly(β-cyclodextrin) as the backbone and acetal bond-linked PGEA as the arms. The cationic host PCD-acetal-PGEA polymer could effectively compact DNA into stable nanosized polyplexes in the extracellular neutral environment and quickly release the DNA in the intracellular acidic environment, which showed lower cytotoxicity and higher transfection efficiency than the PEI control. After the conjugation of the guest module adamantyl terminated polyethylene glycol (Ad-PEG-OH) and adamantyl and folate terminated PEG (Ad-PEG-FA) by host–guest interaction, this multifunctional gene delivery system showed increased serum stability and cell-targeting capacity. In vitro experiments revealed that the uptake efficiency, plasmid DNA transfection efficiency and siRNA silencing efficiency of the FA-targeted supramolecular polyplexes in folate-receptor positive cells were better than those of the control 25 kDa PEI based polyplexes. Therefore, this acid-sensitive multifunctional supramolecular gene vector based on poly(β-cyclodextrin) might be very useful in practical applications.

中文翻译：

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基于酸敏感的聚（β-环糊精）的多功能超分子基因载体†

制造包含多种功能成分以克服基因传递过程中的多种生物屏障的基因载体系统是一个巨大的挑战。在这项工作中，我们开发了一种超分子方法，使用具有特定功能的两个模块来构建通用的基因递送系统。通过原子转移自由基聚合（ATRP）和开环反应，我们合成了pH敏感的刷状乙醇胺官能化的聚甲基丙烯酸缩水甘油酯（PGEA）衍生物（PCD-acetal-PGEA）作为阳离子主体模块，其中包含聚（β-环糊精）为骨架，乙缩醛键连接的PGEA为臂。阳离子主体PCD-乙缩醛-PGEA聚合物可在细胞外中性环境中有效地将DNA压缩成稳定的纳米级多链体，并在细胞内酸性环境中快速释放DNA，与PEI对照相比，具有更低的细胞毒性和更高的转染效率。通过宿主-客体相互作用，将来宾模块金刚烷基末端的聚乙二醇（Ad-PEG-OH）与金刚烷基末端和叶酸末端的PEG（Ad-PEG-FA）偶联后，该多功能基因递送系统显示出更高的血清稳定性和细胞靶向性容量。体外实验显示，叶酸受体阳性细胞中以FA为靶点的超分子多链体的摄取效率，质粒DNA转染效率和siRNA沉默效率均优于基于对照25 kDa PEI的多链体。因此，这种基于聚（β-环糊精）的酸敏感性多功能超分子基因载体可能在实际应用中非常有用。