CAS Key Laboratory of Nanosystem and Hierarchical Fabrication, National Center for Nanoscience and Technology, Beijing 100190, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
J Am Chem Soc. 2023 Apr 26;145(16):9343-9353. doi: 10.1021/jacs.3c02756. Epub 2023 Apr 18.
DNA origami has played an important role in various biomedical applications, including biosensing, bioimaging, and drug delivery. However, the function of the long DNA scaffold involved in DNA origami has yet to be fully exploited. Herein, we report a general strategy for the construction of a genetically encoded DNA origami by employing two complementary DNA strands of a functional gene as the DNA scaffold for gene therapy. In our design, the complementary sense and antisense strands can be directly folded into two DNA origami monomers by their corresponding staple strands. After hybridization, the assembled genetically encoded DNA origami with precisely organized lipids on the surface can function as the template for lipid growth. The lipid-coated and genetically encoded DNA origami can efficiently penetrate the cell membrane for successful gene expression. After decoration with the tumor-targeting group, the antitumor gene (p53) encoded DNA origami can elicit a pronounced upregulation of the p53 protein in tumor cells to achieve efficient tumor therapy. The targeting group-modified, lipid-coated, and genetically encoded DNA origami has mimicked the functions of cell surface ligands, cell membrane, and nucleus for communication, protection, and gene expression, respectively. This rationally developed combination of folding and coating strategies for genetically encoded DNA origami presents a new avenue for the development of gene therapy.
DNA 折纸在各种生物医学应用中发挥了重要作用，包括生物传感、生物成像和药物传递。然而，DNA 折纸中涉及的长 DNA 支架的功能尚未得到充分利用。在此，我们报告了一种通过使用功能基因的两条互补 DNA 链作为基因治疗的 DNA 支架来构建基因编码 DNA 折纸的通用策略。在我们的设计中，互补的有义和反义链可以通过其相应的订书链直接折叠成两个 DNA 折纸单体。杂交后，表面具有精确组织脂质的组装基因编码 DNA 折纸可以作为脂质生长的模板。脂质包被和基因编码 DNA 折纸可以有效地穿透细胞膜，从而成功地进行基因表达。经过肿瘤靶向基团的修饰，编码 p53 的抗肿瘤基因（p53）的 DNA 折纸可以在肿瘤细胞中引起 p53 蛋白的明显上调，从而实现有效的肿瘤治疗。靶向基团修饰、脂质包被和基因编码 DNA 折纸分别模拟了细胞表面配体、细胞膜和细胞核的功能，用于通讯、保护和基因表达。这种针对基因编码 DNA 折纸的折叠和涂层策略的合理组合为基因治疗的发展提供了新途径。
