State Key Laboratory of Biogeology and Environmental Geology, Engineering Research Center of Nano-Geomaterials of Ministry of Education, Faculty of Materials Science and Chemistry, China University of Geosciences, Wuhan, 430074, China.
Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430074, China.
Angew Chem Int Ed Engl. 2024 Dec 2;63(49):e202410744. doi: 10.1002/anie.202410744. Epub 2024 Oct 18.
Molecular spherical nucleic acids (m-SNAs) are a second generation of spherical nucleic acids (SNAs), which are of significance in potential application of targeted delivery of nucleic acids or gene regulation due to their defined molecular structures. Nevertheless, m-SNAs typically involve a single DNA sequence which greatly limits its functions as either targeting purpose or gene regulation. In response, we proposed here a third generation, supramolecular spherical nucleic acids (Supra-SNAs) with two different sequences to achieve both above-mentioned functions. Specifically, we constructed a series of supramolecular self-assembly structures by coupling a cell membrane receptor (i.e., nucleolin)-recognizing aptamer (AS1411)-modified adamantine as targeting probe and human epithelial growth factor receptor 2 (HER2) antisense-functionalized β-cyclodextrin to specifically inhibit the overexpression of HER2 proteins for gene regulations. In comparison to the m-SNA precursors, such Supra-SNA structures exhibited enhanced levels of resistance to nuclease degradation, cellular uptake, gene regulation capabilities and tumor retention capacity. We demonstrated that Supra-SNAs exhibited optimal cell suppression rates and cell apoptosis via a phosphatidylinositol 3-kinase/protein kinase B signaling pathway. The well-defined molecular structures provide an attractive platform for investigating interrelationship between structure and property at the molecular level.
分子球形核酸（m-SNAs）是第二代球形核酸（SNAs），由于其明确的分子结构，在核酸或基因调控的靶向递送方面具有重要的潜在应用价值。然而，m-SNAs 通常涉及单个 DNA 序列，这极大地限制了其作为靶向目的或基因调控的功能。针对这一问题，我们提出了第三代超分子球形核酸（Supra-SNAs），其具有两个不同的序列，以实现上述两种功能。具体来说，我们通过将细胞膜受体（即核仁素）识别适体（AS1411）修饰的金刚烷作为靶向探针与人类表皮生长因子受体 2（HER2）反义功能化的β-环糊精偶联，构建了一系列超分子自组装结构，以特异性抑制 HER2 蛋白的过表达，从而实现基因调控。与 m-SNA 前体相比，这些 Supra-SNA 结构表现出增强的抗核酸酶降解、细胞摄取、基因调控能力和肿瘤保留能力。我们通过磷脂酰肌醇 3-激酶/蛋白激酶 B 信号通路证明了 Supra-SNAs 具有最佳的细胞抑制率和细胞凋亡作用。明确的分子结构为在分子水平上研究结构与性能之间的关系提供了一个有吸引力的平台。
