Anisotropic active ligandations in siRNA-Loaded hybrid nanodiscs lead to distinct carcinostatic outcomes by regulating nano-bio interactions
Anisotropic active ligandations in siRNA-Loaded hybrid nanodiscs lead to distinct carcinostatic outcomes by regulating nano-bio interactions
复制标题
装载 siRNA 的混合纳米圆盘中的各向异性活性配体通过调节纳米生物相互作用产生不同的抗癌结果
DOI：
10.1016/j.biomaterials.2020.120008
复制
发表时间：
2020-08-01
期刊：
影响因子：
14
通讯作者：
Zhang, Qiang
中科院分区：
文献类型：
--
作者：
Chen, Qing;Guan, Guannan;Zhang, Qiang
主动靶向修饰是提高疗效的最重要的纳米医学策略之一。与球形纳米载体上的均匀配位相比，非球形纳米药物通常使配体修饰更加复杂。修饰后的配体总是表现出各向异性和不均匀性。然而，对这些多样化的各向异性改性的系统研究却很少。疗效差异和潜在机制尚不清楚。在这里，我们分别制造了在边缘和平面表面上与cRGD缀合的混合纳米盘（ND），以设计两种各向异性靶向纳米载体（分别为E-cRGD-ND和P-cRGD-ND）用于基因递送。配体的各向异性赋予NDs多样化的细胞相互作用，并导致E-cRGD-NDs和P-cRGD-NDs之间的不同功效。值得注意的是，E-cRGD-ND在siRNA负载、细胞摄取、沉默效率、蛋白质表达和甚至体内功效方面显示出显著的优越性。机制研究揭示了EcRGD-ND的功能各向异性。cRGD的边缘修饰有效地分离靶向和siRNA加载结构域，最大化它们各自的功能。这些发现反映了配体各向异性的独特效应，也为大规模纳米药物的靶向筛选提供了新的策略。
Active targeting modification is one of the foremost nanomedicine strategies for the efficacy improvement. Compared to the homogeneous ligandation on spherical nanocarriers, non-spherical nanomedicines usually make the ligand modification more complicated. The modified ligands always exhibit anisotropy and heterogeneity. However, there is very little systematic study on these diversified anisotropic modifications. The efficacy difference and underlying mechanism were still unclear. Here, we separately fabricated hybrid nanodiscs (NDs) conjugated with cRGD on the edge and plane surfaces to engineer two anisotropic targeting nanocarriers (E-cRGD-NDs and P-cRGD-NDs, respectively) for gene delivery. The ligand anisotropy endowed NDs with diversified cellular interactions, and caused different efficacies between E-cRGD-NDs and P-cRGD-NDs. Of note, E-cRGD-NDs showed significant superiority in siRNA loading, cellular uptake, silence efficiency, protein expression and even in vivo efficacy. The mechanism investigation revealed the functional anisotropy specifically for EcRGD-NDs. The edge modification of cRGD efficiently separated the targeting and siRNA loading domains, maximizing their respective functions. These findings reflected the unique effect of ligand anisotropy, also provided a new strategy for the targeting screening of extensive nanomedicines.