Self-Assembled Nanobodies as Selectively Targeted, Nanostructured, and Multivalent Materials,ACS Applied Materials & Interfaces

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Self-Assembled Nanobodies as Selectively Targeted, Nanostructured, and Multivalent Materials
ACS Applied Materials & Interfaces ( IF 8.3 ) Pub Date : 2021-06-15 , DOI: 10.1021/acsami.1c08092
Laura Sánchez-García _{1,

2,

3} , Eric Voltà-Durán _{1,

2,

3} , Eloi Parladé _{1,

2,

3} , Elisa Mazzega ₄ , Alejandro Sánchez-Chardi _{5,

6} , Naroa Serna _{1,

2,

3} , Hèctor López-Laguna _{1,

2,

3} , Mara Mitstorfer ₇ , Ugutz Unzueta _{2,

3,

8} , Esther Vázquez _{1,

2,

3} , Antonio Villaverde _{1,

2,

3} , Ario de Marco ₄

Affiliation

Nanobodies represent valuable tools in advanced therapeutic strategies but their small size (∼2.5 × ∼ 4 nm) and limited valence for interactions might pose restrictions for in vivo applications, especially regarding their modest capacity for multivalent and cooperative interaction. In this work, modular protein constructs have been designed, in which nanobodies are fused to protein domains to provide further functionalities and to favor oligomerization into stable self-assembled nanoparticles. The nanobody specificity for their targets is maintained in such supramolecular complexes. Also, their diameter around 70 nm and multivalent interactivity should favor binding and penetrability into target cells via solvent-exposed receptor. These concepts have been supported by unrelated nanobodies directed against the ricin toxin (A3C8) and the Her2 receptor (EM1), respectively, that were modified with the addition of a reporter protein and a hexa-histidine tag at the C-terminus that promotes self-assembling. The A3C8-based nanoparticles neutralize the ricin toxin efficiently, whereas the EM1-based nanoparticles enable to selective imaging Her2-positive cells. These findings support the excellent extracellular and intracellular functionality of nanobodies organized in form of oligomeric nanoscale assemblies.

中文翻译：

作为选择性靶向、纳米结构和多价材料的自组装纳米抗体

纳米抗体代表了先进治疗策略中的有价值的工具，但它们的小尺寸（~2.5 × ∼ 4 nm）和有限的相互作用价可能对体内造成限制应用程序，特别是关于它们的多价和协作交互的适度能力。在这项工作中，设计了模块化蛋白质构建体，其中纳米抗体与蛋白质结构域融合，以提供进一步的功能并有利于低聚化成稳定的自组装纳米粒子。纳米抗体对其靶标的特异性在这种超分子复合物中得以保持。此外，它们约 70 nm 的直径和多价相互作用应该有利于通过溶剂暴露受体结合和渗透到靶细胞中。这些概念得到了分别针对蓖麻毒素 (A3C8) 和 Her2 受体 (EM1) 的无关纳米抗体的支持，这些纳米抗体通过在 C 端添加报告蛋白和六组氨酸标签进行修饰，从而促进自我-组装。基于 A3C8 的纳米颗粒有效地中和了蓖麻毒素，而基于 EM1 的纳米颗粒能够对 Her2 阳性细胞进行选择性成像。这些发现支持以寡聚纳米级组件形式组织的纳米体的出色细胞外和细胞内功能。

更新日期：2021-06-30

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