超分子生物结合策略用于抗体靶向siRNA递送

Supramolecular Bioconjugation Strategy for Antibody-Targeted Delivery of siRNA

BIOCONJUGATE CHEMISTRY

影响因子:3.9

分区:化学2区 / 生化研究方法2区有机化学2区生化与分子生物学3区化学：综合3区

发表日期:2024 Sep 25

作者: Manon Ripoll, Héloïse Cahuzac, Igor Dovgan, Sylvain Ursuegui, Patrick Neuberg, Stephane Erb, Sarah Cianférani, Antoine Kichler, Jean-Serge Remy, Alain Wagner

DOI: 10.1021/acs.bioconjchem.4c00304

摘要

RNA干扰是一种广泛应用的生物学过程，通过双链RNA靶向mRNA降解实现序列特异性基因沉默。然而，siRNAs的理化性质使其递送极具挑战性，限制了其在靶点的生物利用度。在此背景下，我们开发了一种多功能且具有选择性的siRNA递送系统——抗HER2单克隆抗体（trastuzumab）偶联纳米载体。这些免疫缀合物由带有寡核苷酸修饰的抗体与阳离子胶束通过静电相互作用组装而成，用于在HER2过表达癌细胞中靶向递送siRNA。结果显示，在与相应的siRNA以适当的N/P比率结合时，该超分子组装能够在体外高效诱导萤火虫荧光素酶和PLK-1基因的沉默，表现出细胞选择性。

Abstract

RNA interference is a widely used biological process by which double-stranded RNA induces sequence-specific gene silencing by targeting mRNA for degradation. However, the physicochemical properties of siRNAs make their delivery extremely challenging, thus limiting their bioavailability at the target site. In this context, we developed a versatile and selective siRNA delivery system of a trastuzumab-conjugated nanocarrier. These immunoconjugates consist of the assembly by electrostatic interactions of an oligonucleotide-modified antibody with a cationic micelle for the targeted delivery of siRNA in HER2-overexpressing cancer cells. Results show that, when associated with the corresponding siRNA at the appropriate N/P ratio, our supramolecular assembly was able to efficiently induce luciferase and PLK-1 gene silencing in a cell-selective manner in vitro.