Gene therapy is rapidly regaining traction in terms of research activity and investment across the globe, with clear potential to revolutionize medicine and tissue regeneration. Viral vectors remain the most commonly utilized gene delivery vehicles, due to their high efficiency, however, they are acknowledged to have numerous drawbacks, including limited payload capacity, lack of cell-type specificity, and risk of possible mutations in vivo, hence, patient safety. Synthetic nanoparticle gene delivery systems can offer substantial advantages over viral vectors. They can be utilized as off-the-shelf components to package genetic material, display targeting ligands, and release payloads upon environmental triggers and enable the possibility of programmed cell-specific uptake and transfection. In this study, we have synthesized three functional polymeric building blocks that, in a rapid, facile, tailorable, and stage-wise manner, associate through both electrostatic and noncovalent hydrophobic “host–guest” interactions to form monodisperse self-assembled nanoparticles (SaNP). We show that these SaNPs successfully package significant amounts of microRNA through to plasmid DNA, present desired ligands on their outer surface for targeted receptor-mediated cell-specific uptake and affect efficient translation of packaged plasmids. We confirm that these SaNPs outperform commercially available, gold standard transfection agents in terms of in vitro transfection efficiencies and have very low cytotoxicity. With facile self-assembly and tailorable composition, our SaNP gene delivery system has significant potential in targeted gene therapy applications.

中文翻译：

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使用方便的自组装超分子纳米粒子系统靶向，刺激性的质粒DNA和miRNA的传递。

基因治疗在全球范围内的研究活动和投资方面正在迅速恢复吸引力，并具有彻底改变医学和组织再生的明显潜力。病毒载体由于其高效率而仍然是最常用的基因传递载体，但是，它们被认为具有许多缺点，包括有限的有效载荷能力，缺乏细胞类型特异性以及体内可能发生突变的风险，因此，患者安全。合成的纳米颗粒基因递送系统可以提供比病毒载体更大的优势。它们可用作现成的组件，用于包装遗传物质，展示靶向配体，在环境触发时释放有效载荷，并能实现程序化的细胞特异性摄取和转染的可能性。在这项研究中，我们合成了三种功能性聚合物结构单元，它们以快速，便捷，可定制和分阶段的方式通过静电和非共价疏水性“主体-客体”相互作用缔合，从而形成单分散的自组装纳米颗粒（SaNP）。我们表明，这些SaNPs成功地将大量的microRNA包装到质粒DNA，在其外表面上呈现所需的配体，以靶向受体介导的细胞特异性摄取，并影响包装质粒的有效翻译。我们证实，就体外转染效率而言，这些SaNPs优于市售的金标准转染剂，并且细胞毒性极低。凭借轻松的自组装和可定制的组成，我们的SaNP基因递送系统在靶向基因治疗应用中具有巨大潜力。