Tryptophan intercalation in siRNA drives the formation of polymeric micelles with enhanced delivery efficiency†

RSC Pharmaceutics Pub Date : 2024-07-02 DOI:10.1039/D4PM00142G

Yuki Nakashima, Wenqian Yang, Pengwen Chen, Keita Masuda, Teahun Hong and Horacio Cabral

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Abstract

The construction of effective carrier systems is essential for delivering therapeutic small interfering RNA (siRNA). In this study, we present an innovative approach using tryptophan intercalation with siRNA to drive the formation of polymeric micelles. Through a facile yet robust method, the siRNA molecules are encapsulated within polymeric micelles formed by flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) block copolymers bearing biocompatible tryptophane units (PEG-PGTrp). Molecular dynamics (MD) simulations indicated the significance of the indole group, demonstrating its crucial role in fostering favorable interactions through π–π stacking. Moreover, the tryptophan moieties not only aid in the formation of stable micelles, but also contributed to intracellular trafficking and endosomal escape, thereby augmenting siRNA delivery. In vitro studies showed that the PEG-PGTrp-based micelles promoted intracellular delivery of siRNA, leading to enhanced gene knockdown.

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siRNA 中的色氨酸插层促使聚合物胶束的形成，从而提高了递送效率†。

构建有效的载体系统对于递送治疗性小干扰 RNA（siRNA）至关重要。在这项研究中，我们提出了一种创新方法，利用色氨酸与 siRNA 的插层作用来驱动聚合物胶束的形成。通过一种简便而稳健的方法，siRNA 分子被包裹在由含有生物相容性色氨酸单元（PEG-PGTrp）的柔性聚乙二醇-聚甘油（PEG-PG）嵌段共聚物形成的聚合物胶束中。分子动力学（MD）模拟显示了吲哚基团的重要性，证明了它在通过π-π堆叠促进有利相互作用方面的关键作用。此外，色氨酸分子不仅有助于形成稳定的胶束，还能促进细胞内转运和内泌体逃逸，从而增强 siRNA 的递送。体外研究表明，基于 PEG-PGTrp 的胶束促进了 siRNA 的胞内递送，从而增强了基因敲除效果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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RSC Pharmaceutics

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