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Development of Diselenide-Containing Poly(β-amino ester)s for Potent mRNA Delivery to the Spleen

IF 5.5 2区化学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biomacromolecules Pub Date : 2025-07-14 DOI:10.1021/acs.biomac.5c00534

Pingge Jiang , Yaxuan Wang , Qiong Wu , Ziyue Wang , Chengfan Wu , Qi Shuai , Yunfeng Yan

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引用次数: 0

Abstract

Polymer-based nanocarriers hold promise for nucleic acid delivery, yet the clinical translation of mRNA polymeric carriers remains hindered by insufficient delivery efficiency and cytotoxicity. Here, we synthesized 180 diselenide-containing poly(β-amino ester)s (PBAEs) via Michael addition. In vitro screening identified PBAEs with superior mRNA delivery efficiency, showing that hydrophobic amine backbones with ionizable cationic amine end-capping are critical. The effective mRNA-PBAE polyplex nanoparticles (PNPs) exhibited moderate positive charge, suitable size, potent cellular uptake, and endosomal escape. Compared with analogs lacking diselenide bonds, diselenide-containing PBAEs demonstrated robust redox responsiveness and formed PNPs with similar mRNA binding and size, but reduced internal hydrophobicity and improved cellular uptake, mediating potent mRNA delivery. Tail vein injection of diselenide-containing PNPs achieved robust splenic-targeted delivery in mice without helper lipids, unlike the lung-targeted delivery of conventional PBAEs. These findings highlight a novel diselenide-containing PBAE platform for effective mRNA delivery, which has great potential in mRNA-based immunotherapeutic applications.

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查看原文本刊更多论文

含有二硒烯的聚（β-氨基酯）s的研制可有效地将mRNA传递到脾脏。

基于聚合物的纳米载体有望用于核酸递送，但mRNA聚合物载体的临床翻译仍然受到递送效率和细胞毒性不足的阻碍。本文采用Michael加成法合成了180个含二硒的聚β-氨基酯（PBAEs）。体外筛选鉴定出具有优越mRNA传递效率的PBAEs，表明具有离子化阳离子胺端盖的疏水胺骨架至关重要。有效的mRNA-PBAE复合纳米颗粒（PNPs）具有中等正电荷，合适的大小，有效的细胞摄取和内体逃逸。与缺乏二硒烯键的类似物相比，含二硒烯的PBAEs表现出强大的氧化还原反应能力，并形成了具有相似mRNA结合和大小的PNPs，但降低了内部疏水性，提高了细胞摄取，介导了有效的mRNA传递。与传统PBAEs的肺靶向递送不同，在没有辅助脂质的小鼠中，尾静脉注射含双硒烯的PNPs实现了稳健的脾靶向递送。这些发现强调了一种新的含二硒的PBAE平台，可以有效地递送mRNA，在基于mRNA的免疫治疗应用中具有很大的潜力。

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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来源期刊

Biomacromolecules

Biomacromolecules 化学-高分子科学

CiteScore

10.60

自引率

4.80%

发文量

417

审稿时长

1.6 months

期刊介绍： Biomacromolecules is a leading forum for the dissemination of cutting-edge research at the interface of polymer science and biology. Submissions to Biomacromolecules should contain strong elements of innovation in terms of macromolecular design, synthesis and characterization, or in the application of polymer materials to biology and medicine. Topics covered by Biomacromolecules include, but are not exclusively limited to: sustainable polymers, polymers based on natural and renewable resources, degradable polymers, polymer conjugates, polymeric drugs, polymers in biocatalysis, biomacromolecular assembly, biomimetic polymers, polymer-biomineral hybrids, biomimetic-polymer processing, polymer recycling, bioactive polymer surfaces, original polymer design for biomedical applications such as immunotherapy, drug delivery, gene delivery, antimicrobial applications, diagnostic imaging and biosensing, polymers in tissue engineering and regenerative medicine, polymeric scaffolds and hydrogels for cell culture and delivery.

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