Facile Synthesis of Multifunctional Bioreducible Polymers for mRNA Delivery
Facile Synthesis of Multifunctional Bioreducible Polymers for mRNA Delivery
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DOI：
10.1002/chem.202203393
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发表时间：
2023-01-24
影响因子：
4.3
通讯作者：
Guan, Zhibin
中科院分区：
文献类型：
--
作者：
Hickey, James C.;Hurst, Paul J.;Guan, Zhibin
生物可还原的聚合物mRNA载体是用于基因递送和疫苗开发的新兴载体家族。已经通过硫辛酸衍生物的水相开环聚合产生了一些生物可还原的系统，然而这种方法限制了疏水基团并入和功能性到所得聚合物中。在本文中，合成了聚（活性酯）二硫化物聚合物，其可以在化学计量控制和温和反应条件下与含胺底物进行容易的氨解，以产生多官能聚二硫化物聚合物库。官能化的聚二硫化物聚合物物质形成稳定的mRNA-聚合物纳米颗粒，用于体外mRNA的细胞内递送。烷基官能化的聚二硫化物-RNA纳米颗粒在体外向细胞递送EGFP和OVA mRNA时表现出快速的细胞摄取和优异的生物降解性。这种简化的聚二硫化物合成提供了一种新的简便方法，用于获得多功能生物可还原聚合物作为RNA递送和其他应用的生物材料。
Bioreducible polymeric mRNA carriers are an emerging family of vectors for gene delivery and vaccine development. A few bioreducible systems have been generated through aqueous-phase ring-opening polymerization of lipoic acid derivatives, however this methodology limits hydrophobic group incorporation and functionality into resulting polymers. Herein, a poly(active ester)disulfide polymer is synthesized that can undergo facile aminolysis with amine-containing substrates under stoichiometric control and mild reaction conditions to yield a library of multifunctional polydisulfide polymers. Functionalized polydisulfide polymer species form stable mRNA-polymer nanoparticles for intracellular delivery of mRNAs in vitro. Alkyl-functionalized polydisulfide-RNA nanoparticles demonstrate rapid cellular uptake and excellent biodegradability when delivering EGFP and OVA mRNAs to cells in vitro. This streamlined polydisulfide synthesis provides a new facile methodology for accessing multifunctional bioreducible polymers as biomaterials for RNA delivery and other applications.