| Literature DB >> 34878786 |
Shuai Liu1, Xu Wang1, Xueliang Yu1, Qiang Cheng1, Lindsay T Johnson1, Sumanta Chatterjee1, Di Zhang1, Sang M Lee1, Yehui Sun1, Ting-Chih Lin1, John L Liu1, Daniel J Siegwart1.
Abstract
Polymers represent a promising therapeutic platform for extrahepatic messenger RNA (mRNA) delivery but are hampered by low in vivo efficacy due to polyplex serum instability and inadequate endosomal escape following systemic administration. Here, we report the rational design and combinatorial synthesis of zwitterionic phospholipidated polymers (ZPPs) via cationic polymer postmodification by alkylated dioxaphospholane oxides to deliver mRNA to spleen and lymph nodes in vivo. This modular postmodification approach readily produces tunable zwitterionic species for serum resistance and introduces alkyl chains simultaneously to enhance endosomal escape, thereby transforming deficient cationic polymers to efficacious zwitterionic mRNA carriers without the need to elaborately synthesize functional monomers. ZPPs mediated up to 39 500-fold higher protein expression than their parent cationic counterparts in vitro and enabled efficacious mRNA delivery selectively in spleen and lymph nodes following intravenous administration in vivo. This zwitterionic phospholipidation methodology provides a versatile and generalizable postmodification strategy to introduce zwitterions into the side chains of cationic polymers, extending the utility of cationic polymer families for precise mRNA delivery and demonstrating substantial potential for immunotherapeutic applications.Entities:
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Year: 2021 PMID： 34878786 PMCID： PMC9437927 DOI： 10.1021/jacs.1c09822
Source DB: PubMed Journal: J Am Chem Soc ISSN： 0002-7863 Impact factor: 16.383