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Block catiomers with flanking hydrolyzable tyrosinate groups enhance in vivo mRNA delivery via π-π stacking-assisted micellar assembly

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机构： [1]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. [2]Department of Radiology, Center for Medical Imaging, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China. [3]Kanagawa Institute of Industrial Science and Technology, Ebina, Japan. [4]Department of Materials Science and Engineering, School of Materials and Chemical Technology, Tokyo Institute of Technology, Tokyo, Japan. [5]Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan. [6]Graduate School of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Messenger RNA (mRNA) therapeutics have recently demonstrated high clinical potential with the accelerated approval of SARS-CoV-2 vaccines. To fulfill the promise of unprecedented mRNA-based treatments, the development of safe and efficient carriers is still necessary to achieve effective delivery of mRNA. Herein, we prepared mRNA-loaded nanocarriers for enhanced in vivo delivery using biocompatible block copolymers having functional amino acid moieties for tunable interaction with mRNA. The block copolymers were based on flexible poly(ethylene glycol)-poly(glycerol) (PEG-PG) modified with glycine (Gly), leucine (Leu) or tyrosine (Tyr) via ester bonds to generate block catiomers. Moreover, the amino acids can be gradually detached from the block copolymers after ester bond hydrolyzation, avoiding cytotoxic effects. When mixed with mRNA, the block catiomers formed narrowly distributed polymeric micelles with high stability and enhanced delivery efficiency. Particularly, the micelles based on tyrosine-modified PEG-PG (PEG-PGTyr), which formed a polyion complex (PIC) and π-π stacking with mRNA, displayed excellent stability against polyanions and promoted mRNA integrity in serum. PEG-PGTyr-based micelles also increased the cellular uptake and the endosomal escape, promoting high protein expression both in vitro and in vivo. Furthermore, the PEG-PGTyr-based micelles significantly extended the half-life of the loaded mRNA after intravenous injection. Our results highlight the potential of PEG-PGTyr-based micelles as safe and effective carriers for mRNA, expediting the rational design of polymeric materials for enhanced mRNA delivery.© 2023 The Author(s). Published by National Institute for Materials Science in partnership with Taylor & Francis Group.

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出版当年[2023]版：

大类 | 3 区材料科学

小类 | 3 区材料科学：综合

最新[2023]版：

大类 | 3 区材料科学

小类 | 3 区材料科学：综合

第一作者：

第一作者机构： [1]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. [2]Department of Radiology, Center for Medical Imaging, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.

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通讯作者：

通讯机构： [1]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan. [*1]Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan

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