Safe and Effective Delivery of mRNA Using Modified PEI-Based Lipopolymers
Huijing Wang,
Xin Liu,
Xuefeng Ai,
K. C. Remant-Bahadur,
Teo A. Dick,
Bingqian Yan,
Tingting Lu,
Xingliang Zhou,
Runjiao Luo,
Minglu Liu,
Xiangying Wang,
Kaixiang Li,
Wei Wang,
Hasan Uludag,
Wei Fu
Affiliations
Huijing Wang
Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China
Xin Liu
Department of Dental Materials, Shanghai Biomaterials Research & Testing Center, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, National Clinical Research Center of Stomatology, No. 427, Jumen Rd., Shanghai 200011, China
Xuefeng Ai
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
K. C. Remant-Bahadur
Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2R3, Canada
Teo A. Dick
Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2R3, Canada
Bingqian Yan
Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China
Tingting Lu
Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China
Xingliang Zhou
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Runjiao Luo
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Minglu Liu
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Xiangying Wang
Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China
Kaixiang Li
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Wei Wang
Department of Pediatric Cardiothoracic Surgery, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
Hasan Uludag
Department of Chemical & Materials Engineering, Faculty of Engineering, University of Alberta, Edmonton, AB T6G 2R3, Canada
Wei Fu
Institute of Pediatric Translational Medicine, Shanghai Children’s Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China
Chemically modified mRNA (modRNA) has proven to be a versatile tool for the treatment of various cancers and infectious diseases due to recent technological advancements. However, a safe and effective delivery system to overcome the complex extracellular and intracellular barriers is required in order to achieve higher therapeutic efficacy and broaden clinical applications. Here, we explored All-Fect and Leu-Fect C as novel transfection reagents derived from lipopolymers, which demonstrated excellent biocompatibility, efficient delivery capabilities, and a robust ability to escape the lysosomes. These properties directly increase mRNA stability by preventing mRNA degradation by nucleases and simultaneously promote efficient gene translation in vitro and in vivo. The modRNA delivered with lipopolymer vectors sustained effective transfection in mouse hearts following direct intramyocardial injection, as well as in major organs (liver and spleen) after systemic administration. No observable immune reactions or systemic toxicity were detected following the systemic administration of lipopolymer-mRNA complexes to additional solid organs. This study identified commercial reagents for the effective delivery of modRNA and may help facilitate the advancement of gene-based interventions involving the safe and effective delivery of nucleic acid drug substances.
