Wang Huijing, Liu Xin, Ai Xuefeng, Remant-Bahadur K C, Dick Teo A, Yan Bingqian, Lu Tingting, Zhou Xingliang, Luo Runjiao, Liu Minglu, Wang Xiangying, Li Kaixiang, Wang Wei, Uludag Hasan, Fu Wei
Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, 1678 Dong Fang Road, Shanghai 200127, China.
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.
Pharmaceutics. 2023 Jan 26;15(2):410. doi: 10.3390/pharmaceutics15020410.
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.
由于最近的技术进步，化学修饰的mRNA（modRNA）已被证明是治疗各种癌症和传染病的通用工具。然而，为了实现更高的治疗效果并扩大临床应用，需要一种安全有效的递送系统来克服复杂的细胞外和细胞内障碍。在这里，我们探索了All-Fect和Leu-Fect C作为源自脂质聚合物的新型转染试剂，它们表现出优异的生物相容性、高效的递送能力以及强大的逃离溶酶体的能力。这些特性通过防止核酸酶降解mRNA直接提高了mRNA的稳定性，同时在体外和体内促进了有效的基因翻译。用脂质聚合物载体递送的modRNA在直接心肌内注射后能在小鼠心脏中持续有效转染，在全身给药后也能在主要器官（肝脏和脾脏）中持续有效转染。向其他实体器官全身给药脂质聚合物-mRNA复合物后，未检测到明显的免疫反应或全身毒性。本研究确定了有效递送modRNA的商业试剂，并可能有助于推动涉及安全有效递送核酸药物的基于基因的干预措施的进展。
