Hu Bo, Li Bo, Li Kun, Liu Yuanyuan, Li Chunhui, Zheng Lulu, Zhang Mengjie, Yang Tongren, Guo Shuai, Dong Xiyu, Zhang Tian, Liu Qing, Hussain Abid, Weng Yuhua, Peng Ling, Zhao Yongxiang, Liang Xing-Jie, Huang Yuanyu
School of Life Science; Advanced Research Institute of Multidisciplinary Science; Institute of Engineering Medicine; Key Laboratory of Molecular Medicine and Biotherapy; Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering, Beijing Institute of Technology, Beijing 100081, China.
Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, Beijing Institute of Technology, Beijing 100081, China.
Sci Adv. 2022 Feb 18;8(7):eabm1418. doi: 10.1126/sciadv.abm1418. Epub 2022 Feb 16.
Small interfering RNA (siRNA) therapeutic is considered to be a promising modality for the treatment of hyperlipidemia. Establishment of a thermostable clinically applicable delivery system remains a most challenging issue for siRNA drug development. Here, a series of ionizable lipid-like materials were rationally designed; 4 panels of lipid formulations were fabricated and evaluated on the basis of four representative structures. The lead lipid (A1-D1-5) was stable at 40°C, and the optimized formulation (iLAND) showed dose and time dual-dependent gene silencing pattern with median effective dose of 0.18 mg/kg. In addition, potent and durable reduction of serum cholesterol and triglyceride were achieved by administering siRNAs targeting or () in high-fat diet-fed mice, db/db mice, and human transgenic mice, respectively, accompanied by displaying ideal safety profiles. Therefore, siRNA@iLAND prepared with thermostable A1-D1-5 demonstrates substantial value for siRNA delivery, hyperlipidemia therapy, and prevention of subsequent metabolic diseases.
小干扰RNA（siRNA）疗法被认为是治疗高脂血症的一种有前景的方式。建立一种热稳定的临床适用递送系统仍然是siRNA药物开发中最具挑战性的问题。在此，合理设计了一系列可电离的类脂质材料；基于四种代表性结构制备并评估了4组脂质制剂。先导脂质（A1-D1-5）在40°C下稳定，优化后的制剂（iLAND）表现出剂量和时间双重依赖的基因沉默模式，中位有效剂量为0.18 mg/kg。此外，通过分别在高脂饮食喂养的小鼠、db/db小鼠和人转基因小鼠中施用靶向 或 （）的siRNA，实现了血清胆固醇和甘油三酯的有效且持久降低，同时显示出理想的安全性。因此，用热稳定的A1-D1-5制备的siRNA@iLAND在siRNA递送、高脂血症治疗以及预防后续代谢疾病方面具有重要价值。
