Wang Qiu, Wan Bin, Feng Yao, Yang Zimeng, Li Dan, Liu Fan, Gao Ya, Li Chang, Liu Yanhua, Sun Yongbing, He Zhonggui, Luo Cong, Sun Jin, Jiang Qikun
Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
Department of Biomedical Engineering, College of Future Technology, Peking University, Beijing 100871, China.
Acta Pharm Sin B. 2025 Jun;15(6):2867-2883. doi: 10.1016/j.apsb.2025.04.003. Epub 2025 Apr 6.
Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' p , thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNF exhibits potential in preventing ALI by decreasing tumor necrosis factor (TNF) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol -acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.
定制脂质纳米颗粒（LNPs）介导的小干扰RNA（siRNA）纳米药物在治疗肝病方面显示出前景，如急性肝损伤（ALI）和非酒精性脂肪性肝炎（NASH）。然而，构建解决生物安全问题、确保有效递送并靶向特定肝亚细胞组分的LNPs一直具有挑战性。为了规避上述障碍，我们通过引入二硫键并修饰酯键长度和叔胺头部，开发了三种新型的可自降解“类双子星”离子izable脂质（SS-MA、SS-DC、SS-MH）。我们的研究结果表明，二硫键桥接的LNPs表现出还原响应性药物释放，提高了生物安全性和siRNA递送效率。此外，酯键和叔胺头部的距离显著影响LNPs的p，从而影响内体逃逸、溶血效率、载脂蛋白E的吸收能力、肝细胞摄取效率和肝脏蓄积。我们还开发了修饰甘露糖的LNPs（M-LNP）以特异性靶向肝巨噬细胞。优化后的M-MH_LNP@TNF通过降低巨噬细胞中肿瘤坏死因子（TNF）水平在预防ALI方面显示出潜力，而MH_LNP@DGAT2可以通过选择性降解肝细胞中的二酰甘油酰基转移酶2（DGAT2）来治疗NASH。我们的研究结果为开发新型高效低毒的“类双子星”离子izable脂质以构建LNPs提供了新见解，有望实现对肝病更有效的治疗。
