Self-degradable "gemini-like" ionizable lipid-mediated delivery of siRNA for subcellular-specific gene therapy of hepatic diseases.
10.1016/j.apsb.2025.04.003
- Author:
Qiu WANG
1
;
Bin WAN
1
;
Yao FENG
2
;
Zimeng YANG
1
;
Dan LI
3
;
Fan LIU
1
;
Ya GAO
1
;
Chang LI
1
;
Yanhua LIU
4
;
Yongbing SUN
5
;
Zhonggui HE
1
;
Cong LUO
1
;
Jin SUN
1
;
Qikun JIANG
1
Author Information
1. Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
2. Kangya of Ningxia Pharmaceutical Co., Ltd., Yinchuan 750000, China.
3. Department of Pharmacy, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing 400038, China.
4. Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
5. Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330006, China.
- Publication Type:Journal Article
- Keywords:
Acute liver injury;
Gene therapy;
Hepatic diseases;
Lipid nanoparticles;
Liver macrophages targeting;
Non-alcoholic steatohepatitis;
Self-degradable “gemini-like” ionizable lipids;
siRNA delivery
- From:
Acta Pharmaceutica Sinica B
2025;15(6):2867-2883
- CountryChina
- Language:English
-
Abstract:
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' pK a, 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@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-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.
