2. Academic Validation
  3. Ether bond-modified lipid nanoparticles for enhancing the treatment effect of hepatic fibrosis

Ether bond-modified lipid nanoparticles for enhancing the treatment effect of hepatic fibrosis

  • Int J Pharm. 2025 Feb 25:671:125192. doi: 10.1016/j.ijpharm.2025.125192.
Runxuan Chu 1,  Jianglong Kong 2,  Qiang Gao 1,  Yani Yang 1,  Ting Pan 3,  Xiaohong Lu 1,  Zhefeng Wang 4,  Yi Wang 5,  Jun He 6
Affiliations

Affiliations

  • 1 National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China.
  • 2 College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China.
  • 3 National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China; Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
  • 4 National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China. Electronic address: [email protected].
  • 5 College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China. Electronic address: [email protected].
  • 6 National Advanced Medical Engineering Research Center, China State Institute of Pharmaceutical Industry, 285 Gebaini Road, Shanghai 201203, China. Electronic address: [email protected].
PMID: 39824265 DOI: 10.1016/j.ijpharm.2025.125192
Abstract

Lipid nanoparticle (LNP)-mediated RNA delivery holds significant potential for the treatment of various liver diseases. Ionizable lipids play a crucial role in the formulation of LNPs and directly influence their delivery efficiency. In this study, we introduced an innovative concept by incorporating an ether bond into the hydrophobic tail of ionizable lipids for the first time. Three ionizable lipids, namely, ND-O1, ND-O2, and ND-O3, were synthesized based on 1-octylnonyl 8-[(2-hydroxyethyl)-[8-(nonyloxy)-8-oxooctyl] amino] octanoate (Lipid M). The efficacy of lipids-based LNPs for the delivery of the Heat Shock Protein 47 (HSP47)-targeted siRNA to the liver was investigated. Compared to Lipid M-based LNP (LNP-M), it was observed that ND-O1 based LNP (LNP-O1) exhibited enhanced siRNA transfection efficiency in activated fibroblasts. In the fibrosis mice, LNP-O1 effectively suppressed HSP47 expression by approximately 84%, which was three times more effective than LNP-M, resulting in a significant decrease of Collagen deposition and an amelioration of liver fibrosis. These findings highlighted the potential application of ND-O1 as an ionizable lipid for enhancing the efficient delivery of LNPs-delivered siRNA to the liver. Furthermore, this ionizable lipid design strategy offers a promising avenue for the improvement of the LNP delivery system.

Keywords

Gene editing; Heat shock protein 47; Hepatic fibrosis; Ionizable lipids; Lipid nanoparticles.

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