@article{Zhang2025, 
author = {Zongxu Zhang and Fengyang Han and Hongye Lihe and Linwei Lu and Qiankun Xiong and Xi Kang and Dongsheng Pan and Zimiao Luo and Jiasheng Lu and Weiyue Lu and Jianxin Wang and Min Liu},
title = {Molecular dynamics-guided design of 2-aminoimidazole derived lipid nanoparticles for efficient muscle transfection},
year = {2025},
journal = {Nano Research},
volume = {18},
number = {9},
pages = {94907727},
keywords = {lipid nanoparticle (LNP), ionizable lipid, molecular dynamics, definitive screening design},
url = {https://www.sciopen.com/article/10.26599/NR.2025.94907727},
doi = {10.26599/NR.2025.94907727},
abstract = {Lipid nanoparticles (LNPs) formulated with ionizable lipids, such as ALC-0315 and SM-102, suffer from significant hepatic off-target expression following intramuscular administration, which could potentially impair hepatic function and reduce therapeutic efficacy. Currently, novel ionizable lipid discovery predominantly relies on stochastic high-throughput screening. Here, we designed a 2-aminoimidazole (AM)-based ionizable lipid library and established a molecular dynamics-guided strategy for quantitatively analyzing the lipid-mRNA interaction strength, which might offer a rational screening alternative. A33-D268 emerged as the top-performing candidate through molecular dynamics simulations. Following formulation optimization via definitive screening design experiments, the AM-LNP/mRNA formulated with A33-D268 demonstrated an intramuscular transfection efficiency similar to that of ALC-0315-based LNPs, with markedly reduced hepatic off-target expression.}
}