近日，中国科学院高能物理所程贺团队报道了可电离脂质异构在调节脂质纳米颗粒mRNA递送中的作用。该项研究成果发表在2026年3月2日出版的《美国化学会志》上。

脂质纳米颗粒已被证实是高效的mRNA递送系统，其中可电离脂质作为决定其体内递送效率的关键因素，起着至关重要的作用。然而，阐明可电离脂质的构效关系仍是一项艰巨挑战，这阻碍了具有更高效率和靶向特异性的下一代脂质纳米颗粒的理性设计。

研究组提出了一种简洁高效的异构体策略，利用四组分Ugi反应实现了9种异构可电离脂质的便捷合成。分子动力学模拟和小角中子散射研究表明，可电离脂质异构体的差异导致了脂质纳米颗粒内部不同的可电离脂质-mRNA分子间相互作用以及可电离脂质分布模式，最终引起脂质纳米颗粒表观pK_a值的变化。

体内评估表明，异构可电离脂质在静脉注射后影响不同肝细胞类型的转染特征，在肌肉注射后增强肌肉选择性mRNA递送，并调控DOTAP介导的肺靶向脂质纳米颗粒的递送效率。可电离脂质异构体概念的建立，不仅为可电离脂质优化引入了新的分子设计维度，也为实现靶向mRNA递送的可电离脂质理性设计奠定了基础，从而拓展了mRNA疗法的潜在应用范围。

附：英文原文

Title: Unraveling the Role of Ionizable Lipid Isomerism in Modulating Lipid Nanoparticles for mRNA Delivery

Author: Zepeng He, Zhijia Liu, Taisen Zuo, Zhan Gao, Haihong Yang, Ziying Zhang, Yongzhen Chu, Zheqi Li, Xueer Ge, Xiaorong Pan, Gege Zeng, Hong Zhu, Yuqing Li, Hong Liu, Yi Shi, Lixin Liu, He Cheng, Yongming Chen

Issue&Volume: March 2, 2026

Abstract: Lipid nanoparticles (LNPs) have been demonstrated as effective mRNA delivery systems, with ionizable lipids (ILs) serving as critical determinants of their in vivo delivery efficacy. However, elucidating the structure–activity relationship of ILs remains a formidable challenge, hindering the rational design of next-generation LNPs with improved efficiency and targeting specificity. Here, we present a straightforward and powerful isomerism strategy for the efficient synthesis of 9 isomeric ILs using a four-component Ugi reaction (Ugi-4CR). Molecular dynamics simulations and small-angle neutron scattering investigations revealed that differences in IL isomerism lead to distinct IL-mRNA intermolecular interactions and varied IL distribution patterns within LNPs, ultimately resulting in variations in the apparent pKa of LNPs. In vivo evaluation demonstrated that isomeric ILs contribute to different transfection profiles across liver cell types following intravenous administration, enhance muscle-selective mRNA delivery after intramuscular administration, and modulate the delivery efficiency of DOTAP-mediated lung-targeted LNPs. The establishment of IL isomerism not only introduces a new molecular design dimension for IL optimization but also lays the foundation for the rational design of ILs for targeted mRNA delivery, thus expanding the potential applications of mRNA therapeutics.

DOI: 10.1021/jacs.5c20438

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c20438