用于高效递送小干扰RNA的可电离聚合物胶束

Ionizable polymeric micelles (IPMs) for efficient siRNA delivery.

作者信息

Zhou Ziyu, Feng Yu, Jiang Mingzhou, Yao Zijun, Wang Jing, Pan Feng, Feng Rulan, Zhao Chong, Ma Yinyu, Zhou Jinge, Sun Lei, Sun Xiaotian, Zhan Changyou, He Xiao, Jiang Kuan, Yu Jiahui, Yan Zhiqiang

机构信息

Institute of Biomedical Engineering and Technology, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China.

School of Pharmacy, East China Normal University, Shanghai, PR China.

出版信息

Nat Commun. 2025 Jan 3;16(1):360. doi: 10.1038/s41467-024-55721-w.

DOI:10.1038/s41467-024-55721-w

PMID:39753560

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11699125/

Abstract

Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect. We design three ionizable oligomers (IOs) that, with polylactide-polyethylene glycol (PLA-PEG), form a potential siRNA delivery system, named Ionizable Polymeric Micelles (IPMs). The siRNA encapsulated IPMs escape from lysosomes upon cellular uptake, and silence the target gene. A fibroblast activation protein inhibitor modified IPMs (FAPi-IPMs) show higher targeting for activated hepatic stellate cells (HSCs) compared to that for hepatocytes, silencing both HSP47 and HMGB1, reducing collagen secretion and liver inflammation, thereby treating fibrosis. Moreover, IPMs and FAPi-IPMs mitigate ABC effect and produce fewer PEG antibodies than LNPs, and show minimal apolipoprotein adsorption in vivo compared with LNPs, differentiating their targeting effects from LNPs. In conclusion, IPMs represent a nucleic acid delivery system with alternative targeting ability and reduced ABC effect.

摘要

脂质纳米颗粒（LNPs）被广泛用于核酸递送，但面临着诸如靶向性有限和加速血液清除（ABC）效应等挑战。我们设计了三种可电离低聚物（IOs），它们与聚乳酸-聚乙二醇（PLA-PEG）形成一种潜在的小干扰RNA（siRNA）递送系统，称为可电离聚合物胶束（IPMs）。包裹有siRNA的IPMs在细胞摄取后从溶酶体中逃逸，并使靶基因沉默。与肝细胞相比，一种经成纤维细胞活化蛋白抑制剂修饰的IPMs（FAPi-IPMs）对活化的肝星状细胞（HSCs）具有更高的靶向性，可使热休克蛋白47（HSP47）和高迁移率族蛋白B1（HMGB1）均沉默，减少胶原蛋白分泌和肝脏炎症，从而治疗肝纤维化。此外，与LNPs相比，IPMs和FAPi-IPMs减轻了ABC效应，产生的聚乙二醇抗体更少，并且在体内与LNPs相比显示出最小的载脂蛋白吸附，这使其靶向作用与LNPs不同。总之，IPMs代表了一种具有替代靶向能力和降低ABC效应的核酸递送系统。