Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

• Published in: Nature communications Vol. 16; no. 1; pp. 360 - 15
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 03.01.2025; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 14/34; 38/77; 38/89; 49/31; 59; 631/61/350/354; 631/61/391/3932; 639/301/54/152; 64/60; 82/51; Animals; Cell activation; Fibroblast activation protein; Fibrosis; Gene silencing; Gene Transfer Techniques; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; Hepatocytes; Hepatocytes - metabolism; HMGB1 protein; Humanities and Social Sciences; Humans; Lactates; Lipids; Liver; Liver - metabolism; Lysosomes; Male; Mice; Mice, Inbred C57BL; Micelles; multidisciplinary; Nanoparticles; Nanoparticles - chemistry; Nucleic acids; Polyesters - chemistry; Polyethylene glycol; Polyethylene Glycols - chemistry; Polylactic acid; Polymers - chemistry; RNA, Small Interfering - administration & dosage; Science; Science (multidisciplinary); siRNA; Stellate cells
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-55721-w

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. Authors develop a siRNA delivery system, named Ionizable Polymeric Micelles (IPMs) which employs a FAPi modification, enabling IPMs to target activated hepatic stellate cells, silencing target genes and treating liver fibrosis.