Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

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

doi:10.1038/s41467-024-55721-w

Nature Communications (Jan 2025)

Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

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

Affiliations

Ziyu Zhou: 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
Yu Feng: 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
Mingzhou Jiang: Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University
Zijun Yao: 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
Jing Wang: 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
Feng Pan: Ministry of Education & Department of Pharmacy, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Shanghai Fudan University
Rulan Feng: 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
Chong Zhao: 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
Yinyu Ma: Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University
Jinge Zhou: Institute of Biomedical Engineering, Kunming Medical University
Lei Sun: 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
Xiaotian Sun: Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University
Changyou Zhan: Ministry of Education & Department of Pharmacy, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Shanghai Fudan University
Xiao He: 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
Kuan Jiang: Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University
Jiahui Yu: 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
Zhiqiang Yan: 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

DOI: https://doi.org/10.1038/s41467-024-55721-w
Journal volume & issue: Vol. 16, no. 1
pp. 1 – 15

Abstract

Read online

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.

Published in Nature Communications

ISSN: 2041-1723 (Online)
Publisher: Nature Portfolio
Country of publisher: United Kingdom
LCC subjects: Science
Website: https://www.nature.com/ncomms/

About the journal