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

Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

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

Authors

Ziyu Zhou^#^{1

2}, Yu Feng^#¹, Mingzhou Jiang³, Zijun Yao¹, Jing Wang¹, Feng Pan⁴, Rulan Feng¹, Chong Zhao¹, Yinyu Ma⁵, Jinge Zhou⁶, Lei Sun^{1

7}, Xiaotian Sun³, Changyou Zhan^{4

5}, Xiao He^{8

9}, Kuan Jiang^{10

11}, Jiahui Yu¹², Zhiqiang Yan^{13

14}

Affiliations

¹ 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.
² School of Pharmacy, East China Normal University, Shanghai, PR China.
³ Department of Cardiothoracic Surgery, Huashan Hospital of Fudan University, Shanghai, PR China.
⁴ Ministry of Education & Department of Pharmacy, School of Pharmacy, Key Laboratory of Smart Drug Delivery, Shanghai Fudan University, Shanghai, PR China.
⁵ Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, PR China.
⁶ Institute of Biomedical Engineering, Kunming Medical University, Kunming, PR China.
⁷ Department of NanoEngineering, Chemical Engineering Program, University of California San Diego, La Jolla, CA, USA.
⁸ 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. [email protected].
⁹ Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China. [email protected].
¹⁰ Department of Pharmacology School of Basic Medical Sciences & State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, PR China. [email protected].
¹¹ Eye Institute and Department of Ophthalmology, Eye and ENT Hospital, Fudan University, Shanghai, PR China. [email protected].
¹² 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. [email protected].
¹³ 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. [email protected].
¹⁴ Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, PR China. [email protected].

^# Contributed equally.

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.

Abstract

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