Ionizable polymeric micelles (IPMs) for efficient siRNA delivery

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...

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Published inNature 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
LanguageEnglish
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
Online AccessGet full text
ISSN2041-1723
2041-1723
DOI10.1038/s41467-024-55721-w

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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. 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.
AbstractList 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.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.
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.
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.
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.
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.
ArticleNumber 360
Author Feng, Rulan
Zhou, Jinge
Zhao, Chong
Zhan, Changyou
Jiang, Mingzhou
Yu, Jiahui
Wang, Jing
Sun, Xiaotian
Zhou, Ziyu
Jiang, Kuan
Yao, Zijun
Pan, Feng
Feng, Yu
Yan, Zhiqiang
Sun, Lei
He, Xiao
Ma, Yinyu
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Snippet Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC) effect....
Abstract Lipid nanoparticles (LNPs) are widely used for nucleic acid delivery but face challenges like limited targeting and accelerated blood clearance (ABC)...
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Gene Transfer Techniques
Hepatic Stellate Cells - drug effects
Hepatic Stellate Cells - metabolism
Hepatocytes
Hepatocytes - metabolism
HMGB1 protein
Humanities and Social Sciences
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Lactates
Lipids
Liver
Liver - metabolism
Lysosomes
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Mice, Inbred C57BL
Micelles
multidisciplinary
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Nanoparticles - chemistry
Nucleic acids
Polyesters - chemistry
Polyethylene glycol
Polyethylene Glycols - chemistry
Polylactic acid
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Title Ionizable polymeric micelles (IPMs) for efficient siRNA delivery
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