Hepatocyte-targeted lipid nanoparticle for full-length ATP7B mRNA delivery in Wilson disease

Oct 13, 2025Journal of controlled release : official journal of the Controlled Release Society

Liver cell-targeted lipid nanoparticles for delivering full-length ATP7B mRNA in Wilson disease

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Abstract

Hepatocyte-targeted delivery of ATP7B mRNA using a low immunoreactivity lipid nanoparticle reduced hepatic copper accumulation by up to 72.1% in a mouse model of Wilson disease.

A low immunoreactivity lipid nanoparticle was developed to deliver ATP7B mRNA specifically to liver cells.
Optimizing the lipid composition increased mRNA expression in liver cells twofold while decreasing it in non-target cells.
In model mice, treatment for six months led to significant reductions in copper levels in the liver.
The intervention restored copper balance in multiple organs and normalized ceruloplasmin activity.
Safety evaluations indicated no allergic reactions or organ toxicity, with most of the lipid being cleared from the body within one week.

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Wilson disease (WD), a copper metabolism disorder caused by ATP7B mutations, requires alternative gene therapies due to the limitations of current treatments such as drug resistance and side effects. Here, we developed a hepatocyte-targeted ATP7B mRNA therapeutic system using a low immunoreactivity lipid nanoparticle (LNP), in which hydroxy-terminated polyethylene glycol lipid (OH-PEG) was utilized to evade human pre-existing anti-PEG antibody recognition and reduce immunogenicity compared with methoxy-terminated polyethylene glycol lipid (MeO-PEG). By optimizing the OH-PEG molar ratio at 3 %, LNP-mediated mRNA expression in hepatocytes increased twofold, while non-target cell expression (Kupffer cells, B cells) decreased by 2 to 6 folds. In vitro studies confirmed ATP7B protein localization to the trans-Golgi network and copper transport functionality. In WD model mice, long-term intervention (6 months) induced reductions in hepatic copper accumulation (up to 72.1 %) in a dose-dependent manner, restored multi-organ copper homeostasis, and normalized ceruloplasmin activity. Safety assessments revealed improved serum biochemical parameters and histopathology, with 95 % of ionizable lipid metabolically cleared within one week after treatment, without allergic reactions or organ toxicity. This study establishes a translatable WD gene therapy platform using a hepatocyte-targeted, low immunoreactivity LNP for full-length ATP7B mRNA delivery, which also serves as an mRNA delivery system for other liver diseases.

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Hepatocyte-targeted lipid nanoparticle for full-length ATP7B mRNA delivery in Wilson disease

Abstract

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