Piperazine-Derived Diamine Lipid Nanoparticles Targeting to the Liver for Delivering Clustered Regularly Interspaced Short Palindromic Repeat Editing of PCSK9 to Durably Maintain Plasmatic Low-Density Lipoprotein Cholesterol in Low Levels

May 4, 2026ACS applied bio materials

Liver-targeted lipid nanoparticles delivering gene editing to lower and keep LDL cholesterol levels low

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Abstract

A single intravenous dose of M10-F4 mediates robust PCSK9 gene editing in mice, resulting in sustained reductions of circulating LDL-C levels for up to 48 days.

M10-F4 demonstrates high nucleic acid encapsulation efficiency (>80%) and forms stable, spherical nanoparticles.
The piperazine-derived ionizable lipid features an optimized apparent pKa of 6.56, enhancing its ability to escape endosomes.
Efficient cellular uptake and cytosolic release of RNA cargo were observed in liver cell lines, with minimal lysosomal entrapment.
The formulation exhibits strong liver targeting after systemic administration.
Acute safety evaluation in mice showed no significant systemic toxicity, with stable body weight and normal liver enzyme levels.

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Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, and durable suppression of low-density lipoprotein cholesterol (LDL-C) via genome editing represents a promising therapeutic strategy. Here, we report the rational design of a piperazine-derived bis-tertiary amine ionizable lipid (M10) and its optimized lipid nanoparticle formulation (M10-F4) for efficient and liver-targeted CRISPR/Cas9 delivery. Compared with benchmark lipids such as SM-102, M10 enables a reduced molar ratio of ionizable lipid while maintaining high nucleic acid encapsulation efficiency (>80%) and forming stable, spherical nanoparticles. The piperazine-based multi-cationic core confers an optimized apparent pKa of 6.56, facilitating endosomal escape through enhanced protonation under acidic conditions. Confocal microscopy in HepG2 and Huh-7 cells reveals efficient cellular uptake and enhanced cytosolic release of RNA cargo with minimal lysosomal entrapment., M10-F4 exhibits strong liver tropism following systemic administration. A single intravenous dose mediates robust PCSK9 gene editing in C57BL/6 mice, resulting in sustained reductions of circulating PCSK9 and LDL-C levels under both normal and high-fat diet conditions for up to 48 days, accompanied by decreased hepatic PCSK9 expression. Importantly, acute safety evaluation in BALB/c mice showed no obvious signs of short-term systemic toxicity, including stable body weight, minimal induction of inflammatory cytokines (IL-6, TNF-α, and CXCL-10), no significant elevation of liver enzymes, and normal gross organ morphology. Collectively, this work establishes M10-F4 as a molecularly engineered, liver-targeted LNP platform in which ionizable lipid architecture and formulation composition enable effectivegenome editing with favorable tolerability, highlighting the importance of rational materials design at the materials-bio interface for cardiometabolic gene-editing applications. In vivo in vivo

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Piperazine-Derived Diamine Lipid Nanoparticles Targeting to the Liver for Delivering Clustered Regularly Interspaced Short Palindromic Repeat Editing of PCSK9 to Durably Maintain Plasmatic Low-Density Lipoprotein Cholesterol in Low Levels

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