A novel ionizable lipid with comprehensive improvements in transfection potency, immune profile and safety of lipid nanoparticle

Aug 16, 2025Journal of controlled release : official journal of the Controlled Release Society

A new ionizable lipid that improves gene delivery strength, immune response, and safety in lipid nanoparticles

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Abstract

FS01-LNPs achieved a particle size of approximately 70 nm with over 90% encapsulation efficiency.

FS01 enhances mRNA stability through interactions between its aromatic tail and nucleobases.
Compared to FDA-approved lipids, FS01-LNPs showed superior mRNA delivery across multiple administration routes in mice.
In vaccine models for Varicella-zoster virus and Hepatitis B virus, FS01-LNPs elicited strong immune responses, including antibodies and memory B cells.
Transcriptomic profiling indicated that FS01-LNPs induced balanced innate immune activation with minimal inflammation.
Safety assessments revealed lower liver toxicity with FS01-LNPs compared to other tested LNPs.

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Ionizable cationic lipid is critical for construction of lipid nanoparticles (LNPs) for mRNA delivery. Here, we reported the rational design and evaluation of FS01, a novel ionizable cationic lipid incorporating an ortho-butylphenyl-modified hydrophobic tail into a squaramide-based lipid headgroup architecture. Molecular dynamics simulations revealed that FS01 enhances mRNA stability through π-π stacking interactions between its aromatic tail and nucleobases aromatic rings, alongside hydrogen bonding via the squaramide headgroup. FS01-LNPs demonstrated smaller particle sizes (∼ 70 nm), high encapsulation efficiency (> 90 %), and superior mRNA delivery performance across intramuscular, subcutaneous, and intravenous routes in mice compared to FDA-approved lipids (Dlin-MC3-DMA, SM-102, ALC-0315). In prophylactic vaccine models (Varicella-zoster virus and Hepatitis B virus), FS01-LNP formulations elicited robust antigen-specific antibodies, memory B cells, and Th1-biased T cell responses, outperforming benchmark LNPs. Further, transcriptomic profiling and safety assessments demonstrated that FS01-LNP induced a well-balanced innate immune activation with minimal inflammation and liver toxicity, contrasting with the pronounced reactogenicity of Dlin-MC3-DMA and ALC-0315 LNPs. These findings highlighted FS01 as a promising ionizable lipid candidate for mRNA therapeutics, offering enhanced delivery efficiency, immunogenicity, and safety, with potential applications extending beyond vaccines to gene editing and protein replacement therapies.

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A novel ionizable lipid with comprehensive improvements in transfection potency, immune profile and safety of lipid nanoparticle

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