Influence of ionizable lipid tail length on lipid nanoparticle delivery of mRNA of varying length

Mar 15, 2024Journal of biomedical materials research. Part A

How lipid tail length affects delivery of different lengths of mRNA by lipid nanoparticles

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Abstract

LNPs formulated with firefly luciferase mRNA and C10-200 enhance liver transfection by over 10-fold.

The structure of ionizable lipid (IL) tails significantly affects the effectiveness of lipid nanoparticles (LNPs) in delivering mRNA.
Small alterations in lipophilicity can drastically influence mRNA translation outcomes.
LNPs containing erythropoietin mRNA and C13-200 IL achieved translation levels comparable to those of the gold standard C12-200 LNP.
LNPs with Cas9 mRNA and C9-200 IL resulted in over three times more genetic modifications than those with C12-200 IL.
Shorter IL tails may enhance the transfection of LNPs with larger mRNA cargos, while longer IL tails may be better for smaller mRNA.

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RNA-based therapeutics have gained traction for the prevention and treatment of a variety of diseases. However, their fragility and immunogenicity necessitate a drug carrier. Lipid nanoparticles (LNPs) have emerged as the predominant delivery vehicle for RNA therapeutics. An important component of LNPs is the ionizable lipid (IL), which is protonated in the acidic environment of the endosome, prompting cargo release into the cytosol. Currently, there is growing evidence that the structure of IL lipid tails significantly impacts the efficacy of LNP-mediated mRNA translation. Here, we optimized IL tail length for LNP-mediated delivery of three different mRNA cargos. Using C12-200, a gold standard IL, as a model, we designed a library of ILs with varying tail lengths and evaluated their potency in vivo. We demonstrated that small changes in lipophilicity can drastically increase or decrease mRNA translation. We identified that LNPs formulated with firefly luciferase mRNA (1929 base pairs) and C10-200, an IL with shorter tail lengths than C12-200, enhance liver transfection by over 10-fold. Furthermore, different IL tail lengths were found to be ideal for transfection of LNPs encapsulating mRNA cargos of varying sizes. LNPs formulated with erythropoietin (EPO), responsible for stimulating red blood cell production, mRNA (858 base pairs), and the C13-200 IL led to EPO translation at levels similar to the C12-200 LNP. The LNPs formulated with Cas9 mRNA (4521 base pairs) and the C9-200 IL induced over three times the quantity of indels compared with the C12-200 LNP. Our findings suggest that shorter IL tails may lead to higher transfection of LNPs encapsulating larger mRNAs, and that longer IL tails may be more efficacious for delivering smaller mRNA cargos. We envision that the results of this project can be utilized as future design criteria for the next generation of LNP delivery systems for RNA therapeutics.

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Influence of ionizable lipid tail length on lipid nanoparticle delivery of mRNA of varying length

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