GEN biotechnologyJan 24, 2025

Prime editing inside living cells using lipid nanoparticles to deliver modified guide RNA and editor mRNA

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 31, 2026

Abstract

Lipid nanoparticles (LNPs) enhanced editing efficiency by 2.8-fold in an immunodeficient mouse model.

Co-delivery of chemically modified pegRNA and prime editor mRNA using LNPs was successful.
Daily-repeat dosing led to significant liver toxicity without an increase in editing efficacy.
Weekly-repeat dosing was well tolerated and resulted in a 1.8-fold increase in editing efficacy.
The type of ionizable lipids and phospholipids used significantly impacted prime editing efficiency.
LNPs present advantages over adeno-associated virus (AAV), such as avoiding vector size and re-dosing limitations.

Simplified

Prime editing has gained significant attention as a next-generation gene editing technology, owing to its unique advantages. However, realizing its potentialrequires effective delivery strategies. While adeno-associated virus (AAV) has been employed fordelivery of prime editors in research settings, it presents inherent limitations related to vector size, ongoing expression, and inability to re-dose patients. Conversely, lipid nanoparticles (LNPs) do not face these limitations and are emerging as a leading non-viral approach for the delivery of gene editors. In this study, we demonstrate successful co-delivery of chemically modified pegRNA and prime editor mRNA using LNPs forprime editing. We investigate the impact of pegRNA chemical modifications on editing efficiency and explore different re-dosing regimens. In a daily-repeat dose regimen, we saw striking liver toxicity and no increase in editing; by contrast, weekly-repeat dosing was well tolerated and enabled 1.8-fold increase in editing efficacy. Furthermore, in the NSG immunodeficient mouse model, the efficacy of LNP-delivered prime editing was enhanced by 2.8-fold. In addition, the nature of the ionizable lipids and phospholipids strongly influenced prime editing efficiency. Overall, these findings will greatly contribute to the future development of LNPs as a robust platform for delivering prime editors, fostering progress in prime editing research and therapeutic applications. in vivo in vivo in vivo in vivo in vivo

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Prime editing inside living cells using lipid nanoparticles to deliver modified guide RNA and editor mRNA

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