Cas9 Protein Outperforms mRNA in Lipid Nanoparticle-Mediated CFTR Repair

Sep 17, 2025Nano letters

Cas9 Protein Works Better Than mRNA for Lipid Nanoparticle Delivery in Fixing CFTR

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CRISPR Gene Editing on OpenScience ↗PubMed ↗DOI ↗

Abstract

Cas9 protein delivered via lipid nanoparticles (LNPs) outperforms Cas9 mRNA for gene editing related to cystic fibrosis.

Lipid nanoparticles are advanced delivery systems for nucleic acid cargo in gene editing.
Efficient delivery of Cas9 with single guide RNA and repair DNA template supports precise editing.
Delivery of Cas9 protein results in better lung editing and functional recovery of the CFTR protein compared to Cas9 mRNA.
Optimizing CRISPR/Cas9 LNPs could enhance therapeutic applications for cystic fibrosis.

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Lipid nanoparticles (LNPs) are currently one of the most clinically advanced delivery systems for nucleic acid cargo and hold great potential for clinical applications in gene editing and the treatment of genetic diseases. LNP-mediated delivery of Cas9 with single guide RNA (sgRNA) and homology-directed repair DNA template (ssDNA) enables efficient and precise editingand. Comparative analysis of LNP delivery of Cas9 as protein or mRNA for relevant clinical targets, such as cystic fibrosis (CF), which is caused by mutations in the CFTR gene, is imperative in the design of corrective therapeutics for genetic diseases. Here, we show that delivery of Cas9 protein LNPs outperforms Cas9 mRNA LNPs when evaluated forlung editing as well as corrective CRISPR/Cas9 editing and functional recovery of the CFTR protein. These results demonstrate the ability to optimize the use of CRISPR/Cas9 LNPs for cystic fibrosis applications. in vitro in vivo in vivo