Strain-Promoted mRNA Transdermal Delivery by Lipoic Lipid Nanoparticles for Therapeutic Skin Genome Editing

Area of Science:

• Biotechnology
• Nanomedicine
• Gene Therapy

Background:

• Lipid nanoparticle (LNP)-mRNA formulations are key nucleic acid therapeutics.
• Inflammatory side effects and oxidative stress limit LNP-mRNA clinical use, especially in inflammatory diseases.

Purpose of the Study:

• To design and synthesize lipoic acid-based ionizable lipids to overcome LNP-mRNA limitations.
• To identify an optimal LNP candidate with enhanced antioxidant and uptake properties.

Main Methods:

• Structure-activity relationship study and design of experiments (DOE) to optimize lipoic acid-based lipids.
• In vitro and in vivo evaluation of LNP efficacy, including reactive oxygen species scavenging, mRNA translation, and cytokine production.
• Application of optimized LNPs for transdermal delivery of Cas9 mRNA and CD93 sgRNA in a psoriasis mouse model.

Main Results:

• LA-A2B2CD3 LNPs demonstrated superior reactive oxygen species scavenging and enhanced mRNA translation.
• Reduced inflammatory cytokine production was observed both in vitro and in vivo.
• Effective CD93 genome editing and therapeutic improvement in a psoriasis model were achieved via transdermal delivery.

Conclusions:

• Lipoic acid-based LNPs offer a robust, biocompatible platform with minimized immunogenicity.
• The reducible disulfide ring of lipoic acid is crucial for cellular uptake and transdermal delivery.
• This LNP platform holds significant potential for mRNA-based genome editing therapies in inflammatory conditions.