Corosolic acid derivative-based lipid nanoparticles for efficient RNA delivery

Area of Science:

• Biotechnology
• Nanomedicine
• Drug Delivery

Background:

• Lipid nanoparticles (LNPs) are the primary platform for in vivo RNA delivery.
• Current LNP formulations face challenges including limited transfection efficiency and off-target hepatic delivery.
• These limitations necessitate higher doses and raise safety concerns.

Purpose of the Study:

• To develop novel cholesterol-free lipid nanoparticles for improved RNA delivery.
• To synthesize and evaluate corosolic acid (CA) derivatives as components of lipid nanoparticles.
• To identify a superior LNP formulation with enhanced efficacy and reduced side effects.

Main Methods:

• Synthesis of three corosolic acid (CA) derivatives to create a library of cholesterol-free lipid nanoparticles (CAxLNPs).
• Evaluation of CAβLNP's performance against cholesterol-containing LNPs, focusing on tumor cell uptake and endosomal membrane fusion.
• Assessment of endosomal escape, cytoplasmic delivery of mRNA/siRNA, and biodistribution after intratumoral injection.

Main Results:

• CAβLNP demonstrated enhanced tumor cell uptake and superior endosomal membrane fusion compared to traditional LNPs.
• Optimal endosomal escape and efficient cytoplasmic delivery of mRNA/siRNA were achieved with CAβLNP.
• CAβLNP showed improved retention and penetration in tumor tissues with minimized hepatic transfection.

Conclusions:

• CAβLNP represents a highly effective, cholesterol-free LNP formulation for RNA delivery.
• This novel LNP platform offers enhanced efficacy and safety, reducing off-target effects.
• CAβLNP holds significant promise for expanding the therapeutic applications of RNA-based medicines.