Bile Acid-Histidine Decapeptide Conjugates as Promising Additives in Lipid Nanoparticle Formulation for siRNA...

Area of Science:

• Biotechnology
• Drug Delivery Systems
• Nanomedicine

Background:

• Repeated administration of siRNA therapeutics can lead to in vivo safety issues due to ionizable lipid accumulation.
• Lipid nanoparticles (LNPs) are crucial for siRNA delivery but often require high proportions of ionizable lipids.

Purpose of the Study:

• To investigate a bile acid-histidine decapeptide (H10) conjugate as a biocompatible additive to reduce ionizable lipids in LNPs.
• To assess the efficacy and safety of LNPs formulated with reduced ionizable lipids using the novel conjugate.

Main Methods:

• Synthesis of a lithocholic acid (LCA)-H10 conjugate (LH conjugate).
• Formulation of low ionizable lipid LNPs (LiLNPs) incorporating the LH conjugate (LiLNP-LH).
• Evaluation of gene silencing activity, particle characteristics, in vivo liver accumulation, and inflammatory cytokine release.

Main Results:

• LH conjugate-containing LiLNPs (LiLNP-LH) showed enhanced gene silencing compared to LiLNPs.
• LiLNP-LH exhibited increased liver accumulation and significantly reduced inflammatory cytokine release versus conventional high ionizable lipid LNPs (HiLNPs).
• Particle size and morphology remained similar between LiLNPs and LiLNP-LH.

Conclusions:

• LH conjugates effectively reduce the proportion of ionizable lipids required in LNPs.
• This strategy offers a promising approach for developing safer and more effective siRNA therapeutics.
• The developed LiLNP-LH system demonstrates potential as a versatile carrier for diverse siRNA applications.