Bile Acid–Histidine Decapeptide Conjugates as Promising Additives in Lipid Nanoparticle Formulation for siRNA Delivery

For siRNA-based therapeutics that require repeated administration, the accumulation of ionizable lipids in the body could cause <i>in vivo</i> safety issues. In the present study, we examined the feasibility of a bile acid-histidine decapeptide (H10) conjugate as a novel, biocompatible, and potential additive to reduce the proportion of ionizable lipids for the formulation of LNPs. A lithocholic acid (LCA)-H10 conjugate (LH conjugate) was synthesized and incorporated into the LNPs with low proportions of ionizable lipids (LiLNPs). The fabricated LH conjugate-containing LiLNPs (LiLNP-LH) exhibited more promising gene silencing activity than LiLNPs, despite their similar particle size and morphology. Additionally, LiLNP-LHs exhibited an elevated liver accumulation after intravenous injection and significantly decreased release of the inflammatory cytokines, compared with conventional LNPs with high proportions of ionizable lipids (HiLNPs). Thus, we successfully reduced the proportion of ionizable lipids in LNPs by adding LH conjugates, which could serve as carriers for diverse siRNA therapeutics with promising silencing activity and superior <i>in vivo</i> safety.