Effects of Histidine Oligomers in Lipid Nanoparticles on siRNA Delivery.

In this study, we developed histidine oligomer (oHis; 10mer)-incorporating LNPs (H10LNPs) as a novel carrier for efficient siRNA delivery. Notably, the unmodified oHis (10mer) was greatly incorporated within LNPs through ionic interaction with siRNAs, which serves as an endosome escape enhancer. H10LNPs with a size of approximately 65 nm demonstrated a significantly enhanced extent of endosomal escape, as evidenced by calcein assay and confocal microscopy images of intracellular fluorescence, surpassing conventional LNPs. Furthermore, the half inhibitory concentration (IC 50 ) of the human endogenous globotriaosylceramide synthase (Gb3 synthase) gene in H10LNPs-treated cells exhibited a significant three-fold decrease, compared to that in LNP-treated cells. Notably, H10LNPs maintained comparable biocompatibility and biodistribution both in vitro and in vivo. Considering that the fabricated siRNA H10LNPs exhibited excellent biocompatibility and superior gene silencing activity over conventional LNPs, these particles can be harnessed for the safe delivery of therapeutic siRNAs. Additionally, this study introduces promising, feasible, simple, and alternative formulation processes for integrating unmodified functional cationic peptides into LNPs to enhance the delivery efficiency of a wide range of nucleic acid-based drugs. This article is protected by copyright. All rights reserved.