Combinatorial Synthesis of a Lipidoid Library by Thiolactone Chemistry: In Vitro Screening and In Vivo Validation for siRNA Delivery

Transcriptional inhibition by small interfering RNA (siRNA) delivery using synthetic transfection agents eliminates the subsequent risk of introducing mutations in relevant genes, as opposed to viral vectors. However, synthetic vectors with comparable transfection efficiency to that of viral vectors are yet to be developed. Hence, synthesizing new transfection vehicles with low toxicity is important. In this study, a library of lipid-like molecules (lipidoids) was synthesized by thiolactone chemistry. This library facilitated non-viral delivery of siRNA to mammalian cells, inducing sequence-specific knockdown of a target gene. The liposomal nanoparticles complexed with anti-green fluorescent protein (GFP) siRNA were successfully screened for transfection efficiency using a HeLa-GFP cell line. The five best performing lipidoids identified in the screening were found to exhibit superior GFP-knockdown efficiency compared to commercially available transfection reagents. The efficiency of siRNA delivery by one...