Guanidinated Thiourea-Decorated Polyethylenimines for Enhanced Membrane Penetration and Efficient siRNA Delivery

RNA interference (RNAi) provides the promising treatments of gene-related diseases while hindered by the lack of highly efficient delivery platform with low cytotoxicity. Moreover, the intracellular fates of nonviral gene carriers are closely related to their internalization pathway, and eventually influence their RNAi efficiency. Herein, a series of guanidinated thiourea-modified polyethylenimines (PEI-MTU-Gs) are synthesized and utilized as the efficient carriers of small interfering RNA (siRNA) with up to 71.6% inhibition of luciferase activity in the luciferase-expressing cell lines (i.e., HeLa/Luc cells). The introduction of noncationic hydrogen bond donors, that is, thiourea groups, provides the carriers with much lower cytotoxicities and relatively looser complex structures that facilitate the intracellular release of siRNAs. Furthermore, the multiguanidino structures endow the PEI-MTU-G/siRNA complexes with the ability to directly penetrate cell membrane, which facilitates the cellular internalization while avoiding them suffering from the rigorous lysosomes. The results demonstrate PEI-MTU35-Gs as promising siRNA carriers for further gene therapy.