A multi-responsive biomimetic nano-complex platform for enhanced gene delivery

Abstract

RNA interference (RNAi) is widely regarded as a promising technology for disease treatment, yet one major obstacle for its clinical application is the lack of enhanced siRNA delivery vehicles to circumvent complex extra- and intracellular barriers. By integrating unique peculiarities of thioglycolic acid conjugated chitosan nanoparticles (TCS NPs), biomimetic transfersomes (T) and amphiphilic hyaluronic acid (HA-GMS), a novel nano-complex was prepared, where vascular endothelial growth factor (VEGF) siRNA loaded TCS NPs were cloaked by transfersomes with HA-GMS assembled on the surface (HT-TCS-siRNA NPs). The nano-complex provided superior siRNA protection and desirable stability at pH 7.4 and 6.5 (mimicking tumor tissue) and exerted proton sponge effects at acidic pH 5.0 (mimicking endo/lysosomes). The TCS NPs were stable at pH 5.0 but disintegrated in the presence of 10 mM glutathione (GSH) at pH 7.4 (mimicking tumor cytosol), which was favorable to release siRNA to the cytoplasm. In vitro cell uptake and gene silencing assays exhibited enhanced intracellular siRNA accumulation and VEGF silencing efficacy of HT-TCS-siRNA NPs in HeLa cells. The enhanced gene delivery capacity of the multi-responsive biomimetic nano-complex gives them potential for application in cancer therapy.