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A multifunctional nanoparticle constructed with a detachable albumin outer shell and a redox-sensitive inner core for efficient siRNA delivery to hepatocellular carcinoma cells

Abstract Successful delivery of small interfering RNA (siRNA) into the cytoplasm of target cells relies on biocompatible and efficient vectors. In this study, a novel multifunctional core/shell nanoparticle [CS-SS-9R/BSA-c(RGDyK)] was developed to effectively deliver siVEGF to hepatocellular carcinoma cells (Bel-7402 cells). To improve the gene payload and transfection efficiency, a positively charged inner core (CS-SS-9R) was constructed by grafting nona-arginine (9R) onto chitosan (CS) using disulphide bonds. The negatively charged outer shell [BSA-c(RGDyK)] assembled on the surface of the inner core by electrostatic forces that shielded high cationic charges and provided improved targeting. The protein outer shell gradually detached from the inner core in the acidic lysosomal environment, leaving the cationic inner core exposed in order to escape from lysosomes. The nanoparticles were capable of delivering siVEGF into Bel-7402 cells via integrin receptor-mediated endocytosis. Successful lysosomal escape of the inner core and the rapid release of siVEGF into the cytoplasm resulted in a 78.9% decrease in VEGF expression and 81.2% inhibition of tumour cell proliferation. In conclusion, this nanoparticle is responsive to the intracellular environment and accurately delivered siRNA into the cytoplasm, providing a safe and highly efficient gene delivery strategy for cancer therapy.