Soft Nanocapsules for Systemic Gene Delivery

Systemic delivery of nucleic acids to target tissues is one of the major challenges in non-viral gene delivery. We hypothesize that cationic charges common to non-viral gene carriers cause non-specific protein binding, leading to premature clearance and poor biodistribution profiles. Moreover, tissue penetration of gene complexes needs to be improved to achieve efficient gene transfection. Here we describe the preparation of soft nanocapsules with negative surface charge as a carrier of PDL1-targeting siRNA (siPDL1). Nanocapsules were created by (i) amine functionalization of mesoporous silica nanoparticles (MSN) (ii) siPDL1 adsorption, (iii) assembly of polydopamine (pD) layers on the siPDL1-bound MSN, and (iv) removal of the sacrificial MSN template. The nanocapsules showed hollow structure with an average diameter of 176.7±1.6 nm and surface charge of -22.6 ± 7.1mV and retained 84% of siPDL1 after the removal of MSN template. We confirmed cellular uptake of nanocapsules with Cy3-labelled GAPDH siRNA in CT26 cells by confocal microscopy. We also confirmed transfection of siRNAs targeting GAPDH, luciferase, and PDL1 in CT26 and 4T1-luciferase cells, which resulted in significant suppression of target gene expression (by 42.1% of GAPDH, 86.1% of luciferase, and 33.8% of PDL1).