Hyaluronic acid (HA) has been described as a biocompatibility enhancer for gene delivery systems; however, the mechanistic implications of its inclusion on the formation and activity of such systems and subsequent gene release are poorly understood. To better understand these issues, we describe herein the preparation and characterization of chitosan and chitosan-hyaluronic acid nanoparticles (CS and CS:HA NPs) for gene silencing. Different formulations were prepared by ionotropic gelation and evaluated for their physicochemical properties and biological activities in A549-Luc cells. Inclusion of HA to CS NPs resulted in a comparable silencing activity with Lipofectamine RNAiMAX (≈85% of luciferase knockdown) and significantly improved cell viability compared with CS NPs. As depicted by isothermal titration calorimetry, HA competed with siRNA for CS binding, lowering CS-siRNA binding strength by 25%. This suggests that besides improving cell biocompatibility of CS NPs, HA might also promote their gene release by loosening the CS-siRNA binding.
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