Development and functionality analysis of lipoplex-loaded polysaccharide-based surface coatings for local nucleic acid delivery

Abstract

Although therapeutic nucleic acids reached the clinical application for a decade, the success of these new drugs is dependent on their delivery strategies, which are still a challenge. In particular, local delivery of nucleic acids is a promising approach to develop therapies with a spatially controlled site of action. However, compared to techniques for systemic administration, local nucleic acid delivery systems are still rarely described. In this study, we present a promising approach to fill this gap by the design of surface coatings based on polysaccharides for local delivery of nucleic acids. An automatized Layer-by-Layer deposition approach was applied using hyaluronic acid and chitosan to form polyelectrolyte multilayer systems, into which lipid nanoparticles, more specific lipoplexes, were embedded as nucleic acid carriers. Different manufacturing parameters, in particular the number of deposited polyelectrolyte layers and the preparation buffer, were varied. The multilayer film characteristics were investigated systematically regarding their physical properties, with a focus on thickness and topology as well as lipoplex deposition, to identify a system with efficient transfection properties. The multilayer systems prepared in acetate buffer were characterized by a good lipoplex embedding with a more uniform distribution and lower tendency for formation of large lipoplex aggregates in the polyelectrolyte film. Additionally, we were able to demonstrate the functionality of the developed system for nucleic acid delivery. The nucleic acids were successfully transferred into cells in a contact-triggered manner. Furthermore, we could demonstrate the enzymatic degradation-based release of nucleic acid cargo from the delivery system caused by hyaluronidase, followed by successful in vitro transfection.