A versatile coiled-coil tethering system for the oriented display of ligands on nanocarriers for targeted gene delivery

Abstract Surface modification of non-viral gene delivery nanocarriers may provide advanced features such as receptor targeting, endosomal escape and nuclear import. We here report the design of a versatile and tunable immobilization protocol to functionalize nanocarriers for improved transient gene expression. Our strategy is based on specific interactions occurring between a coil-tagged ligand and a complementary coil-functionalized nanocarrier. As a proof of concept, targeting of DNA/polyethylenimine polyplexes to the epidermal growth factor receptor of A431 cells was investigated. Coiled-coil-mediated oriented tethering of epidermal growth factor triggered a drastic increase of the internalization rate of the targeted polyplexes. To explore the tunability of our platform, surface density of targeting ligand was varied; our results indicated that the internalization rate varied with the ligand-to-polyplex ratio in a “switch mode” fashion. This work prefigures possible avenues for our coiled-coil platform in multiplex functionalization to address transient gene expression bottlenecks in recombinant protein production.