Ionic liquid-based in situ dynamically self-assembled cationic lipid nanocomplexes (CLNs) for enhanced intranasal siRNA delivery

This research aims to develop a non-invasive strategy for small interfering RNA (siRNA) nasal delivery based on ionic liquids (ILs) and cationic lipids (2,3-dioleoyloxy-propyl)-trimethylammonium-chloride (DOTAP). Other than the classical role of penetration enhancer, ILs also acted as superior solvents to simultaneously load siRNA and DOTAP, forming siRNA-DOTAP-ILs (siRNA-DILs) formulations. During nasal mucosa penetration, DOTAP and ILs components self-assembled into cationic lipid nanocomplexes to load siRNA for enhanced in situ transfection. The siRNA-DILs demonstrated resistance against RNase, significant mucosa penetration, prolonged nasal retention, and satisfying gene-silencing efficacy at lower dosage. Meanwhile, DILs were also able to deliver KCa3.1-targeted siRNA effectively for the treatment of allergic rhinitis in rat model by nasal route. Thus, DILs have great potentials to deliver biological macromolecules across nasal mucosa by in situ dynamic self-assembly.