Ionic liquid self-assembly enables high-loading inhalable delivery of remdesivir.

Clinical use of remdesivir (RDV), the first FDA-approved antiviral for COVID-19 treatment, is limited by poor aqueous solubility and intravenous administration. In this study, an inhalable dry powder (IDP) based on hyaluronic acid (HA)-coated cholinium ionic liquid (IL)-core liposomes (HA-CAGE-Lp@IDP) was developed to overcome these limitations. Two ILs, cholinium maleate (CAME) and cholinium geranate (CAGE), markedly enhanced RDV solubility. Mechanistic studies revealed distinct IL localization within liposomes, with CAME predominantly dissolved in the aqueous core, whereas CAGE self-assembled into an IL-rich dense core that enabled superior RDV solubilization and loading (30% w/w). The optimized HA-coated CAGE liposomes were lyophilized into an IDP that preserved nanoparticle integrity. HA-CAGE-Lp@IDP exhibited favorable powder flowability (Hausner's ratio = 1.08) and aerodynamic properties suitable for deep lung deposition (FPF = 53.5%; MMAD = 2.99 µm). The formulation retained potent anti-SARS-CoV-2 activity in vitro with excellent cytocompatibility (selectivity index = 296.87). In a SARS-CoV-2 hamster model, inhaled HA-CAGE-Lp@IDP achieved rapid viral suppression comparable to marketed RDV, with approximately 99% inhibition of viral replication in the lungs and trachea and marked histopathological improvement. These findings establish HA-coated IL-core liposomes as a promising inhalable platform for localized pulmonary RDV delivery and outpatient antiviral therapy.