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Dehydroandrographolide succinate (DAS) injection, which was approved in China for the treatment of viral pneumonia and upper respiratory tract infections, is often off-label used for nebulization therapy to avoid the adverse drug reactions associated with the injection. However, the aerodynamic properties and pulmonary fate of nebulized DAS was largely uninvestigated. In this study, the main objectives were to evaluate the in vitro aerodynamic deposition profiles of nebulizer generated aerosols and comparatively investigate the local drug availability and anti-inflammatory efficacy of DAS between intratracheal and intravenous dosing. The in vitro evaluation of aerodynamic characteristics and droplet size distribution showed more than 50% aerosol particles with size being5 μm, allowing the aerosols to reach the lower respiratory tract. Following intratracheal administration, the drug underwent pulmonary absorption into the bloodstream, rendering an absolute bioavailability of 47.3%. Compared to the intravenous delivery, the intratracheal administration dramatically increased the drug availability in the lung tissue in rats by more than 80-fold, leading to an improved and prolonged local anti-inflammatory efficacy in a lipopolysaccharide induced lung injury model in mice. The present results demonstrated that inhalation delivery of DAS is a convenient and effective alternative to intravenous injections.