Inhalable cryptotanshinone spray-dried swellable microparticles for pulmonary fibrosis therapy by regulating TGF-β1/Smad3, STAT3 and SIRT3 pathways

•Cryptotanshinone (CTS) was encapsulated into inhalable chitosan/L-leucine based swellable microparticles (SMs) for efficient pulmonary fibrosis (PF) therapy. They showed a desirable aerosolization performance, storage stability, sustained drug release, enhanced intracellular uptake andin vitro anti-fibrosis efficacy.•Compared to oral delivery, pulmonary delivery was associated with a high CTS concentration in pulmonary lesion areas at a significantly lower dose, with reduced exposure to blood and non-targeted tissues.•The pathological status of PF enhanced the action of inhaled CTS in lung regions and reduced the risk of systemic adverse reactions.•Compared to oral CTS and the positive control drug (pirfenidone) group, inhaled SMs exhibited similar in vivo anti-fibrosis efficacies at a 60-fold low dose relative to oral delivery. Besides, a sustained therapeutic efficacy was demonstrated.•Major mechanism-related signaling pathways of SMs against PF were identified. Moreover, a satisfactory safety profile of the developed SMs was provenin vitro andin vivo.