Nebulized Inhalation of ROS-Responsive Dexamethasone-Loaded Liposomes Enhances Therapeutic Efficacy against Pulmonary Fibrosis

This study aimed to develop and evaluate reactive oxygen species (ROS)-responsive (Thioketal-grafted DSPE-PEG2000, DTP) liposomes loaded with dexamethasone (DTP@DEX-LP) for aerosol inhalation to achieve targeted drug delivery and controlled release in the pulmonary fibrosis microenvironment. DTP@DEX-LP was prepared and optimized. The liposomes were characterized for particle size, zeta potential, encapsulation efficiency (EE), and morphology. Their aerosol performance, ROS-responsive drug release, and cellular uptake were assessed <i>in vitro</i>. <i>In vivo</i> pulmonary deposition, pharmacokinetics, and antifibrotic efficacy were evaluated in a bleomycin-induced mouse model, alongside safety profiling. The optimized DTP@DEX-LP exhibited a uniform particle size of ∼ 115 nm, a high EE of >82%, and desirable aerosol properties (FPF ∼ 50%, MMAD ∼ 4.9 μm). The formulation demonstrated ROS-triggered drug release and enhanced cellular uptake <i>in vitro</i>. Following inhalation, DTP@DEX-LP significantly prolonged lung retention and reduced systemic exposure of DEX compared to controls. In the fibrosis model, DTP@DEX-LP treatment yielded superior therapeutic outcomes, markedly improving survival, and reducing collagen deposition. It also showed a notably improved safety profile, with reduced hepatotoxicity compared to intravenous DEX. The ROS-responsive liposomal system represents a promising inhaled platform for the precise treatment of pulmonary fibrosis, effectively enhancing the therapeutic index of dexamethasone by simultaneously improving its efficacy and mitigating systemic toxicity.