Ciclesonide/indacaterol-encapsulated liposomes: optimizing corticosteroid-bronchodilator therapy for a more effective...

Combination therapy with inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) is the clinical cornerstone of asthma management. However, therapeutic efficacy is frequently compromised by high drug hydrophobicity, which enhances entrapment within the pulmonary mucus and promotes recognition and clearance from alveolar macrophages. This results in reduced drug availability at the target site, requiring higher doses or more frequent administrations. To overcome these biological barriers and improve the therapeutic outcomes, we report the systematic optimization of a liposomal formulation for the co-delivery of ciclesonide (CIC) and indacaterol maleate (IND). Among various PEGylated lipids, DSPE-PEG was chosen because its amine function maximizes IND encapsulation via amine-phosphate interactions and its 18-carbon chain exhibited superior biocompatibility with macrophages compared to C14 and C16 analogs. Incorporating DSPE-PEG at 15% ensured robust mucopenetration and macrophage evasion, significantly improving the ex vivo relaxation effect of IND compared to the drug solution. DLPC was utilized as the main phospholipid since its high degree of unsaturation (two double bonds) was essential for achieving high encapsulation efficiency of both hydrophobic payloads, efficient epithelial cell uptake in vitro and improved ex vivo efficacy and potency of IND. In an OVA-induced murine model, the optimized formulation markedly attenuated airway hyperresponsiveness and suppressed the type 2 inflammatory cascade, including upstream epithelial-derived alarmins, downstream inflammatory cytokines and inflammatory cell recruitment. Notably, liposomal encapsulation also provided a potential dose-sparing effect for both compounds, suggesting that efficient pulmonary delivery of ICS/LABA via lipid nanoparticles is a promising asthma management strategy and may be applicable to other respiratory diseases.