Introduction: Liposomal metered dose inhalers possess ample superiorities in pulmonary disease therapy. Nevertheless, liposomes are vulnerable to aggregate in the propellant medium, giving the bottleneck low stability for the clinical translation. Current stabilization strategies based on the physical barrier become invalid in the propellant medium, and there is anurgent need to seek a valid approach to overcome the bottleneck issue. To achieve this goal, we have proposed a new strategy: a micro-coagulated ion-doping protein corona “repulsive barrier”.

Methods: In this research, a liposomal inhalation aerosol was prepared based on the encapsulation system of liposome-Ca²⁺-Cl^--bovine serum albumin. Its size, charge, and morphology were characterized, followed by in vitro release and encapsulation capacity analysis by dialysis. Finally, fluorescent labelling was assessed for aerosol particle distribution and deposition to evaluate its aerodynamic properties.

Results: The findings indicated that the coronated nanoparticles were more homogeneous than other control formulations. Concurrently, the zeta potential was approximately -19 mV, suggesting the surface charge properties were unaffected. The formulation achieved 90% cumulative in vitro release without burst release. The three prepared systems exhibited comparable drug encapsulation efficiencies, reaching 80%. In addition, strong fluorescence signals were detected by fluorescence imaging, which confirmed the excellent encapsulation effect.

Conclusions: The consistent and reproducible results of particle size, zeta potential, morphology, drug release profile, and encapsulation efficiency collectively demonstrated the successful fabrication of the micro-coagulated ion-doping protein corona “repulsive barrier” system. Furthermore, the aerodynamic property assessment showed that the particle size distribution was reasonable and the aerodynamic properties were satisfactory after nebulization.