Chitosan-Coated Pirfenidone/Azithromycin Coloaded Liposomal Inhalation Platform for Synergistic Treatment of Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), frequently triggered by infections, is characterized by acute inflammation occurring on top of progressive fibrosis, resulting in high mortality rates and a lack of effective treatments. This study aimed to disrupt the “infection–inflammation–fibrosis” cascade through a chitosan-coated liposomal formulation that co-loads pirfenidone (PFD) and azithromycin (AZM) for nebulized inhalation (CS-PFD/AZM-Lip). Methods: The formulation utilized a dipalmitoylphosphatidylcholine (DPPC)/cholesterol lipid backbone that closely resembles the endogenous pulmonary surfactant. The liposomal surface was electrostatically coated with chitosan to enhance mucoadhesion, antibacterial synergy, and aerosolization stability. We characterized particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency, alongside stability assessments during nebulization and storage at 4 °C. In vitro release was evaluated in bronchoalveolar lavage fluid from bleomycin/lipopolysaccharide-challenged mice, simulating the pathological microenvironment. Cellular uptake and antifibrotic effects were examined in TGF-β1-activated fibroblasts, while efficacy and safety were tested in a bleomycin- and lipopolysaccharide-induced AE-IPF mouse model. Results: CS-PFD/AZM-Lip demonstrated a uniform size of 138.83 ± 0.31 nm (PDI 0.251 ± 0.009), a zeta potential of +23.67 ± 1.27 mV, and encapsulation efficiencies of 83.7% (PFD) and 86.0% (AZM), all of which remained unchanged following nebulization, with an 8-week stability at 4 °C. Both drugs exhibited enhanced release in the simulated pathological microenvironment. The formulation was efficiently internalized by activated fibroblasts, significantly suppressing migration, myofibroblast differentiation, and collagen production at both transcriptional and protein levels. In AE-IPF mice, nebulized CS-PFD/AZM-Lip attenuated pulmonary inflammation and collagen deposition compared to oral free drugs, improved lung function and survival, and showed no detectable toxicity in major organs or in hematological, serum biochemical, and hemolysis assessments. Conclusions: This study successfully synthesized the CS-PFD/AZM-Lip nano-liposome for nebulized inhalation. By integrating clinically established therapeutic regimens with an inhalable nanocarrier platform, CS-PFD/AZM-Lip presents a highly promising novel strategy for the treatment of AE-IPF.