Inhalable Mucus-Penetrating Engineered Hybrid Nanomedicine for Enhanced Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a life-threatening interstitial lung disease and is one of the complications observed in individuals following COVID-19 infection. Although inhalable nanomedicines hold promise, nebulization-induced shear stress, dense airway mucus barrier, and inefficient <i>in vivo</i> clearance substantially compromise nanomedicine delivery efficiency and biosafety, thereby limiting their therapeutic efficacies. Herein, an inhalable microenvironment-responsive hybrid nanomedicine (PFD@FPNs-CAT) encapsulated with pirfenidone (PFD) and modified with catalase (CAT) is developed, which is able to overcome the supramolecular interactions owing to the small particle size, electronegativity, and PEGylated surface, thus enhancing the accumulation of PFD@FPNs-CAT in the lesions. Moreover, the surface-anchored CAT is demonstrated to relieve hypoxia, thus reversing the immunosuppressive microenvironment and further enhancing the therapeutic efficacy against IPF. Notably, due to the relatively low quantity of silica doping, PFD@FPNs-CAT demonstrates high stability and excellent biocompatibility. This inhalable mucus-penetrating nanomedicine remarkably inhibits the progression of IPF, illuminating the bright prospects for IPF therapy.