Inhalable myofibroblast targeting nanoparticles for synergistic treatment of pulmonary fibrosis.

Pulmonary fibrosis (PF) is a life-threatening interstitial lung disease, characterized by excessive fibroblast activation and collagen deposition, leading to progressive pulmonary function decline and limited therapeutic efficacy. Here, the inhalable, myofibroblast-targeted, and pH-responsive liposomes (FL-NI) were developed for effective codelivery of nintedanib, a mainstream antifibrotic drug in clinic, and siIL11, a small interfering RNA that silences the key profibrosis cytokine IL-11. Notably, FL-NI achieved a 117.8% increase in pulmonary drug delivery by noninvasive inhalation and a 71.5% increase in delivery specifically to fibroblast activation protein-positive myofibroblasts while reducing nonspecific immune cell and epithelial uptake by 29.8 and 55.8%, respectively. The accurate inhalation codelivery of nintedanib and siIL11 into myofibroblasts achieved synergistic effects, effectively enhanced myofibroblast deactivation, reduced pathological collagen deposition by 50.8%, and promoted epithelial tissue repair. FL-NI remodeled the aberrant immune microenvironment without inducing systemic toxicities. Therefore, this work demonstrated the notable potential for this pluripotent strategy for improving PF outcomes and its promising clinical translation.