Biomimetic design of inhalable self-assembled polypeptide nanozymes for cascade intervention in pulmonary fibrosis progression

Pulmonary fibrosis is a chronic, progressive disease characterized by heightened oxidative stress and irreversible inflammatory damage in lung tissue, with limited therapeutic options and insufficient clinical efficacy. Here, we design an inhalable, self-assembled polypeptide nanozyme (PepNzyme) that mimics the natural enzyme active centers. This nanozyme demonstrates enhanced superoxide dismutase-like activity (10,000 U/mg) and catalase-like activity (70,000 U/mg), optimized through activity screening of the PepNzymes library biomineralized from a polypeptide library and molecular dynamics simulations. This design incorporates a lung epithelial cell-targeting peptide, along with a pH-sensitive and mitochondria-targeted peptide sequence, achieving high-efficiency localized inhalation delivery of PepNzyme. It enables lysosomal escape and mitochondrial accumulation, significantly enhancing therapeutic efficacy and minimizing side effects. The inhaled PepNzyme effectively scavenged free radicals in pulmonary lesions, thereby reversing the inflammatory immune environment, downregulating the TGF-β/SMAD signaling pathway, and inhibiting fibrosis progression. This groundbreaking antioxidant strategy offers promising implications for the treatment of pulmonary fibrosis.