Inhalable Artificial Polymeric Nucleases Degrading Neutrophil Extracellular Trap‐DNAs and Alleviating Pulmonary Fibrosis

Abstract Pulmonary fibrosis resulting from recurrent lung inflammation due to pathogen infection may lead to serious problems and death. Neutrophil extracellular traps (NETs), consisting of DNAs and proteins released by neutrophils in response to infection, are major pathogenesis factors for pathogen‐associated pulmonary fibrosis. By mimicking nucleic acid hydrolase, polymeric artificial DNases bearing imidazole units (PEG‐PIm) are developed to degrade the DNAs and thus deconstruct NETs, inhibiting pulmonary fibrosis. By tailoring the PIm segments with varied imidazole units, the polymer hydrolase with a defined number of imidazole units outperforms other samples in the cleavage of DNAs and inhibits the transition of pulmonary fibroblasts to myofibroblasts. This polymer digests the DNAs complexed with cationic peptides, unlike natural DNase I. By aerosol inhalation, it reduces NET infiltration in lungs and significantly alleviates inflammatory cytokines and fibrosis. Molecular dynamics simulations indicate that the optimized polymer may expose more effective imidazole units to the DNA backbones and thus enhance the affinity and hydrolysis of phosphodiester linkages. The function is also confirmed by systematic administration of PEG‐PIm to rheumatoid arthritis. Thus, a strategy is provided for treating pulmonary fibrosis that can be applied in a pandemic to reduce high mortality because of pathogen infection.