Inhalable Artificial Polymeric Nucleases Degrading Neutrophil Extracellular Trap-DNAs and Alleviating Pulmonary
Yibo Du1, Chenxu Zhu1, Ruifeng Wang2,3
1School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, 510275, China.
Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 20, 2025
Summary
New polymeric artificial DNases (PEG-PIm) effectively degrade neutrophil extracellular traps (NETs) to inhibit pulmonary fibrosis. This innovative treatment shows promise for reducing mortality from lung inflammation during pandemics.
Area of Science:
- Biomaterials Science
- Nanotechnology
- Pulmonary Medicine
Background:
- Recurrent lung inflammation from infections can cause fatal pulmonary fibrosis.
- Neutrophil extracellular traps (NETs), composed of DNA and proteins, are key contributors to this fibrosis.
- Current treatments have limitations in addressing NET-mediated pathogenesis.
Purpose of the Study:
- To develop and evaluate polymeric artificial DNases (PEG-PIm) as a novel therapeutic strategy for pulmonary fibrosis.
- To investigate the mechanism of action of PEG-PIm in deconstructing NETs and inhibiting fibroblast activation.
- To assess the in vivo efficacy of PEG-PIm via aerosol inhalation for treating lung fibrosis.
Main Methods:
- Synthesis of polymeric artificial DNases (PEG-PIm) mimicking nucleic acid hydrolase activity.
- Tailoring imidazole units within the polymer to optimize DNA cleavage efficiency.
- In vitro assessment of DNA degradation and inhibition of fibroblast to myofibroblast transition.
- In vivo studies involving aerosol inhalation in a pulmonary fibrosis model.
- Molecular dynamics simulations to elucidate polymer-DNA interactions.
Main Results:
- Optimized PEG-PIm demonstrated superior DNA cleavage compared to other formulations.
- The polymer effectively inhibited the transition of pulmonary fibroblasts to myofibroblasts.
- PEG-PIm successfully degraded DNA complexed with cationic peptides, unlike natural DNase I.
- Aerosol administration reduced NET infiltration, inflammatory cytokines, and fibrosis in the lungs.
- Molecular dynamics simulations supported enhanced polymer-DNA binding and hydrolysis.
Conclusions:
- Polymeric artificial DNases (PEG-PIm) offer a promising therapeutic approach for pathogen-associated pulmonary fibrosis.
- This strategy effectively deconstructs NETs and mitigates lung inflammation and fibrosis.
- The findings suggest a potential application for treating pandemic-related lung injury and reducing mortality.
