Du Yibo, Zhu Chenxu, Wang Ruifeng, Chen Shi, Li Chuang, OuYang Defang, Liu Lixin, Chen Yongming
School of Materials Science and Engineering, Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-sen University, Guangzhou, 510275, China.
State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences (ICMS), University of Macau, Macao, 999078, China.
Adv Sci (Weinh). 2025 Sep;12(34):e05357. doi: 10.1002/advs.202505357. Epub 2025 Jun 20.
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.
由病原体感染引起的反复肺部炎症导致的肺纤维化可能会引发严重问题甚至死亡。中性粒细胞胞外陷阱（NETs）由中性粒细胞响应感染而释放的DNA和蛋白质组成，是病原体相关肺纤维化的主要发病因素。通过模拟核酸水解酶，开发了带有咪唑单元的聚合物人工脱氧核糖核酸酶（PEG-PIm）来降解DNA，从而解构NETs，抑制肺纤维化。通过用不同的咪唑单元定制PIm片段，具有特定数量咪唑单元的聚合物水解酶在DNA切割方面优于其他样品，并抑制肺成纤维细胞向肌成纤维细胞的转变。与天然脱氧核糖核酸酶I不同，这种聚合物能消化与阳离子肽复合的DNA。通过气溶胶吸入，它可减少肺部的NET浸润，并显著减轻炎症细胞因子和纤维化。分子动力学模拟表明，优化后的聚合物可能会使更有效的咪唑单元暴露于DNA主链，从而增强对磷酸二酯键的亲和力和水解作用。对类风湿性关节炎系统性施用PEG-PIm也证实了该功能。因此，提供了一种治疗肺纤维化的策略，该策略可应用于大流行情况，以降低因病原体感染导致的高死亡率。
