A Tailored Artificial DNase Blocks Sensor Activation and Prevents Autoimmune and Autoinflammatory Diseases

Abstract

AbstractExcessive self‐DNAs recognized by intracellular DNA sensors can initiate innate immunity to express disordered TNF‐α or type I IFN resulting in several autoimmune diseases. Cationic polymers have been profoundly proved to alleviate the inflammatory symptoms by removing the debris of cell‐free DNA (cfDNA). However, clinical applications of cationic materials have been impeded by concerns of their toxicity and the fate of cfDNA in polymer‐cfDNA complex. Herein, it is showed that PEGylated polyimidazoles as a biomimetic DNase potently alleviate pathologic symptoms of self‐DNA‐associated rheumatoid arthritis (RA) rats and Trex1 (DNase III) deficient Aicardi‐Goutiéres syndrome (AGS) mice. The mechanism studies demonstrate that the polyimidazole efficiently attacks the phosphodiester linkages of NAs and cleavages them into small pieces. As imidazole unit is a much weaker organic base that occurs in natural proteins, the polyimidazoles are less toxic to cells and tissues, as manifested by the IC50 values larger than 1000 µg mL−1. This work suggests that synthetic tailored DNase can be a new and safe therapeutic agent to treat chronic autoimmune and refractory inflammatory diseases by degradation of excessive nucleic acids.