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

Excessive 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.