Inflammation‐Activatable Nanoscavengers for Sustainable Cell‐Free DNA Capture and Cleavage

Abstract Cell‐free DNA (cfDNA) scavenging using cationic materials represents a promising therapeutic modality for autoimmune diseases (AIDs) such as inflammatory bowel disease (IBD). This approach, however, suffers from critical issues of binding saturation for cfDNA and risk of re‐exposure of the captured cfDNA. Herein, an inflammation‐activatable nanoscavenger integrating both cfDNA capture and cleavage functions is constructed from dendrimer‐templated, charge‐ and conformation‐transformable polypeptides with Cyclen‐Zn complexes conjugated on the backbone termini. At neutral pH, the polypeptides containing both cis ‐aconitic acid and guanidine side chains adopt negative charges and random‐coiled conformation, thus featuring long blood circulation and high accumulation to the inflamed intestinal tissue. Inside the mildly acidic inflammatory microenvironment, the polypeptides transform to the positively charged α‐helices due to removal of the cis ‐aconitic acid groups, thus enabling robust cfDNA capture through electrostatic attraction, salt bridging, and spatial confinement within the cavity between adjacent rod‐like helices. Subsequently, the exposed Cyclen‐Zn endows the nanoscavenger with DNase‐like activity to cleave the captured cfDNA, allowing sustainable cfDNA capture and scavenging. In consequence, the nanoscavenger efficiently inhibits TLR9 activation and restores immune homeostasis in IBD mice. This study proposes an enlightened strategy for sustainable cfDNA scavenging, and it renders a promising modality for AIDs treatment.