Reactive Oxygen Species-Activatable Topological Transition Nanogel Integrated with cfDNA Degradation Function for Adaptive Barrier Repair in Inflammatory Bowel Disease

Therapeutic intervention of cell-free DNA (cfDNA) scavenging via DNase I coupled with rapid dynamic repair of the compromised intestinal epithelial barrier (IEB) in inflammatory bowel disease (IBD) presents a potential approach to disrupt the self-perpetuating inflammatory circuit between cfDNA and reactive oxygen species (ROS). However, enzymatic instability during oral delivery and the imperative for spatiotemporally coordinated DNase I enrichment at the inflamed colon alongside epithelial restitution remain critical challenges. Herein, we report a ROS-activatable nanogel, HSD-NG, capable of concurrent cfDNA scavenging and IEB repair. This system comprises catechol-functionalized hyaluronic acid (HA) polymers cross-linked via microenvironment-dependent diselenide bonds, forming acid-resistant nanocarriers for DNase I encapsulation. Within the pathologically elevated ROS, the cleavage of diselenide bonds triggers intra-decross-linking of the nanogel, while catechol oxidation within the polymeric matrix mediates inter-recross-linking. This ROS-triggered topological transition facilitates cfDNA scavenging as well as physical repair of mucosal breaches via adaptive gelation that dynamically conforms to the injury interface. Consequently, this dual modality suppresses the ROS-driven cytokine storm, restores immune homeostasis by inhibiting cfDNA-mediated immune activation in IBD murine models, and improves pathogen exclusion through IEB repair to promote microbial homeostasis. This work describes a pathology-activated nanotherapeutic paradigm integrating cfDNA scavenging with barrier reconstitution, offering a targeted approach to IBD management.