Self‐Reinforced DNase‐Based Nanosystem With Accelerated Biofilm Disruption and Boosted Antibiotic Delivery for Bacterial Keratitis Therapy

ABSTRACT Biofilm‐associated infections remain refractory to antibiotics due to the extracellular polymeric substance (EPS) barrier limiting drug penetration and promoting drug resistance genes transfer. Deoxyribonuclease I (DNase I)‐based strategies designed to degrade the EPS scaffold paradoxically fail within the biofilm microenvironment, where oxidative stress rapidly deactivates the enzyme and its cleavage efficiency remains intrinsically low. Here, we developed a self‐reinforced nanosystem (D‐HIC) by integrating MnO 2 (HMnO 2 ) with DNase I and co‐loading indocyanine green and ciprofloxacin, simultaneously addressing the intrinsic limitations of enzyme‐based therapies. Crucially, HMnO 2 catalyzed the excess ROS to protect DNase I from oxidative degradation, and this catalytic process is accompanied by the generation of Mn 2+ which was found to significantly accelerate DNase I‐mediated EPS cleavage by nearly fourfold to achieve rapid biofilm skeleton disruption. This potentiation created rapid penetration channels, enabling deep delivery of loadings for near‐infrared‐triggered complete biofilm elimination and remarkable bacterial killing rate (>99%) at reduced antibiotic doses. In a murine bacterial keratitis model, this strategy achieved superior therapeutic outcomes compared to clinical eye drops. By coupling oxidative stress relief with catalytic cofactor generation from a single material platform, this work establishes a versatile strategy that overcomes the fundamental limitations of traditional enzyme‐based antibiofilm approaches.