Inside‐Outside ROS Therapeutic Strategy Based on Piezoelectric Nano‐Urchin for Drug‐Resistant Bacteria Biofilm Infections

ABSTRACT Biofilm‐associated infections pose a critical clinical challenge due to their inherent antibiotic resistance and limited therapeutic penetrability. Herein, we engineered a mechano‐piezoelectric nano‐urchin system, NiCo 2 S 4 @UiO‐66, which utilizes ultrasound to achieve mechanical biofilm disruption and spatially hierarchical reactive oxygen species (ROS) generation for synergistic antimicrobial therapy. The spiky architecture of NiCo 2 S 4 nano‐urchins acts as physical penetrators, mechanically compromising biofilm integrity. Under ultrasound activation, a graded ROS generation mechanism is greatly enhanced via two distinct pathways. Externally, the NiCo 2 S 4 nanozyme activated by piezoelectric UiO‐66 successfully catalyzes pathogenic H 2 O 2 at the biofilm periphery into highly destructive ·OH radicals, which not only degrade the extracellular polymeric matrix, but avoids additional oxidative stress. Internally, the mechanically driven piezoelectric UiO‐66 component generates long‐diffusing singlet oxygen ( 1 O 2 ), capable of targeting and eliminating bacteria embedded deep within the biofilm. Driven by the nano‐urchin mechanical action, this hierarchical ROS mechanism integrates intra‐biofilm 1 O 2 production with peripheral ·OH‐mediated decomposition, ensuring robust and comprehensive biofilm eradication. In a murine model of methicillin‐resistant Staphylococcus aureus ( MRSA ) infected wounds, the system achieved rapid biofilm clearance and accelerated tissue repair through immunomodulation and angiogenesis promotion. This strategy addresses key limitations of conventional antimicrobial therapies and offers an effective approach for treating multidrug‐resistant biofilm infections.