A Nanozyme‐Enabled Peritoneum‐Biomimetic Nano–Hydrogel for Macrophage‐Targeted ROS–STING Modulation in Postoperative Adhesion‐Free Healing

ABSTRACT

Postoperative abdominal adhesion, characterized by its high prevalence, therapeutic intractability, and severe secondary complications, remains an intricate pathological condition following surgery. Here, using a peritoneal adhesion model integrated with multi‐omics analyses, we identify ROS‐driven activation of the cGAS–STING pathway as a central mechanism underlying macrophage activation and adhesion formation. To address this, black phosphorus nanosheets functionalized with Cu ²⁺ and NH ₂ –PEG–polyinosinic acid (BPNS@Cu@PI) are engineered as a peritoneal macrophage‐specific nanozyme to scavenge ROS. Furthermore, a silk fibroin‐based Janus hydrogel with an MMP‐responsive porous layer and a dense barrier layer (MMP‐JSF) is constructed to mitigate copper‐associated impairment of tissue repair. In vitro, this nano‐hydrogel system enables targeted delivery, redox regulation, mitochondrial homeostasis restoration, cGAS‐STING pathway inhibition, inflammation suppression, and wound healing promotion. In a 7‐day rat model, the BPNS@Cu@PI demonstrated significant efficacy in inhibiting adhesions, with the accompanying MMP‐JSF further enhancing therapeutic outcomes for tissue healing. Mechanistically, in a 3‐day model, the platform not only inhibited adhesions but also exhibited robust therapeutic effects in suppressing the ROS‐STING pathway and restoring mitochondrial function, as evidenced by both pathological and transcriptome analysis. Collectively, this work establishes a pathway‐specific nano–hydrogel strategy for adhesion‐free healing with translational potential.