Ultrasound-Activated Janus Heterojunction-Mediated Enhanced Cascade Nanozyme for Inflammatory Bowel Disease Therapy

Abstract Inflammatory bowel disease (IBD) is exacerbated by the excessive accumulation of reactive oxygen species (ROS). To overcome the insufficient catalytic activity of conventional cerium-based nanozymes, we designed an ultrasound-activated Bi@BTC heterojunction nanozyme. The ultrasound-activated carriers generated by bismuth core undergo effective electron-hole separation in the Janus Bi@BTC heterojunction. The holes are enriched in the valence band of the BTC shell, catalyzing the oxidation reaction of Ce3+. Benefiting from the proton-coupled electron transfer (PCET) effect of tannic acid and the electronic coupling at the heterointerface, Bi@BTC accelerates the Ce3+/Ce4+ redox cycling, enabling a highly efficient and stable superoxide dismutase (SOD)−catalase (CAT)-like catalytic cycle and thus robust elimination of multiple ROS in the IBD microenvironment. Density functional theory (DFT) calculations elucidate the catalytic pathways and cyclic mechanisms underlying the dual enzyme-mimetic activities, revealing key intermediates, transition states, and corresponding energy profiles. In vitro and in vivo assays confirmed that Bi@BTC alleviates intestinal inflammation by eliminating excess ROS, upregulating tight-junction proteins, promoting mucosal barrier repair, and restoring gut microbiota homeostasis. This work presents a boosted ROS-elimination strategy via ultrasound-activated heterojunction-mediated effect and PCET-driven cerium redox cycling, establishing a multifunctional paradigm that integrates ROS scavenging, anti-inflammation, mucosal repair, and gut microecological regulation.