Abstract

Inflammatory bowel disease (IBD) progression is sustained by a positive feedback loop. Excessive mucosal ROS activate the TXNIP/NLRP3 inflammasome axis, which in turn drives interleukin-1β-mediated epithelial barrier disruption and dysbiosis. Conventional solid nanozymes suffer from limited catalytic efficiency because dense interiors restrict substrate access. Here, hollow cuprous oxide nanozymes (H-Cu 2 O) are engineered to overcome these limitations. The hollow architecture exposes a larger catalytically accessible surface area, enabling H-Cu 2 O to achieve broad-spectrum reactive oxygen species scavenging with superior efficiency compared with its composition-matched solid counterpart (S-Cu 2 O). In mouse models of colitis, low-dose H-Cu 2 O (4 mg kg −1 ) attenuates oxidative damage, suppresses the TXNIP/NLRP3 cascade, and restores tight junction integrity. Furthermore, 16S rRNA sequencing reveals that H-Cu 2 O remodels the dysbiotic gut microbiota toward homeostasis with Lactobacillus enrichment. Importantly, the sequential co-administration of Lactiplantibacillus plantarum with H-Cu 2 O outperforms the electrostatically assembled hybrid LP@H-Cu 2 O, demonstrating that free nanozyme diffusion is more effective than surface immobilization for combination therapy. This work establishes hollow nanozyme architecture as a key determinant of anti-inflammatory efficacy and validates nanozyme-probiotic co-delivery as a translatable IBD treatment strategy.