Hollow Cu ₂ O Nanozymes Enhance Probiotic Therapy for Colitis via Redox Homeostasis and TXNIP/NLRP3 Inflammasome Inhibition

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.