Multifunctional Cu-doped Mn3O4 nanozyme hydrogel microspheres for oral targeted treatment of inflammatory bowel disease.

Oral drug therapy for inflammatory bowel disease (IBD) is often hindered by inadequate targeting, low bioavailability, and reactive oxygen species (ROS) accumulation. To address these challenges, we have developed hydrogel microspheres@Cu-Mn3O4 nanozymes (HMCM) by encapsulating hydrothermally synthesized Cu-doped Mn3O4 nanozymes (CM NZs) into calcium alginate hydrogel microspheres (HM) using microfluidics. These microspheres are designed for colon-targeted IBD treatment. The CM NZs exhibit exceptional superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, effectively scavenging ROS such as H2O2, ·OH, and O2 -·. The negatively charged HMCM promotes targeted accumulation in inflamed colon regions and facilitates specific nanozyme release. In a dextran sulfate sodium (DSS)-induced colitis mouse model, HMCM administration enhanced the expression of tight junction proteins (Claudin, ZO-1, Occludin) and repaired the damaged intestinal barrier. The oral HMCM group significantly reduced inflammation, enhanced antioxidant activity, and inhibited ferroptosis in colonic tissue through the upregulation of GPX4 and SLC7A11. It also restored gut microbiota balance by increasing probiotic populations and suppressing harmful bacteria. Systemic biosafety assessments confirmed HMCM's colon-specific retention and high biocompatibility. This research establishes HMCM as a precision-targeted colonic drug delivery platform, offering a promising therapeutic strategy for the treatment of inflammatory bowel disease.