Targeted Gut Delivery of Zn, Cu, and Mn Nanominerals Alleviates Oxidative Stress by Activating Endogenous SOD Enzymes.

Abstract

Trace minerals such as Zn, Cu, and Mn are essential for maintaining cellular redox balance as cofactors of key antioxidant enzymes, including SOD1 and SOD2. However, their oral supplementation is often limited by poor stability in the acidic gastric environment and low intestinal absorption. Here, we report the synthesis of methionine-coated-ZnO (Met-ZnO), ascorbic acid-coated Cu₂O (AA-Cu₂O), and dextran-coated MnO₂ (Dex-MnO₂) nanominerals, followed by encapsulation into pH-responsive microcapsules (NMs-MCap) for targeted intestinal delivery. The nanomineral mixture demonstrated strong antioxidant activity at physiological pH by scavenging superoxide radicals, hydrogen peroxide, and ABTS^•+ radicals. In intestinal epithelial (IEC-6) cells, nanominerals significantly alleviated BSO-induced oxidative stress, reducing apoptosis, necrosis, and intracellular ROS accumulation. Oral administration of NMs-MCap in Zn, Cu, and Mn-deficient rats elevated mineral levels in blood and liver, mitigated BSO-induced oxidative damage, reduced lipid peroxidation and pro-inflammatory cytokines, and preserved tissue architecture. Importantly, oral supplementation restored SOD1 and SOD2 expression in key organs, supporting enhanced endogenous antioxidant defense. Metagenomic analysis revealed that mineral deficiency, combined with oxidative stress, caused gut dysbiosis, reducing beneficial taxa and enriching opportunistic ones. Nanomineral supplementation restored microbial balance, increased SCFA-producing bacteria, and improved antioxidant and metal-handling functions, establishing NMs-MCap as a safe, targeted antioxidant strategy supporting host health.