Redox-Active Nanoceria Integrated with Glucose Oxidase for Glucose-Triggered Metformin Release: Promising Nanocarrier for Managing Oxidative Stress and Hyperglycemia in Diabetes Pathophysiology

Abstract

Development of a glucose-responsive drug delivery platform remains a promising strategy for self-regulated treatment of diabetes mellitus. In the present study, we developed a multifunctional nanocarrier system for the glucose-sensitive delivery of metformin (Met) based upon amine-functionalized nanoceria (NC-NH2) coupled with glucose oxidase (GOx) and capped with dextran. Nanoceria's inherent ability to scavenge reactive oxygen species (ROS) was made possible by its nanozyme feature, and GOx converts glucose into gluconic acid, and thereby causing drug release in a glucose-responsive manner. Drug release was controlled by the dextran shell, which served as a biocompatible gatekeeper. Under hyperglycemic conditions, the synthesized nanocarrier (NC-GOx-Met-Dex) demonstrated regulated, glucose-triggered metformin release with little release at normoglycemic levels. NC-GOx-Met-Dex showed good structural stability under physiologically simulated circumstances, selective glucose-dependent drug release kinetics in cell-free, in vitro, and ex vivo systems, and promising cellular uptake in muscle cells without causing any cytotoxicity. NC-GOx-Met-Dex enhanced glucose uptake, glucose utilization and translocation of glucose transporter protein (GLUT4) compared to the metformin-alone-treated group in palmitic acid-treated (PA, 0.75 mM) muscle cells. Further in vivo studies showed that compared to metformin alone-treated group, the nanocarrier group showed remarkable glycemic management, improvement of insulin levels, and increased metformin bioavailability in muscle tissues in animal models of diabetes mellitus. Nevertheless, NC-GOx-Met-Dex gavaging to untreated animals did not cause any abnormal behavior or adverse effects, and levels of hepato-renal biomarkers, as well as blood cell profiling, were comparable to the untreated group. In general, this research provides a viable strategy for personalized diabetes therapy through the use of a dual and multifunctional nanosystem capable of responding to hyperglycemia while preventing oxidative stress.