Surface-Functionalized\nNanoceria: Dual Action in Diabetes\nManagement via Glucose-Responsive Insulin Delivery and Oxidative Stress\nMitigation

Nanoceria\n(NC) is gaining scientific attention due to its widespread\ndrug delivery efficacy and modulation of oxidative stress. Herein,\nwe developed dextran (Dex) capped insulin (INS)-loaded phenylboronic\nacid (PBA)-functionalized nanoceria (NC-PBA-INS-Dex) for glucose-responsive\ninsulin delivery and mitigating excessive ROS production to regulate\nboth hyperglycemia and oxidative stress in diabetes mellitus (DM).\nThe prepared nanoparticle showed favorable loading capacity and excellent\nencapsulation efficiency of insulin. Glucose-responsive insulin release\nfrom NC-PBA-INS-Dex was observed initially in the cell-free mode when\nsubjected to varying glucose concentrations (5.5, 11, and 25 mM).\nInterestingly, under in vitro setting, promising insulin release from\nNC-PBA-INS-Dex was found in muscle cells (major glucose storage cells)\ncompared to lung cells against exposure to different glucose concentration\nsuggesting a glucose-sensitive intracellular insulin delivery. NC-PBA-INS-Dex\ntreatment further upregulated GLUT4 translocation and glucose uptake/utilization\nin sodium palmitate-exposed muscle cells, and results were significantly\nhigher compared to NC or INS alone treated cells. Studies in diabetic\nanimals demonstrated the maintenance of normoglycemia for up to 12\nh upon gavaging a single dose of NC-PBA-INS-Dex compared to INS alone\ntreatment (subcutaneous/oral). Oral administration of NC-PBA-INS-Dex\nalso increased insulin bioavailability (in both serum and muscle tissue)\ncompared with either subcutaneous or oral insulin administration.\nNC-PBA-INS-Dex further exhibited ROS scavenging (superoxide radical)\npotential in cell-free, in vitro, and in vivo systems, and results\nwere comparable to treatment with NC alone. NC-PBA-INS-Dex could effectively\nregulate the expression of occludin and induce the reversible opening\nof a tight junction in intestinal epithelial cells, allowing the particle\ntransport through the intestinal mucosa. Treatment with NC-PBA-INS-Dex\ndid not exhibit any toxicity to in vitro and in vivo models. The NC-based\ndrug delivery system will mimic the physiological regulation of insulin\nsecretion in a noninvasive manner, offering improved patient compliance,\nreduced risk of hyperglycemia, and enhanced overall management of\nDM.