Glucose-Responsive Insulin Delivery via Surface-Functionalized\nTitanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes\nMellitus

Glucose-dependent\ninsulin delivery systems have been recognized\nas a promising approach for controlling blood sugar levels in individuals\nwith diabetes mellitus (DM). Recently, titanium dioxide nanoparticles\nhave garnered huge attention in scientific research for their small\nsize and effective drug delivery capabilities. In this study, we developed\nalizarin (AL)-capped phenylboronic acid (PBA)-functionalized titanium\ndioxide nanoparticles (TiO<sub>2</sub>) for glucose-sensitive insulin\ndelivery (TiO<sub>2</sub>–PBA–INS–AL) aiming\nto manage both blood sugar levels and its associated organ pathology\nin DM. The synthesized nanoparticles demonstrated favorable loading\ncapacity as well as high insulin encapsulation efficiency. Initial\nstudies demonstrated glucose-responsive insulin release from TiO<sub>2</sub>–PBA–INS–AL in a cell-free environment\nupon exposure to different glucose concentrations. Notably, in vitro\nexperiments revealed that insulin release from TiO<sub>2</sub>–PBA–INS–AL\nwas more effective in muscle cells (primary glucose storage cells)\ncompared to lung cells when subjected to different glucose concentrations\n(5.5–25 mM), indicating a glucose-sensitive intracellular insulin\ndelivery mechanism. Furthermore, treatment with TiO<sub>2</sub>–PBA–INS–AL\nsignificantly enhanced GLUT4 translocation and glucose utilization\nin muscle cells treated with sodium palmitate (PA, 0.75 mM), compared\nto treatments with TiO<sub>2</sub> or insulin alone. In diabetic animal\nmodels, a single oral dose of TiO<sub>2</sub>–PBA–INS–AL\nmaintained normoglycemia for up to 12 h, indicating a significant\nimprovement over subcutaneous or oral insulin treatment. Oral administration\nof TiO<sub>2</sub>–PBA–INS–AL also increased\ninsulin bioavailability in both serum and muscle tissue compared to\nother administration methods. Besides, TiO<sub>2</sub>–PBA–INS–AL\ntreatment showed no toxicity against both in vitro and in vivo models.\nTaken together, this nanocarrier-based drug delivery system mimics\nthe natural regulation of insulin secretion in a noninvasive manner,\nenhancing patient adherence, reducing the risk of hyperglycemia, and\nimproving diabetes management.