Glucose-Responsive Insulin Delivery via Surface-Functionalized Titanium Dioxide Nanoparticles: A Promising Theragnostic against Diabetes Mellitus

Glucose-dependent insulin delivery systems have been recognized as a promising approach for controlling blood sugar levels in individuals with diabetes mellitus (DM). Recently, titanium dioxide nanoparticles have garnered huge attention in scientific research for their small size and effective drug delivery capabilities. In this study, we developed alizarin (AL)-capped phenylboronic acid (PBA)-functionalized titanium dioxide nanoparticles (TiO 2 ) for glucose-sensitive insulin delivery (TiO 2 –PBA–INS–AL) aiming to manage both blood sugar levels and its associated organ pathology in DM. The synthesized nanoparticles demonstrated favorable loading capacity as well as high insulin encapsulation efficiency. Initial studies demonstrated glucose-responsive insulin release from TiO 2 –PBA–INS–AL in a cell-free environment upon exposure to different glucose concentrations. Notably, in vitro experiments revealed that insulin release from TiO 2 –PBA–INS–AL was more effective in muscle cells (primary glucose storage cells) compared to lung cells when subjected to different glucose concentrations (5.5–25 mM), indicating a glucose-sensitive intracellular insulin delivery mechanism. Furthermore, treatment with TiO 2 –PBA–INS–AL significantly enhanced GLUT4 translocation and glucose utilization in muscle cells treated with sodium palmitate (PA, 0.75 mM), compared to treatments with TiO 2 or insulin alone. In diabetic animal models, a single oral dose of TiO 2 –PBA–INS–AL maintained normoglycemia for up to 12 h, indicating a significant improvement over subcutaneous or oral insulin treatment. Oral administration of TiO 2 –PBA–INS–AL also increased insulin bioavailability in both serum and muscle tissue compared to other administration methods. Besides, TiO 2 –PBA–INS–AL treatment showed no toxicity against both in vitro and in vivo models. Taken together, this nanocarrier-based drug delivery system mimics the natural regulation of insulin secretion in a noninvasive manner, enhancing patient adherence, reducing the risk of hyperglycemia, and improving diabetes management.