Oral Dosed Organo‐Silica Nanoparticles Restore Glucose Homeostasis and β‐Cell Function in Diabetes Rats

Abstract Type 2 diabetes mellitus (T2DM) persists as a global health challenge, with current therapies inadequately addressing the intertwined pathologies of hyperglycemia, oxidative stress, and β‐cell dysfunction. Here, an oral nanotherapeutic platform, MOP@T@D, engineered to restore glucose homeostasis and rejuvenate pancreatic β‐cells is developed. The platform is constructed by co‐loading insulin and glucose oxidase (GOx) into diselenide‐bridged mesoporous organosilicon nanoparticles (MON), followed by sequential coating with transferrin (Tf) and functionalization with deoxycholic acid (Dc). MOP@T@D demonstrates efficient intestinal absorption and liver‐targeted delivery, achieving an oral bioavailability of 10.6%. Under hyperglycemic conditions, GOx‐generated H 2 O 2 cleaves the diselenide bonds in the MON framework, resulting in rapid insulin release with 8.7‐fold higher cumulative release compared to normoglycemic conditions. Simultaneously, the metabolized selenium derivatives progressively upregulate key selenoproteins, enhancing glutathione peroxidase (Gpx) activity by 31%, which effectively neutralizes oxidative stress and suppresses NF‐κB‐mediated inflammation. In a T2DM rat model, this therapy increases the islet area by 26.7% and restores insulin secretion to 74.6% of the physiological level. Notably, the system maintains normal blood glucose levels for two weeks after cessation of administration. In summary, through a simple oral dose, MOP@T@D not only stabilizes glycemic fluctuations but also addresses the root pathophysiology of T2DM.