Stiffness-tunable oral nanoparticles facilitate damaged islet β cell restoration for diabetes treatment

Diabetes mellitus remains a global health challenge, as current insulin-based therapies merely control blood glucose without restoring islet β cell function, leaving patients dependent on lifelong medication and vulnerable to hypoglycemia. Antioxidant drugs hold promise for islet β cell repair but are limited by poor gastrointestinal transportation and insufficient pancreatic targetability. Here, we initially identify ferroptosis-associated oxidative stress as a key cause of islet β cell death and develop six stiffness-gradient nanoparticles by embedding bent oleic acid into ordered 1,2-distearoyl- sn -glycero-3-phosphoethanolamine to enhance drug bioavailability. Nanoparticles with intermediate stiffness optimize membrane wrapping and minimize energetic cost, enhancing intestinal M cell transcytosis and macrophage-mediated hitchhiking, thereby increasing pancreatic curcumin accumulation by ~4.5-fold. In diabetic models, this formulation suppresses ferroptosis-associated oxidative stress, promotes in situ islet β cell repair, and restores insulin homeostasis and autonomous glycemic control, maintaining normoglycemia without hypoglycemia even after treatment cessation. This study represents a patient-friendly oral nanotherapy that outperforms insulin therapy in long-standing diabetes management.