Diabetes is a chronic metabolic condition marked by persistently elevated levels of blood glucose, with its pathogenesis involving insulin resistance and impaired insulin secretion. Currently, injectable medications take effect rapidly, but long-term use may pose safety risks such as hypoglycemia; whereas oral medications like metformin carry issues including side effects and drug resistance. Here, we developed a Janus self-propelled nanomotor based on mesoporous silica nanoparticles (MSNs) for targeted delivery of rapeseed protein-derived DPP-IV inhibitory peptide (IPQVS) and liraglutide (Lira). The nanomotors were encapsulated into sodium alginate-based hydrogel microspheres (SAM) to shield IPQVS and Lira from degradation induced by gastric acid. The nanomotor exhibited excellent dimensions (174.69 ± 10.5 nm) and demonstrated fuel-dependent self-propulsion capability (achieving a velocity of 21.87 μm/s under 250 μM H₂O₂ stimulation, 7.3-fold higher than passive diffusion). In vitro experiments demonstrated that compared to passive nanoparticles, nanomotor exhibited a 4.17-fold increase in uptake efficiency within intestinal epithelial cells while boosting insulin secretion by 1.81-fold. The system effectively scavenged intracellular reactive oxygen species (ROS) with an 89.74% scavenging rate and restored mitochondrial membrane potential (JC-1 red/green fluorescence ratio) to 71.5% of the control level. Under hyperglycemic conditions, they restored the survival rate of damaged pancreatic β-cells to 84%. In a type 2 diabetes mouse model, the nanomotor significantly improved glucose tolerance (reducing the area under the OGTT-glucose curve value to 52.25% of diabetic controls) and alleviated insulin resistance. This study provides a multifunctional nano-system for diabetes treatment that combined autonomous mobility, targeted delivery, and gastrointestinal protection.
