Curcumin-loaded milk-derived sEVs fused with platelet membrane attenuate endothelial senescence and promote spinal cord injury recovery in diabetic mice

Spinal cord injury (SCI) causes devastating neurological deficits, and cellular senescence critically contributes to the pathogenesis of various diseases. Notably, endothelial cells (ECs) senescence exerts a pivotal effect on the pathogenesis following SCI. In this study, we found that the number of senescent ECs increased by 18.87% ± 5.91%, and the disruption of the blood-spinal cord barrier (BSCB) was aggravated with an 18% increase in Evans Blue dye extravasation in diabetic mice with spinal cord injury (DM-SCI). To address this pathological process, a bioinspired nanotherapeutic platform utilizing milk-derived small extracellular vesicles with platelet membrane fusion (PM-sEVs) was developed for the targeted delivery of curcumin (Cur). In vitro, PM-sEVs-Cur effectively mitigated HG/IL-1β-induced HUVECs senescence by 54.19% ± 5.39% and increased expression of the tight junction protein ZO-1 by 4.33-fold. Mechanistically, Cur attenuated HUVECs senescence by activating the NRF2/HO-1 pathway. In vivo, platelet membrane modification enhanced the lesion targeting of sEVs. Treatment with PM-sEVs-Cur attenuated ECs senescence by 34.96% ± 6.59%, preserved BSCB integrity with a 17% reduction in Evans Blue dye extravasation, promoted axonal regeneration with a 6.36-fold increase in neurofilament expression, and improved motor function recovery with an increase of 2.4 ± 0.55 points in Basso Mouse Scale score in DM-SCI. This study highlights PM-sEVs-Cur as a promising therapeutic delivery platform for DM-SCI treatment.