Targeted H2S Delivery System Attenuates Blood-Spinal Cord Barrier Disruption after Spinal Cord Injury by Reshaping the Ferritinophagy Pathway.

As a severe and disabling central nervous system disorder, spinal cord injury (SCI) remains challenging, partly because of the difficulty in addressing secondary injury caused by the blood-spinal cord barrier (BSCB) disruption. As the neurovascular unit's crucial component, the BSCB regulates the homeostasis of the spinal cord. Inspired by the established protective effect of H2S in pan-vascular pathologies, we engineered an intravenously administered nanoparticle SPRC@MPDA-RGD. By utilizing the overexpression of αvβ3 integrin on endothelial cells after SCI, the functionalized peptide c(RGDyK) can guide SPRC@MPDA-RGD for precise delivery to the BSCB. The MPDA scaffold has the ability to both deliver S-propargyl-cysteine (SPRC) and scavenge reactive oxygen species (ROS). Subsequently, the release of SPRC upregulates cystathionine γ-lyase (CSE) and stimulates endogenous H2S production in injured endothelial cells, thereby protecting the BSCB. We also investigated the biological mechanisms underlying the therapeutic effects of SPRC@MPDA-RGD. The production of H2S in endothelial cells activates the PI3K/Akt/mTOR pathway, which subsequently suppresses ferritinophagy, reduces ferritin degradation, and ultimately suppresses ferroptosis. In summary, our work proposes a nanotherapeutic strategy that coordinates H2S production and ROS scavenging to inhibit ferritinophagy, thereby promoting BSCB repair, showing significant potential in promoting SCI treatment.