Targeted H ₂ S Delivery System Attenuates Blood‐Spinal Cord Barrier Disruption after Spinal Cord Injury by Reshaping the Ferritinophagy Pathway

ABSTRACT 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 H ₂ S in pan‐vascular pathologies, we engineered an intravenously administered nanoparticle SPRC@MPDA‐RGD. By utilizing the overexpression of α _v β ₃ 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 H ₂ S 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 H ₂ S 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 H ₂ S production and ROS scavenging to inhibit ferritinophagy, thereby promoting BSCB repair, showing significant potential in promoting SCI treatment.