H 2 S Click Delivery: Responsive Release for Multidimensional Therapy of Thoracic Aortic Dissection

Thoracic aortic dissection (TAD), a lethal cardiovascular emergency, lacks effective pharmacological interventions. Endothelial dysfunction and hydrogen sulfide (H₂S) deficiency drive TAD progression, but existing H₂S donors exhibit uncontrolled release and cytotoxicity. Herein, we developed a GSH-responsive H₂S-releasing polymer, named PSG12, using a gas-click polymerization strategy under mild conditions. PSG12 achieved tunable H₂S release (4.27-fold higher at 2 mm than 0.5 mm GSH) and sustained plasma levels (more than 650 nm for 12 h post-injection). In TNF-α-challenged endothelial cells, PSG12 reduced the level of ROS (77% reduction), suppressed senescence (92.4% reduction), inhibited apoptosis (63% reduction), reduced inflammation (29.35% decrease in IL-1β protein expression), and preserved extracellular matrix (47.83% decrease in MMP-2 protein expression). In BAPN-induced TAD mice, PSG12 reduced aortic rupture (from 53.3% to 20.0%), improved survival (from 46.7% to 80.0%). On the one hand, PSG12 restored the homeostasis of endothelial cells in multiple dimensions; on the other hand, PSG12 maintained the concentration of plasma H₂S. This precision gas therapy platform enables multi-pathway synergistic modulation for TAD.