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

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ABSTRACT Thoracic aortic dissection (TAD), a lethal cardiovascular emergency, lacks effective pharmacological interventions. Endothelial dysfunction and hydrogen sulfide (H 2 S) deficiency drive TAD progression, but existing H 2 S donors exhibit uncontrolled release and cytotoxicity. Herein, we developed a GSH‐responsive H 2 S‐releasing polymer, named PSG12, using a gas‐click polymerization strategy under mild conditions. PSG12 achieved tunable H 2 S release (4.27‐fold higher at 2 m m than 0.5 m m GSH) and sustained plasma levels (more than 650 n m 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 H 2 S. This precision gas therapy platform enables multi‐pathway synergistic modulation for TAD.

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