Engineered mesenchymal stem cells for targeted delivery of H2S to suppress cGAS-STING inflammation and enhance cardioprotection in myocardial ischemia-reperfusion.

Myocardial ischemia-reperfusion (MI/R) injury remains a significant clinical challenge, primarily attributed to excessive oxidative stress and sterile inflammation resulting from dysregulated activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Therapeutic strategies that target single pathological factors demonstrate limited efficacy, highlighting a critical need for integrative approaches targeting the complex ischemic microenvironment. Herein, this study develops a therapeutic platform termed "Hydro-guarder", integrating mesenchymal stem cells (MSCs)-mediated delivery of hydrogen sulfide (H₂S) donor 5-(4-Hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) via ROS-responsive nanoparticles. Specifically, Hydro-guarder utilizes bioorthogonal click chemistry to covalently anchor reactive oxygen species (ROS)-responsive nanoparticles loaded with the advanced H₂S donor, ADTOH, onto MSCs. Upon MSCs homing to infarcted myocardium, elevated ROS enabling the spatiotemporally controlled, on-demand release of H₂S. This targeted release protects MSCs from oxidative damage, enhancing their survival and paracrine function. In turn, revitalized MSCs amplify H₂S-mediated suppression of the cGAS-STING inflammatory cascade. In murine MI/R models, Hydro-guarder significantly preserves mitochondrial integrity, improves cardiac function, and reduces infarct size and fibrosis. Furthermore, Hydro-guarder induced a pronounced immunoregulatory shift, characterized by restoration of cytokine homeostasis and robust polarization of macrophages from the M1 to the M2 phenotype. Mechanistically, we found that Hydro-guarder potently suppressed the cGAS-STING inflammatory cascade. This study provides the first systematic demonstration that co-delivery of H₂S and MSCs via a bioorthogonally engineered platform can synergistically attenuate MI/R-induced cGAS-STING inflammation. The "Hydro-guarder" system thus represents a promising and potentially translatable therapeutic strategy for ischemic cardiovascular diseases.