Sequential controlled H₂S/CO dual delivery via a self-reporting fluorogenic donor synergistically attenuates myocardial ischemia-reperfusion injury

Abstract

Myocardial ischemia-reperfusion injury (MIRI) presents significant clinical challenges due to its complex multimechanistic pathophysiology. Although hydrogen sulfide (H₂S) and carbon monoxide (CO) exhibit individual cardioprotective effects via anti-apoptotic/anti-inflammatory pathways, their synergistic potential remains underexplored due to the absence of delivery systems enabling spatiotemporal co-regulation of these gasotransmitters. Current approaches face technical limitations in simultaneous gas quantification and therapeutic delivery, often compromising treatment efficacy through gas leakage during monitoring. To address these challenges, we developed HSCOD, a theranostic donor featuring cysteine-activated H₂S release followed by light-controlled CO generation, while incorporating self-reporting fluorescence for real-time gas tracking. In cellular and zebrafish MIRI models, dual-gas co-delivery demonstrated superior efficacy to monotherapies, significantly reducing apoptosis, pyroptosis, oxidative stress, and inflammation through coordinated cardioprotection. This study further validated the “gas waltz therapy” concept of spatiotemporally orchestrated gas interactions, with HSCOD serving as both a therapeutic agent and research tool for decoding gas crosstalk in multifactorial diseases. The platform overcomes critical limitations in gas therapy by integrating controlled release with real-time tracking, advancing targeted treatment strategies for complex pathologies.