Superoxide anion-responsive persulfide and all-trans retinoic acid co-donating peptide assemblies attenuate myocardial ischemia-reperfusion injury.

Myocardial ischemia-reperfusion injury (MIRI) has become a severe threat to human health due to its high mortality rate and poor prognosis. Mutually entangled issues including ROS over-production, excessive inflammatory responses, and myocardial apoptosis are involved during MIRI. Effective inhibition of ROS burst at the beginning of reperfusion has been proved as the key for MIRI treatment. In this work, we report a superoxide anion-responsive peptide co-assembly (S/A-P) capable of delivering the H2S donor (i.e., superoxide-responsive persulfide donor) and all-trans retinoic acid (ATRA) simultaneously for the treatment. Our results suggest that compared with its single peptidic counterparts, the as-prepared system can significantly lower ROS production and repair myocardial mitochondrial dysfunction due to the synergy effect from the persulfides/H2S and ATRA. Moreover, S/A-P can reduce excessive inflammatory response through regulating macrophage polarization, which is further mapped by RNA sequencing. In vivo assessment of the co-assembly also displays an excellent therapeutic effect of MIRI on rats. In terms of good biocompatibility and outstanding efficacy, we believe that S/A-P will have a bright future for the treatment of cardiovascular diseases or other related diseases.