Poly‐Lipoic Acid Trisulfide Particles: A New Donor With Continuous and Steady H ₂ S Supply

Abstract The core challenge of H 2 S therapy is to supply H 2 S in a continuous and steady way. By self‐polymerizing lipoic acid trisulfide, herein a new H 2 S donor called poly‐lipoic acid trisulfide particles (pLATP) is developed with the steady H 2 S supply over 48 h at both cellular and animal levels, the longest time reported so far. Mechanistically, the pLATP high‐efficiently enters the cytoplasm via the poly(trisulfides) mediated membrane penetration. In cells, thanks to the polymerized solid sphere structure, the pLATP releases H 2 S by a layer‐by‐layer decomposed way. Only when the outer layer decomposes, the inner layer can be exposed. After H 2 S release, the pLATP degrades to lipoic acid, which is not only a B vitamin, but also enhances the expression of 3‐mercaptopyruvate sulfurtransferase, a H 2 S synthesizing enzyme promoting the production of endogenous H 2 S. The dual pathways of exogenous supplementation and endogenous recovery warrant the continuous and steady supply of H 2 S at the lesion site. As a proof of concept, the pLATP normalized cardiac function in rats with myocardial ischemia‐reperfusion injury.