Poly-Lipoic Acid Trisulfide Particles: A New Donor With Continuous and Steady H2S Supply

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.