Self-Assembled Nanostructures Regulate H₂S Release from Constitutionally Isomeric Peptides

We report here on three constitutionally isomeric peptides, each of which contains two glutamic acid residues and two lysine residues functionalized with S-aroylthiooximes (SATOs), termed peptide-H₂S donor conjugates (PHDCs). SATOs decompose in the presence of cysteine to generate hydrogen sulfide (H₂S), a biological signaling gas with therapeutic potential. The PHDCs self-assemble in aqueous solution into different morphologies, two into nanoribbons of different dimensions and one into a rigid nanocoil. The rate of H₂S release from the PHDCs depends on the morphology, with the nanocoil-forming PHDC exhibiting a complex release profile driven by morphological changes promoted by SATO decomposition. The nanocoil-forming PHDC mitigated the cardiotoxicity of doxorubicin more effectively than its nanoribbon-forming constitutional isomers as well as common H₂S donors. This strategy opens up new avenues to develop H₂S-releasing biomaterials and highlights the interplay between structure and function from the molecular level to the nanoscale.