Self-Assembled Nanostructures Regulate H(2)S Release from Constitutionally Isomeric Peptides

[Image: see text] 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–H(2)S donor conjugates (PHDCs). SATOs decompose in the presence of cysteine to generate hydrogen sulfide (H(2)S), 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 H(2)S 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 H(2)S donors. This strategy opens up new avenues to develop H(2)S-releasing biomaterials and highlights the interplay between structure and function from the molecular level to the nanoscale.