Cysteine-Rich Peptide for Chiral Self-Assembly: A Multi-Functional Antioxidant with Novel SH-Mediated ROS-Responsive Disassembly from Natural Medicine

Abstract

Peptide self-assembly is a promising strategy for developing bioactive nanomaterials with improved drug delivery and therapeutic performance. However, artificial design approaches may not fully incorporate natural paradigms and typically avoid cysteine-rich sequences due to their inherent instability. Challenging this convention, we established a natural medicine-inspired discovery pipeline to identify self-assembling thiol-rich peptides. From pangolin scales, we identified a novel natural peptide, Ac-KCSQLNVNCKG, containing two free cysteine thiols that spontaneously self-assembles into chiral supramolecular nanostructures. Structural studies confirm β-sheet stacking that shields thiols from atmospheric oxidation, thereby conferring relative stability under ambient conditions. In Caenorhabditis elegans, the assemblies exert systemic antioxidant activity by activating endogenous pathways, including the upregulation of key antioxidant enzymes (SOD, CAT, and GSH-Px). Gradually released monomers further enhance intracellular antioxidant activity and show notable α-glucosidase inhibitory effects. This work presents a rarely reported natural peptide-based assembly that integrates antioxidant, enzyme-inhibitory, and membrane-penetrating functions into a single biocompatible, sustained-release platform, highlighting its potential for treating oxidative stress-related diseases such as diabetes. Notably, the supramolecular gel undergoes ROStriggered disassembly to a sol state under physiological conditions (e.g., H2O2), representing a rarely reported form of ROS responsiveness mediated by the oxidation of natural cysteine thiol groups. Overall, this study introduces a natural, multifunctional antioxidant supramolecular system that shows strong potential for addressing complex clinical conditions, with inherent biosafety supported by its all-L-amino-acid composition and hierarchically propagated chiral architecture.