A Carrier-Free Peptide Nanomedicine Orchestrates Dual Redox Therapy via Ferroptosis and Disulfidptosis

Carrier-free nanomedicines offer a promising strategy to simplify formulation while maximizing therapeutic function. Here, we report a disulfide-containing self-assembling peptide, Fmoc-Cys(StBu)-Phe-Phe-Tyr-Lys-Cys(StBu) ( Fmoc-S-S ), as a minimalist nanomedicine for dual redox cancer therapy. Fmoc-S-S spontaneously formed uniform spherical nanoparticles with favorable hemocompatibility, glutathione-responsive structural transformation, and enhanced tumor accumulation in vivo. Mechanistically, Fmoc-S-S disrupted intracellular redox homeostasis by depleting glutathione, altering the NADP+/NADPH balance, suppressing SLC7A11 and GPX4, promoting lipid peroxidation, and reducing mitochondrial membrane potential, consistent with ferroptosis induction. Meanwhile, biochemical evidence of intracellular disulfide stress, including decreased cysteine levels, together with partial rescue by dithiothreitol and marked F-actin disruption, supported the involvement of disulfidptosis. In MC38 tumor-bearing mice, Fmoc-S-S nanoparticles significantly inhibited tumor growth without obvious systemic toxicity. Proteomic analysis further revealed coordinated dysregulation of pathways associated with glutathione metabolism, mitochondrial function, oxidative phosphorylation, and cytoskeletal organization. Together, this work presents a self-assembled peptide biomaterial that integrates nanostructure formation, tumor delivery, and dual induction of ferroptosis and disulfidptosis within a single carrier-free system, providing a new strategy for redox-directed cancer therapy.