Blood-Triggered In Vivo Reassembly of Oral Cystine Spherulites with Fasting Synergy Induces Disulfidptosis for Cancer Metabolic Intervention.

Integrating localized amino acid perturbation with systemic metabolic regulation represents a compelling strategy to exploit tumor metabolic vulnerabilities. However, current metabolic modulators remain challenged by poor tumor selectivity, limited oral bioavailability, and reliance on complex delivery systems that hinder clinical translation. Here, we report a fasting-augmented amino acid intervention strategy using iron-cystine spherulites (FeCST). Following oral administration, FeCST is converted in the stomach into ultrasmall cystine nanoparticles (FeCST-NPs) that traverse intestinal mucus and enter systemic circulation via the paracellular pathway. In the bloodstream, FeCST-NPs spontaneously reassemble with specific plasma proteins into nanoclusters, which may contribute to their preferential accumulation in tumors. Synergistically, FeCST and intermittent fasting (IF) robustly induce disulfidptosis, resulting in potent tumor suppression and enhanced antitumor immunity. This synergistic effect is associated with multiple IF-induced metabolic alterations, including glucose restriction and transient modulation of intestinal epithelial permeability, which collectively facilitate FeCST bioavailability and increase tumor susceptibility to disulfide stress. This study presents a disulfidptosis-mediated paradigm that integrates controlled amino acid intervention with fasting-mediated systemic metabolic modulation.