Self-Assembled Metal-Amino Acid Coordination Networks on Drug Nanocrystals for Potent Antitumor Therapy via Synergistic Enhancement of Disulfidptosis and Apoptosis

• • The CPGZC nanoplatform achieves synergistic activation of disulfidptosis and apoptosis, with in vitro and in vivo studies confirming potent antitumor efficacy; this dual-mechanism approach addresses adaptive resistance that limits single-modality therapies, potentially reducing clinical relapse rates. • • GOx-mediated glucose depletion reduces NADPH levels, impairing cystine-to-cysteine conversion and causing rapid intracellular disulfide accumulation; this metabolic intervention creates a vulnerability that can be exploited to overcome antioxidant defenses in malignant cells. • • The reduction in NADPH inhibits GSH biosynthesis, augmenting ROS levels elicited by Cur DNCs; elevated oxidative stress, combined with Zn2+ release, aggravates mitochondrial damage, amplifying apoptosis. This cascade enhances therapeutic index by targeting multiple death pathways simultaneously. • • Surface modification of Cur DNCs with zinc-cystine coordination networks significantly enhances stability, facilitates controlled release, and improves bioavailability; these formulation advances are critical for translating nanocrystal-based therapies from bench to bedside, ensuring consistent pharmacokinetics and reduced off-target effects.