Self-Assembled Metal-Amino Acid Coordination Networks on Drug Nanocrystals for Potent Antitumor Therapy via Synergistic Enhancement of Disulfidptosis and Apoptosis
Multifunctional nanoplatforms capable of efficiently regulating both emerging and classical cell death mechanisms, thereby overcoming the adaptive resistance of malignant cells to certain cell death modalities, remain a significant challenge. Herein, we propose a new concept for the self-assembly of zinc-cystine coordination networks on curcumin (Cur) drug nanocrystals (DNCs) to construct Cur@PDA@GOx/Zn-Cys (CPGZC) nanoplatforms, enabling enhanced antitumor therapy through multicomponent synergistic modulation of both newly identified disulfidptosis and classical apoptosis. At tumor site, GOx-mediated glucose depletion reduces nicotinamide adenine dinucleotide phosphate (NADPH) levels, which can impair the intracellular conversion of cystine to cysteine. Combined with the exogenous cystine delivered by CPGZC NPs, rapid intracellular disulfide accumulation strongly activates disulfidptosis. Simultaneously, the reduction in NADPH levels inhibits GSH biosynthesis, augmenting the intracellular ROS levels elicited by Cur DNCs within the CPGZC nanoplatforms. Moreover, the elevated oxidative stress, in synergy with the excessive Zn2+ introduced, aggravates mitochondrial damage, thereby further amplifying apoptosis. Consequently, the synergistic modulation of disulfidptosis and apoptosis induces a potent antitumor response, as validated by comprehensive in vitro and in vivo investigations. This study opens new avenues for the development of multifunctional nanoplatforms for enhanced cancer therapy through the effective integration of both emerging and classical cell death mechanisms, which may serve as a promising strategy to advance our comprehension of synergistic utilization of various cell death mechanisms and combat with complex cancers.