Metal-Free Nanocomposites with Endogenous Labile Iron Pool Disturbing Capacity for Tumor Therapy through Synergetic Stock Depletion and Supply Blockage Strategy

Metal iron plays exceedingly important roles in maintaining normal biological activities and is stored as an intracellular labile iron pool (LIP). Disturbing LIP balance to disorganize physiological reactions holds great promise in tumor therapy yet is still lacking exploration. Herein, a novel synergetic strategy was designed for tumor therapy with high efficacy and biocompatibility, which was realized through the metal-free poly(lactic-co-glycolic acid) (PLGA)-ethylenediaminetetraacetic acid (EDTA)-ebselen (EBS) nanocomposites. After degradation, EDTA chelates Fe2+ to deplete intracellular LIP, and EBS inactivates DMT1 protein to inhibit iron supplementation from extracellular regions. This LIP destruction causes the downregulation of iron-sulfur cluster levels, which compromises mitochondrial energy metabolism and arrests the cell cycle. Effective tumor elimination is achieved under PLGA-EDTA-EBS treatment with negligible side effects. This work presents an effective formulation for tumor therapy through a synergetic stock depletion and supply blockage strategy, thereby providing essential implications for the design of tumor therapeutic methods with minimal biosafety issues.