Nanomedicine-driven ferroptosis has emerged as a promising tumor treatment strategy through delivering exogenous iron and aggravating the lethal accumulation of lipid peroxides (LPO). However, the compensatory mechanisms of ferroptosis defense systems in cancer cells compromise the therapeutic efficacy and lead to potential side effects. Herein, a highly effective ferroptotic nano-amplifier is designed to synergistically promote ferroptosis via increasing intracellular labile iron, exacerbating lipid peroxidation and overcoming the defense system. Briefly, a natural-derived amphiphilic polymer composing of chondroitin sulfate (CS), arachidonic acid (AA) and a redox-sensitive linker, cystamine (CYS) is constructed to self-assemble as a GSH-responsive nanodrug delivery system for loading bioactive ingredient Polyphyllin I (PPI) and ferric ion (Fe