Exploiting Macropinocytosis Drives Redox Vulnerability to Preferentially Target Drug-Resistant Cancer

Therapy-resistant cancers remain largely incurable because malignant cells acquire metabolic adaptations that sustain survival under chronic cytotoxic and oxidative stress. One such adaptation is constitutively enhanced macropinocytosis, enabling aggressive cancer cells to scavenge extracellular nutrients and maintain redox homeostasis. Here, we introduce a macropinocytosis-exploiting polymer-metal strategy that converts this metabolic dependency into a lethal vulnerability. We developed PPS02, a polyaspartic acid sodium salt-based metal complex that is preferentially internalized by cancer cells via macropinocytosis, while remaining largely excluded from normal epithelial cells. This cancer-preferential uptake enables intracellular delivery of selenomethionine and ferrous iron, resulting in intracellular H2O2 accumulation, mitochondrial reactive oxygen species overload, and activation of necroptotic cell death. Macropinocytic activity was significantly elevated in patient-derived metastatic colorectal cancer cells but remained minimal in normal colonic epithelial cells, demonstrating pronounced cancer selectivity. Accordingly, PPS02 exhibited negligible cytotoxicity toward normal colonic epithelial cells while effectively suppressing the viability of both nonmetastatic and platinum-resistant metastatic colorectal cancer cells. In patient-derived xenograft models, PPS02 induced sustained tumor regression without overt systemic toxicity under the experimental conditions, whereas cisplatin failed to control metastatic tumors and caused significant adverse effects. Collectively, these findings support macropinocytosis-driven redox imbalance as a therapeutically exploitable vulnerability and demonstrate a polymer-metal platform that preferentially induces necroptosis in drug-resistant cancer while sparing normal tissues.