Glucose Deprivation‐Driven Concurrent Induction of Apoptosis/Disulfidptosis/Ferroptosis by Tumor Targeting Nanoassemblies in Triple‐Negative Breast Cancer Therapy

ABSTRACT Hybrid nanoassemblies were designed to simultaneously induce apoptosis, disulfidptosis, and ferroptosis in triple‐negative breast cancer (TNBC) cells under glucose‐deprived conditions. Cystine transport via SLC7A11 is essential for glutathione (GSH) biosynthesis, therefore the concurrent induction of ferroptosis (through GSH depletion) and disulfidptosis (via cystine accumulation) seems to be contradictory. Glucose deprivation markedly reduces intracellular nicotinamide adenine dinucleotide phosphate (NADPH) levels, and this NADPH insufficiency compromises cystine reduction to cysteine, thereby enabling the simultaneous onset of ferroptosis and disulfidptosis in cancer cells. To exploit this metabolic vulnerability, phloretin (PHL) was incorporated into the nanoassemblies as a glucose transporter‐1 inhibitor to suppress glucose uptake. In addition, hydrophobic ferrocene (Fc) and D‐α‐tocopherol succinate (TS) were chemically conjugated to a hyaluronic acid (HA) oligomer, serving as an iron‐containing ferroptosis inducer and a mitochondria‐destabilizing apoptosis trigger, respectively. The resulting amphiphilic hybrid conjugate (Fc‐HA‐TS) spontaneously self‐assembles into nanoscale structures in aqueous environments. The designed Fc‐HA‐TS/PHL nanoassemblies are expected to orchestrate multiple programmed cell death modalities: (1) disulfidptosis induction, GSH depletion, and GSH‐independent ferroptosis suppressor protein 1 deactivation via glucose starvation (PHL), (2) ferroptosis activation through lipid peroxidation (Fc), and (3) apoptosis induction via mitochondrial destabilization (TS), ultimately offering a synergistic and metabolically targeted therapeutic strategy for TNBC.