Self‐Cascade Catalytic Reaction–Assisted Apoptosis/Calcicoptosis/Ferroptosis Induction with Microsphere‐Aggregated Hydrogels in Triple‐Negative Breast Cancer Therapy

Abstract Cisplatin‐loaded hyaluronic acid‐dopamine microsphere (MS) is interconnected by metal ion (e.g., calcium ion and iron ion)‐catechol coordination and polydopamine linkages to form an MS‐aggregated hydrogel (MAH) system to enable convenient peritumoral injection and efficient tumor infiltration in triple‐negative breast cancer (TNBC) therapy. Cisplatin (inhibition of DNA replication and cellular H 2 O 2 generation), calcium peroxide (self‐generation of H 2 O 2 ), and ferrous sulfate (conversion of H 2 O 2 to OH radicals) are integrated into the MAH system for chemo/cascade chemodynamic therapy. Reactive oxygen species (ROS) are produced by calcium peroxide and ferrous sulfate, which can assist Ca 2+ overload in inducing calcicoptosis in cancer cells. Both iron and calcium ions increase the degree of lipid peroxidation, leading to enhanced ferroptosis in cancer cells. Cisplatin and ROS generation induces apoptosis in cancer cells. Viscoelastic modulation for prolonged therapeutic delivery with enhanced tumor penetration of the jammed MAH system is demonstrated physicochemically and mechanically. Anticancer capabilities are also assessed in 4T1 cells and orthotopic 4T1 tumor mouse models. Remarkably, the MAH system strongly inhibited the recurrence of residual 4T1 tumors in a mouse model. These findings indicate that the MAH system can be applied for the ROS‐assisted induction of multiple apoptosis/calcicoptosis/ferroptosis pathways in TNBC therapy.