Doxorubicin-Loaded Nickel Carbonate Nanosheets with Acidic-Microenvironment-Responsive Capacity for Tumor Apoptosis and Ferroptosis

The combination of apoptosis and ferroptosis has been explored as an effective pathway for tumor therapy. Herein, a kind of doxorubicin (DOX)-loaded nickel carbonate (NiCO3) nanosheet (NS) was developed for tumor treatment via combined chemodynamic therapy and chemotherapy, inducing both apoptosis and ferroptosis. These NiCO3 NSs were prepared in combination with the polymerization of dopamine, which were then coated with poly(acrylic acid) (PAA), modified with polyethylene glycol (PEG) chains. After the loading of DOX, NiCO3-polydopamine (PDA)–PAA–PEG–DOX (NPPPD) NSs were formed. When internalized by tumor cells, these NSs showed acid-responsive degradation capacity, releasing Ni2+ and DOX. The released Ni2+ could act as the Fenton-like agent to convert hydrogen peroxide into toxic hydroxyl radicals, inducing apoptosis and ferroptosis. After this reaction, the generated Ni3+ could further deplete glutathione and inactivate glutathione peroxidase 4, promoting lipid peroxide accumulation to enhance ferroptosis. The level of apoptosis could be enhanced by the chemical drug DOX. In vitro and in vivo results demonstrated that a desirable tumor-killing outcome could be achieved by these NSs through combined apoptosis and ferroptosis.