Single-atom nanozymes based nanobee vehicle for autophagy inhibition-enhanced synergistic cancer therapy

Single-atom nanozymes (SAzyme) have shown great promise in the area of anti-tumor therapy due to their ultrahigh atom utilization efficiency. However, the therapeutic effect is far from satisfactory because of cunning cancer cell's self-protective autophagy. Herein, to solve this dilemma, we design a large-pore mesoporous Fe SAzyme loaded with macromolecular melittin pro-peptide to form Fe SAzyme@melittin pro-peptide (FePM) nanobee. When the FePM enter cells through endocytosis and are entrapped in endo/lysosomes, Fe SAzyme with glutathione oxidase (GSHOx), peroxidase (POD) and oxidase (OXD) mimicking activities can trigger collaborative CDT and ferroptosis by provoking a GSH depletion-enhanced ROS storm. Additionally, the strong absorption ability in the near-infrared II region endows Fe SAzyme with excellent PTT performance (42.1%). More importantly, the non-toxic melittin pro-peptide can be activated to membrane-lytic active melittin by overexpressed legumain in the lysosomes of cancer cells. Activated melittin then disrupts lysosomes, in this case inhibiting autophagy by reducing the formation of autolysosomes. Therefore, FePM nanobee can effectively damage cytoplasmic components to induce cancer cells death by synergistic ferroptosis, CDT and PTT. This study sheds light on the first example of large-pore mesoporous SAzyme for autophagy inhibition-enhanced multimodal synergistic antitumor therapy.