High-entropy intermetallic alloy/carbon nanoflower cascade nanozyme for multi-modal synergistic cancer therapy

Although nanozyme-mediated chemodynamic therapy (CDT) has been extensively investigated, its therapeutic efficacy is hindered by tumor microenvironment (TME), which features low endogenous H 2 O 2 level and high glutathione (GSH) concentration. In this work, PtFeCoMoMn high-entropy intermetallic alloy/N-doped carbon nanoflowers (HEIA/NCNFs) was synthesized by a one-step pyrolysis. The HEIA/NCNFs exhibited multiple peroxidase (POD)-, catalase (CAT)-, oxidase (OXD)-, glutathione oxidase (GSHOx)-, and NADPH oxidase (NOX)-like activities, which were integrated with glucose oxidase (GOx) and doxorubicin (DOX) to establish a cascade nanotherapeutic platform (termed HEIA/NCNFs-GOx/DOX). Shortly, GOx consumed glucose in tumor cells, generating H 2 O 2 to compensate for the TME's H 2 O 2 deficiency. Subsequently, the HEIA/NCNFs converted H 2 O 2 into reactive oxygen species (ROS) via the POD/CAT/OXD-like activity. Also, the HEIA/NCNFs depleted intracellular GSH via its GSHOx-like activity, and simultaneously suppress GSH regeneration by consuming NADPH via its NOX-like activity, thereby inactivating glutathione peroxidase 4 and inducing ferroptosis. By combining starvation therapy, CDT, ferroptosis, and chemotherapy, the established cascade nanozyme system significantly enhanced the therapeutic efficacy of breast cancer, validated by the in vitro and in vivo studies. This multifunctional nanodrug improves therapeutic precision, reduces off-target effect, and advances the development of safe, efficient cancer treatments.