Multifunctional DSF-loaded ICG-chelated nanozyme for four-in-one enhanced synergistic tumor therapy

Conventional chemotherapy remains a mainstay of cancer treatment but suffers from poor tumor selectivity and severe side effects. Addressing these limitations, we developed an innovative "4-in-1" strategy utilizing Disulfiram (DSF)-loaded Fe-based near-infrared-triggered DMTICH nanozymes integrating synergistic chemotherapy, chemodynamic therapy, photothermal therapy, and photodynamic therapy. DMTICH nanozymes can specifically release DSF and Cu²⁺ within the tumor microenvironment, enabling in situ formation of a highly toxic bis (<i>N</i>, <i>N</i>-diethyldithiocarbamate) copper (II) complex (CuET) to reduce the off-target effects and side effects of Chemotherapy. Notably, DMTICH nanozymes demonstrated triple enzyme-mimicking functions in vitro, including catalase-like, peroxidase-like, and glutathione peroxidase-like activities to efficiently mediate Chemodynamic therapy. These enzymatic functions were significantly reinforced by hyperthermia (Photothermal therapy) under NIR irradiation, thereby boosting total therapeutic efficacy within TME. Furthermore, by chelating Cu²⁺ with the hydrophilic domains of ICG to form ICG/Cu (II), DMTICH maintained the enhanced effect on ¹O₂ quantum yield, enabling effective Photodynamic therapy. The potent anticancer capability of DMTICH was also validated in animal studies, where it elevated the tumor site temperature to ∼58.3 °C and reduced tumor size to 12.6 % of that in the control group after a complete treatment period. This innovative approach highlights a promising synergistic "4-in-1" strategy, offering a powerful enzymatic platform for multimodal cancer therapies.