A versatile NiS2/FeS2 hybrid nanocrystal for synergistic cancer therapy by inducing ferroptosis and pyroptosis

Due to the heterogeneous and complex tumor microenvironment (TME), it remains challenging to effectively treat solid tumors with monotherapy. The development of a versatile nanomaterial strategy for synergistic chemodynamic/photodynamic/photothermal therapies has the potential to overcome this challenge. Herein, we designed and synthesized NiS2/FeS2 hybrid nanoparticles (NiS2/FeS2 NPs), which are further modified with polyvinyl pyrrolidone (PVP) to improve their biocompatibility. PVP-NiS2/FeS2 NPs exhibit synergistic activities of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) with multi-modal imaging capabilities. With the presence of Fe2+/Fe3+ and Ni2+/Ni3+ redox couples, the PVP-NiS2/FeS2 NPs exhibit GSH peroxidase-like reactivity and trigger Fenton reaction, leading to robust .OH generation and pyroptosis/ferroptosis after near infared irradiation (NIR). In response to the PVP-NiS2/FeS2 NPs and PVP-NiS2/ FeS2 NPs + NIR treatment, the breast tumors formed in the syngeneic BABL/c mice were eliminated and their metastases suppressed by inhibiting the EMT pathway. Consistent with the apparent involvement of these pro-grammed cell death pathways in activating tumor immunity, we demonstrate that PVP-NiS2/FeS2 NPs + NIR can eliminate metastatic tumors in an immune system dependent manner. Therefore, PVP-NiS2/FeS2 NPs represent a promising strategy to treat metastatic breast cancer.