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 NiS 2 /FeS 2 hybrid nanoparticles (NiS 2 /FeS 2 NPs), which are further modified with polyvinyl pyrrolidone (PVP) to improve their biocompatibility. PVP-NiS 2 /FeS 2 NPs exhibit synergistic activities of chemodynamic therapy (CDT), photodynamic therapy (PDT), and photothermal therapy (PTT) with multimodal imaging capabilities. With the presence of Fe 2+ /Fe 3+ and Ni 2+ /Ni 3+ redox couples, the PVP-NiS 2 /FeS 2 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-NiS 2 /FeS 2 NPs and PVP-NiS 2 /FeS 2 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 programmed cell death pathways in activating tumor immunity, we demonstrate that PVP-NiS 2 /FeS 2 NPs + NIR can eliminate metastatic tumors in an immune system dependent manner. Therefore, PVP-NiS 2 /FeS 2 NPs represent a promising strategy to treat metastatic breast cancer.