Multifunctional ZnO@CuS nanoparticles cluster synergize chemotherapy and photothermal therapy for tumor metastasis

The poor drug delivery and unsatisfying therapeutic effects remain to be the primary challenges for cancer therapy. Nanosystem that combines multiple functions into a single platform is an ideal strategy. Here, a smart drug delivery nanoplatform (Z@C-D/P) based on ZnO@CuS nanoparticles, loaded with doxorubicin (DOX) and pirfenidone (PFD) was constructed. Importantly, the β-CD-DMA and PEG-DMA could be activated in the mild acidic tumor microenvironment, then the nanosystem underwent charge reversal and PFD release. PFD could inhibit cancer-associated fibroblasts (CAFs) activation and enhance tumor penetration. And the residual nanostructure ZnO@CuS could trigger cascade amplified ROS generation to induce tumor cell death. The photothermal effect further strengthened the anti-tumor efficacy. Finally, the nanosystem showed remarkable inhibition of tumor growth (89.7%) and lung metastasis. The innovatively designed nanosystem integrating chemotherapy and photothermal effect would provide a promising strategy in breast cancer therapy. A new drug-delivery nanosystem combing ZnO and CuS, loading two kinds of drugs simultaneously, DOX and PFD, was established. This nanosystem could respond to the tumor acidic microenvironment, and then the size got smaller and the charge reversed, leading to the deep penetration of nanoparticles. ZnO, CuS, and DOX could facilitate tumor cell death through amplified ROS production and GSH-GPX4 pathways regulation. PFD, as the TGF-β downregulation agent, restrained tumor metastasis. Photothermal therapy combined with chemotherapy further enhanced the anti-tumor effect. [Display omitted]