Single-site bimetallic nanosheet for imaging guided mutually-reinforced photothermal-chemodynamic therapy

The combination of chemodynamic therapy (CDT) and photothermal therapy (PTT) is a promising strategy against malignant tumor. However, its clinical application is significantly restricted by the suboptimal Fenton reaction rate, hyperthermia-induced heat shock response, and available agents with superior performance in both CDT and PTT. Herein, we reported an ultrathin single-site bimetallic (copper hexacyanocobaltate) nanosheet (CuCo NS) possessing superior Fenton-like activities and high photothermal conversion efficiency (PCE) (22.62%) for mutually-reinforced PTT-CDT. Within tumor microenvironment, the CuCo NS can not only deplete tumor-overexpressed glutathione (GSH), but also could exert Fenton-like activity to produce OH for CDT. More importantly, the GSH-depletion and OH-generation can be further enhanced by its photothermal effect, resulting in a large intracellular accumulation of OH and lipid peroxides (LPO), which, in turn, could disrupt the heat shock proteins to attenuate the thermoresistance of tumor cells, thus leading to a mutually-reinforced PTT-CDT. Additionally, the high PCE and the presence of high-spin Cu/Co species allow CuCo NS as a photoacoustic/magnetic resonance imaging contrast agent to real-time monitor the agents’ bio-distribution and treatment progress. Both in vitro and in vivo experiments consistently confirmed that the mutually-reinforced PTT-CDT can significantly inhibit the tumor growth via a synergistic ferroptosis-apoptosis pathway. Therefore, this work pioneers a credible paradigm to integrate photothermal and Fenton-like activities into one nanoplatform through single-site dual-metal coordination strategy and provides an ideal candidate for achieving mutually-reinforced PTT-CDT.