Endogenous Fe2+-activated nanomedicine to amplify ROS generation and in-situ response NIR-II photothermal therapy of tumor

Endogenous activated nanomedicines have great potential in improving therapeutic efficacy and minimizing side effects in cancer therapy. Herein, a novel nanomedicine (CuHCF) was developed based on a mixed-metal (Cu2+/Fe3+) Prussian blue analogue via a facile co-precipitation method, which could respond to the endogenous labile iron pool (LIP) achieving enhanced chemodynamic therapy (CDT) and in situ NIR-II photothermal therapy (PTT) of tumor. Notably, the prepared CuHCF itself shows low Fenton catalytic activity, which however, is found to significantly amplify the generation of reactive oxidative species (ROS) when exposed to the over-expressed Fe2+ in tumor region, since the intracellular Fe2+ triggers the redox cycles between Fe3+/Fe2+ and Cu2+/Cu+ of CuHCF. More interestingly, it is found that the CuHCF presents an obviously enhanced near-infrared absorption after reacting with Fe2+, enabling in situ hyperthermia under NIR-II (1064 nm) irradiation. Both in vitro and in vivo results demonstrated that a highly efficient synergistic therapy of CDT/PTT was achieved via a ferroptosis pathway when CuHCF was combined with the ferroptosis inducer erastin (ERA). Such an endogenous activated nanomedicine provides a promising paradigm to enhance specific CDT in synergy with in situ NIR-II PTT for precise cancer therapy.