Fe(III)-juglone nanoscale coordination polymers for cascade chemodynamic therapy through synergistic ferroptosis and apoptosis strategy

Chemodynamic therapy (CDT) relying on the transformation of endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (·OH) based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment. However, the inadequate H2O2 supply and intricate redox homeostasis in tumor microenvironment (TME) severely impair the efficacy of CDT. Herein, we design self-assembled 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated polyethylene glycol (DSPE-PEG)-modified Fe(III)-juglone nanoscale coordination polymers (FJP NCPs) as redox homeostasis disruptors for juglone-enhanced CDT. Responding to glutathione (GSH)-rich and acidic TME, the Fe2+/Fe3+-guided CDT and GSH consumption by Fe3+ are activated, resulting in ·OH downstream and up-regulation of lipid peroxidation (LPO). In addition, the released juglone not only depletes GSH through Michael addition, but also elevates intracellular H2O2 level for achieving ·OH further bursting. With the impressive efficiency of GSH exhaustion and reactive oxygen species (ROS) storm generation, ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo. In brief, this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.