Ultrafast self-assembled supramolecular nanoparticles for enhanced chemodynamic therapy and ferroptosis through lactic acid metabolism regulation

Chemodynamic therapy (CDT) is an antitumor strategy based on the Fenton response. However, the mild acidity in the tumor microenvironment (TME) limits the efficiency of the Fenton response. Lactic acid has the potential to regulate pH in TME by regulating its metabolism. α-cyano-4-hydroxycinnamic acid (CHCA) can block lactate transport and induce lactate accumulation in cells, thus enhancing intracellular acidity. Nevertheless, CHCA is insoluble in water and the existing nanodrug delivery systems have complex synthesis and low drug-loading. Herein, we use Fe 3+ and CHCA to form ultrahigh drug-loading supramolecular nanoparticles (FC NPs) by an ultrafast self-assembly strategy at room temperature for only 5 min. Polyethylene glycol (PEG) modified FC (FCP) NPs undergo lactate metabolism regulation-enhanced CDT in tumor cells to generate toxic hydroxyl radicals to induce apoptosis. Besides, glutathione is consumed and glutathione peroxidase 4 is down-regulated to induce ferroptosis due to the oxidation of Fe 3+ . In vitro and in vivo experiments show FCP induced synergetic effect of CDT and ferroptosis as well as the excellent therapeutic effect compared with either CHCA or Fe 3+ alone. We believe that the ideal design of the CHCA supramolecular nanosystem will provide more revelations on the future research about CDT and lactate metabolism therapy.