Supramolecular catalytic nanomedicines based on coordination self-assembly of amino acids for cascade-activated and -amplified synergetic cancer therapy

Simple biomolecule-based supramolecular nanomedicines hold great promise in cancer therapy, but their clinical translation is greatly hindered by low tumor-specificity and unsatisfactory antitumor performance. Herein, we developed an amino acid basedsupramolecular nanomedicine that could be co-activated by multiple stimuli in tumor tissue to trigger cascade catalytic reactions in situ for synergetic therapy. The supramolecular nanomedicine was developed based on a combination of coordination and hydrophobic noncovalent interactions among amphiphilic amino acids, glucose oxidase (GOx), copper ions, as well as doxorubicin (DOX)-camptothecin (CPT) prodrugs. The cascade reactions including the catalytic oxidation of glucose to generate H₂O₂, GSH reducing Cu²⁺ to Cu⁺, a Fenton-like reaction between H₂O₂ and Cu+ to produce hydroxyl radicals (^•OH), and ^•OH-triggered rapid release of dual parent drugs were specifically activated in tumor cells. With these cascade reactions, the catalytic-chemo synergetic therapy was realized for high-efficiency tumor suppression.