A coordination-assembled ferric nanoenzyme enables spatiotemporal radical storm for amplifying chemodynamic...

Artificial enzymes show great promise in cancer therapy, yet inadequate in vivo catalytic selectivity and robustness restrict their therapeutic potencies. Here, we report a coordination-driven nanoassembly of ferric-indocyanine green complex in albumin nanocages as an activatable antitumor nanoenzyme for tumor-selective chemodynamic immunotherapy against aggressive cancers. The nanoenzyme undergoes the reduction of ferric ions into ferrous ions in lysosomes in response to pH and glutathione stimuli, followed by photooxidation-mediated lysosomal escape of ferrous ions into cytosol. The abundant ferrous ions catalyze cytosolic H₂O₂ to yield highly cytotoxic hydroxyl radicals (·OH) in cytosol via Fenton reaction, which is further amplified to elevate the yield efficiency of ·OH by increasing the Fenton reaction rate under the photoirradiated tumor hyperthermia. Meanwhile, the frequently overexpressed metabolic NAD(P)H:quinone oxidoreductase 1 (NQO1) in tumor cells catalyzes its substrate (e.g. molecularly targeted compound β-lapachone) to continuously produce excessive hydrogen peroxide (H₂O₂) for yielding a reactive oxygen species (ROS) storm under abundant ferrous ions. The photoamplified and metabolism-dependent ROS storm effectively disrupts the redox homeostasis, thus inhibiting aggressive triple-negative breast cancers. The ROS surge further induces immunogenic cell death and promotes dendritic cell maturation, thus synergizing with immune checkpoint inhibitors to elicit both robust innate and adaptive immunities against primary, distant, and rechallenged tumors. This study provides insights into rational design of robust and activatable nanoenzymes for precise cancer therapy.