Self-Activated Cascade Biocatalysis of Glucose Oxidase-Polycation-Iron Nanoconjugates Augments Cancer Immunotherapy

Biocatalytic therapy by reactive-oxygen-species-generating enzymes not only kills cancer cells directly but also stimulates an anticancer immune response and inverses the immunosuppressive microenvironment of a variety of solid tumors, which is potentially beneficial to overcoming the limitations of cancer immunotherapy. Herein, we report the in situ growth of polycation chains from glucose oxidase to generate glucose oxidase-polycation conjugates, which can be used as a template for the in situ reduction of ferrous ions into iron nanoparticles to yield glucose oxidase-polycation-iron nanoconjugates. The nanoconjugates exhibit enhanced cellular uptake and cancer retention as well as self-activated cascade biocatalysis that consumes glucose and generates highly toxic hydroxyl radicals, leading to enhanced starvation-like and chemodynamic cancer therapy. The cancer treatment with the nanoconjugates efficiently triggers the program of immunogenic cell death for enhanced immune checkpoint blockade therapy. The synergy of self-activated cascade biocatalysis and immune checkpoint blockade not only eradicates primary cancers but also inhibits the progression of distant cancers, which leads to the abscopal effect on cancers. Our findings provide a method for the in situ synthesis of self-activated cascade nano-biocatalysts for cascade biocatalysis-enhanced immunotherapy of cancer.