Nanozyme-Initiated In Situ Cascade Reactions for Self-Amplified Biocatalytic Immunotherapy

Abstract

Biocatalytic nanomaterials have been verified to modulate the immunosuppressive state of an extensive range of solid tumors and directly induce antitumor immune response, which effectively combats the holdbacks in cancer immunotherapy. Herein, biomimetic cascade enzyme-initiated toxic-radical-generating devices (GHZD NCs) are fabricated by enveloping glucose oxidase (GOx), artificial nanozyme hemin, and sesquiterpene lactone endoperoxide derived dihydroartemisinin (DHA) into zeolitic imidazolate framework (ZIF-8) for enhanced biocatalytic immunotherapy. The GHZD NCs exhibit amplified multienzyme-mimic (glucose oxidase, peroxidase, and glutathione peroxidase) cascade reactions in artificial nanoscale proximity. Concurrently, a glutathione (GSH)-stimulated labile iron-current amplifier boosts C-centered free radicals, which endows the GHZD NCs with tumor-specific and self-circulating generation ability of vicious C-centered free radicals. Irreversible free radicals (·C and ·OH) and sustainable H2O2 from sequential catalytic processes logically and selectively elevate the oxidative stress in the tumor, which further triggers an efficient immunogenic cell death (ICD) progress. In addition, the in situ nanozyme-based immunotherapy employed for tumor suppression successfully elicits the long-lasting immunological memory effect, which hinders the growth of distant tumors and lung metastasis.