Catalytic nanovaccine for cancer immunotherapy: A NADPH oxidase-inspired Fe-polyphenol network nanovaccine for enhanced antigen cross-presentation.

• A catalytic OVA@FG nanovaccine provides a new perspective for vaccine design. • "Fe-GA catalytic unit" mimicked the ROS transfer process of NOX2 in organisms. • The fusiform-like OVA@FG exerted effective antigen cross-presentation in vivo. • OVA@FG promoted potent antitumor immunotherapy. Limited efficacy of antigen cross-presentation has become a great challenge in cancer vaccine development for increased cytotoxic T lymphocytes (CTLs). Recent studies have found that NADPH oxidase 2 (NOX2) complex, the main catalyst for reactive oxygen species (ROS) generation in organisms to facilitate exogenous antigens leaking to cytoplasm, enhances the cross-presentation of antigen-presenting cells (APCs). Herein, inspired by the NOX2 catalytic ROS production, a cascade catalytic nanovaccine named OVA@FG was successfully developed to achieve biomimic oxidative effect. Specifically, metal-polyphenol networks (MPN), formed by naturally-derived gallic acid (GA) with Fe3+ ions, were spontaneously adsorbed on the model antigen ovalbumin (OVA) templates to construct OVA@FG. OVA@FG featured with a fusiform-like structure, can effectively migrate into lymph nodes (LNs) and accumulate in APC endo-/lysosomes. GA, within the nanovaccine structure, enabled to act as reducing agents to promote Fe3+/Fe2+ transformation in the acidic endo-/lysosomal environment. The cascade catalytic reaction between GA and Fe3+ ions mimicked the transfer process of NOX2 biological mechanism in "O 2 to O 2 •− to H 2 O 2 /•OH" cycling iteration. The process promoted the OVA antigen escape from endo-/lysosomes, APCs maturation and antigen cross-presentation to T lymphocytes. Notably, high levels of antigen-specific CD8+ T cell responses, accompanied by the induction of CD4+ T helper cells and remarkably therapeutic efficacy, were achieved in the B16-OVA tumor bearing mice treated with OVA@FG nanovaccines. The NOX2-inspired catalytic approach represents a facile applicable strategy for effective cross-presentation of exogenous antigens. [ABSTRACT FROM AUTHOR]