Nanovaccine biomineralization for cancer immunotherapy: a NADPH oxidase-inspired strategy for improving antigen cross-presentation via lipid peroxidation.

Abstract

Current efforts to develop novel vaccine nanotechnologies to increase cytotoxic T lymphocytes have met the challenges of the limited efficacy of antigen cross-presentation. Recent studies have uncovered a unique biological mechanism by which activation of the NADPH oxidase 2 (NOX2) complex, a major source of reactive oxygen species (ROS), enhances the cross-presentation by antigen-presenting cells (APCs). Inspired by the NOX2 mechanism, we devise biomineralized nanovaccines named NVs^cp, which are developed by in situ growth of calcium peroxide on nanovaccines self-assembled with the model antigen ovalbumin. The ~80 nm NVs^cp efficiently flow to the draining lymph nodes, where they accumulate within APC endo-/lysosomes, and generate a rapid burst of ROS in response to the acidic endo-/lysosomal environment with the subsequent endo-/lysosomal lipid peroxidation. Accompanied by the process, NVs^cp stimulate distinct APCs maturation and antigen presentation to T lymphocytes. Notably, high levels of antigen-specific CD8⁺ T cell responses, accompanied by the induction of CD4⁺ T helper cells, are achieved. More importantly, NVs^cp significantly increase the ratios of intratumoral CD8⁺ T/regulatory T cells and achieve prominent tumor therapy effects. The NOX2-inspired biomineralized NVs^cp represent an effective and easily applicable strategy that enables the strong cross-presentation of exogenous vaccine antigens.