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

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 NVscp, which are developed by in situ growth of calcium peroxide on nanovaccines self-assembled with the model antigen ovalbumin. The ~80 nm NVscp 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, NVscp 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, NVscp significantly increase the ratios of intratumoral CD8+ T/regulatory T cells and achieve prominent tumor therapy effects. The NOX2-inspired biomineralized NVscp represent an effective and easily applicable strategy that enables the strong cross-presentation of exogenous vaccine antigens.