Acidity-responsive polyphenol-coordinated nanovaccine for improving tumor immunotherapy via bidirectional reshape of immunosuppressive microenvironment and controllable release of antigen

The tumor immunosuppressive microenvironment (TIME) and uncontrollable release of antigen can cause poor efficacy of nanovaccine-based immunotherapy (NBI). It is necessary to develop new strategy for TIME reshape and controllable release of antigen to improve the NBI efficacy. Herein, an acidity-responsive Schiff-base conjugated polyphenol-coordinated nanovaccine was constructed to realize bidirectional TIME reshape and controllable release of antigen for activating T cells for the first time. Specially, the acidity-responsive tannic acid-ovalbumin (TA-OVA) nanoconjugate was prepared via Schiff-base reaction. FeⅢ was coordinated with TA-OVA to produce FeⅢ-TA-OVA nanosystem, and 1-methyltryptophan (1-MT) as indoleamine 2,3-dioxygenase inhibitor was loaded to form polyphenol-coordinated nanovaccine. The coordination between FeⅢ and TA could cause the photothermal ablation of primary tumor, and the acidity-triggered Schiff-base dissociation of TA-OVA could controllably release OVA to realize lysosome escape, initiating the body’s immune response. More importantly, oxidative stress generated by tumor-specific Fenton reaction of Fe ion could promote the polarization of tumor-associated macrophages from M2 to M1 phenotype, resulting in the upregulation of cytotoxic T cells and helper T cells. Meanwhile, 1-MT could downregulate immunosuppressive regulatory T cells. Overall, such skillful combination of bidirectional TIME reshape and controllable antigen release into one coordination nanosystem could effectively enhance NBI of tumors.