Metal-Phenolic Network-Encapsulated Nanovaccine with pH and Reduction Dual Responsiveness for Enhanced Cancer Immunotherapy.

Cancer nanovaccines have been widely explored to enhance immunotherapy efficiency, in which the significant irritation of antigen-specific cytotoxic T cells (CTLs) is the critical point. In this study, we developed a pH and reduction dual-sensitive nanovaccine (PMSN@OVA-MPN) composed of two parts. The inner part was made up of polyethyleneimine (PEI)-modified mesoporous silica nanoparticles (MSNs) loaded with model antigen ovalbumin (OVA) and the outer part was made up of disulfide bond-involved metal-phenolic networks (MPNs) as a protective corona. In vitro release experiments proved that PMSN@OVA-MPN could intelligently release OVA in the presence of reductive glutathione, but not in neutral phosphate-buffered saline (PBS). Moreover, in vitro cell assays indicated that the nanovaccine promoted not only the OVA uptake efficiency by DC2.4 cells but also antigen lysosome escape due to the proton sponge effect of PEI. Furthermore, in vivo animal experiments indicated that PMSN@OVA-MPN induced a large tumor-specific cellular immune response so as to effectively inhibit the growth of an existing tumor. Finally, the immune memory effect caused by the nanovaccine afforded conspicuous prophylaxis efficacy in neonatal tumors. Hence, the multifunctional vaccine delivery system prepared in this work exhibits a great application potential in cancer immunotherapy and offers a platform for the development of nanovaccines.