Manganese immunotherapy for treating osteosarcoma: Glycosylating 1V209 anchored MnO2 nanosheets prompt pro-inflammatory macrophage polarization

Current immunotherapy has not met the curative expectations in the treatment of osteosarcoma. As the most abundant immune cells in the tumor microenvironment (TME), macrophages are closely related to the progression of osteosarcoma. Recently, bivalent manganese ions (Mn2+) have been found to present great potential for immunotherapy in natural killer cells and dendritic cells. However, the effect of Mn2+ on macrophage polarization remains entirely unclear, especially in the TME. Toll-like receptor 7 (TLR7) agonists can initiate innate immune responses but are limited in clinical application for their hydrophobicity. Herein, we prepare BSA-templated MnO2 nanosheets (BMs) and conjugate 1V209, a small molecule TLR7 agonist, with a sugar group to improve hydrophilicity and immunostimulatory effects. Sugar-conjugated 1V209 (SV) is further anchored onto BMs to construct [email protected] In our study, [email protected] can react with glutathione (GSH) to release Mn2+ and produce plenty of reactive oxygen species (ROS) via Mn2+-mediated Fenton-like reactions in macrophages. ROS generated by pro-inflammatory macrophages can induce apoptosis of tumor cells. Mn2+ and co-released SV together promote pro-inflammatory macrophage polarization, which may depend on the activation of the NF-κB signal pathway. In vivo, the application of [email protected] significantly activates local and systematic immunity, eliminates tumor cells and reduces lung metastases.