The ideal vaccine delivery systems can not only deliver antigens in intelligent manners but also act as adjuvants. Recently found that Mn can effectively stimulate anti-tumor immune responses, and Ca can regulate autophagy to promote the cross-presentation of antigens. Thus, we constructed such a manganese-containing multimode vaccine delivery system by using calcium-doped manganese carbonate microspheres (Ca@MnCO) and perforin-listeria hemolysin (LLO), as termed as Ca@MnCO/LLO. The two components Ca@MnCO and LLO, not only act as vaccine adjuvants by themselves, but also contribute to achieve cellular immunity. Among them, Ca@MnCO microspheres as an excellent Mn and Ca reservoir, can continuously release adjuvants Mn and Ca to enhance immune response in dendritic cells, while LLO can contribute to induce lysosomal escape. Particularly, Ca was added firstly to MnCO microspheres to improve the stability and load capacity of the microspheres. Along with the degradation of intracellular Ca@MnCO microspheres, and the lysosomal membrane-lytic effects of perforin LLO, the Mn, Ca and OVA were released to the cytoplasm. These outcomes cooperatively promote antigen cross-presentation, elicit CD8 T cell proliferation, and finally achieve prominent anti-tumor effects. The results indicate that the manganese-containing vaccine delivery system Ca@MnCO/LLO provides a promising platform for the construction of tumor vaccines.
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