Multifunctional manganese-containing vaccine delivery system Ca@MnCO3/LLO for tumor immunotherapy

The ideal vaccine delivery systems can not only deliver antigens in intelligent manners but also act as adjuvants. Recently found that Mn²⁺ can effectively stimulate anti-tumor immune responses, and Ca²⁺ 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@MnCO₃) and perforin-listeria hemolysin (LLO), as termed as Ca@MnCO₃/LLO. The two components Ca@MnCO₃ and LLO, not only act as vaccine adjuvants by themselves, but also contribute to achieve cellular immunity. Among them, Ca@MnCO₃ microspheres as an excellent Mn²⁺ and Ca²⁺ reservoir, can continuously release adjuvants Mn²⁺ and Ca²⁺ to enhance immune response in dendritic cells, while LLO can contribute to induce lysosomal escape. Particularly, Ca²⁺ was added firstly to MnCO₃ microspheres to improve the stability and load capacity of the microspheres. Along with the degradation of intracellular Ca@MnCO₃ microspheres, and the lysosomal membrane-lytic effects of perforin LLO, the Mn²⁺, Ca²⁺ 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@MnCO₃/LLO provides a promising platform for the construction of tumor vaccines.