Antigen-caged-adjuvant nanovaccines elicit potent humoral and cellular immune responses

Although the metal adjuvant like aluminum hydroxide is regarded as the prevailing adjuvant in licensed vaccines, it is undermined by gigantic size, rapid antigen detachment and hampered migration to lymphoid system, thus leading to weak adjuvanticity and the failure to trigger cellular immune response. The integrated delivery of antigen and adjuvant to the antigen-presenting cells (APCs) in lymph nodes is vital to improving the poor adjuvanticity of alum-adjuvant. Herein, we demonstrated that an antigen-caged adjuvant strategy significantly promoted the integration between aluminum adjuvant and protein antigen. With controlled bio-mineralization, a single molecule antigen with caged single or alloyed metal adjuvant cluster was prepared. This antigen-caged adjuvant (ACs@Ag) facilitated the migration toward draining lymph nodes and enhanced the internalization of both adjuvant and antigen by APCs, leading to robust antigen-specific humoral and cellular immune responses. Antigen-caged alloyed metal adjuvants containing multiple kinds of metal adjuvants was fabricated and resulted in the activation of various immune pathways. The general adjuvanticity of ACs@Ag was determined with two antigens: spike RBD for SARS-CoV-2 and ovalbumin for melanoma, both of which offered effective protection. This work shows that the antigen-caged adjuvant strategy can be a versatile platform for the rational design of metal adjuvant applied in vaccines.