Mn and Zn‐Doped Multivariate Metal–Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against Tuberculosis Infection

Abstract A first‐in‐class vaccine adjuvant delivery system, Mn‐ZIF, is developed by incorporating manganese (Mn) into the zinc‐containing zeolitic‐imidazolate framework‐8 (ZIF‐8). The mixed metal approach, which allowed for tunable Mn doping, is made possible by including a mild reducing agent in the reaction mixture. This approach allows up to 50% Mn, with the remaining 50% Zn within the ZIF. This multivariate approach exhibits significantly decreased cytotoxicity compared to ZIF‐8. The porous structure of Mn‐ZIF enables the co‐delivery of the STING agonist cyclic di‐adenosine monophosphate (CDA) through post‐synthetic loading, forming CDA@Mn‐ZIF. The composite demonstrated enhanced cellular uptake and synergistic activation of the cGAS‐STING pathway, producing proinflammatory cytokines and activating antigen‐presenting cells (APCs). In a preclinical Mycobacterium tuberculosis ( Mtb ) model, CDA@Mn‐ZIF formulates with the CysVac2 fusion protein elicited a potent antigen‐specific T‐cell response and significantly reduced the mycobacterial burden in the lungs of infected mice. These findings highlight the potential of CDA@Mn‐ZIF as a promising adjuvant for subunit vaccines, offering a novel approach to enhancing vaccine efficacy and protection against infectious diseases such as tuberculosis.