Mn and Zn-Doped Multivariate Metal-Organic Framework as a Metalloimmunological Adjuvant to Promote Protection Against...

Area of Science:

• Materials Science
• Immunology
• Vaccinology

Background:

• Development of effective vaccine adjuvants is crucial for enhancing immunogenicity of subunit vaccines.
• Zeolitic-imidazolate frameworks (ZIFs) offer potential as drug and vaccine delivery vehicles.
• Cytotoxicity and controlled payload delivery remain challenges for existing ZIF-based systems.

Purpose of the Study:

• To develop a novel, less cytotoxic vaccine adjuvant delivery system based on manganese-doped ZIF-8 (Mn-ZIF).
• To investigate the co-delivery of cyclic di-adenosine monophosphate (CDA) using Mn-ZIF for enhanced immune activation.
• To evaluate the efficacy of the CDA@Mn-ZIF composite as an adjuvant in a preclinical model of tuberculosis.

Main Methods:

• Synthesis of Mn-ZIF via a mixed metal approach with tunable manganese doping.
• Post-synthetic loading of CDA into Mn-ZIF to form CDA@Mn-ZIF composite.
• Assessment of cytotoxicity, cellular uptake, and immune pathway activation (cGAS-STING).
• Evaluation in a preclinical Mycobacterium tuberculosis (Mtb) infection model using a subunit vaccine (CysVac2).

Main Results:

• Mn-ZIF exhibited significantly lower cytotoxicity compared to ZIF-8.
• CDA@Mn-ZIF showed enhanced cellular uptake and synergistic activation of the cGAS-STING pathway, leading to cytokine production and APC activation.
• In Mtb-infected mice, CDA@Mn-ZIF formulated with CysVac2 induced potent antigen-specific T-cell responses and significantly reduced lung mycobacterial burden.

Conclusions:

• CDA@Mn-ZIF represents a promising, low-cytotoxicity adjuvant delivery platform.
• The system effectively co-delivers adjuvants and enhances antigen-specific immune responses.
• This approach holds potential for improving the efficacy of subunit vaccines against infectious diseases like tuberculosis.