This presentation examines the role of metal ions—zinc (Zn²⁺), manganese (Mn²⁺), and zirconium (Zr⁴⁺)—in modulating immune responses through their incorporation into metal-organic frameworks (MOFs) for therapeutic and prophylactic applications. Zinc-based ZIF-8 functions as a mild immunostimulant and antigen stabilizer, enhancing immune responses through the formation of a depot and responsive release. Manganese plays a more direct immunological role, activating the cGAS-STING pathway when co-delivered with cyclic dinucleotides (CDNs), resulting in dendritic cell activation and robust cytokine production (TNF-α, IL-6). This synergy is enabled by Mn-ZIF scaffolds, which protect the CDN from enzymatic degradation and facilitate sustained co-release.

Zirconium-based MOFs, particularly NU-1003, serve as long-acting depots for enzyme therapeutics, such as OPAA (Organophosphorus Acid Anhydrolase), thereby extending their tissue residence and therapeutic window. Immunologically, NU-1003 elicited significantly lower anti-OPAA IgG and IgM titers compared to ZIF-8, suggesting Zr-MOFs may be inherently less immunogenic. This reduced immune recognition likely contributes to longer circulation and improved tolerability. These findings position Zr-MOFs as superior scaffolds for sustained delivery of biologics where immune evasion is critical.

Together, these data highlight how specific metal ions within MOFs shape immune outcomes, either by amplifying innate signaling pathways or by minimizing adaptive responses, enabling tailored immunomodulation across diverse biomedical applications.