Cyclic di-(3′,5′)-guanosine monophosphate-loaded metal-organic frameworks for mucosal immunization against giardiasis

ABSTRACT Giardiasis caused by the intestinal protozoan Giardia lamblia is a major global cause of diarrheal disease and malabsorption particularly affecting young children and populations in low- and middle-income countries. Despite evidence of immunity after infection, no human vaccine is available. Induction of effective mucosal immunity is critical for protection against this lumen-dwelling pathogen, but has been hampered by the lack of suitable adjuvants. We show here in a murine model that cyclic di-(3′,5′)-guanosine monophosphate (CDG) is a potent mucosal adjuvant for immunization against G. lamblia with a defined antigen, α1-giardin. Based on this observation, we developed a novel nanovaccine strategy that employs metal-organic framework (MOF) nanoparticles loaded with CDG and cloaked with native G. lamblia membranes. These particles enable simultaneous delivery of multiple antigens in their native form together with a powerful mucosal adjuvant. CDG-loaded MOFs exhibited efficient cargo encapsulation and controlled release and strong immune-stimulatory activity in dendritic cells. Intranasal immunization of mice with G. lamblia membrane-coated CDG-MOFs elicited robust parasite-specific IgG responses and conferred profound protection against G. lamblia infection that was superior to that achieved with a single defined antigen. Immunization-induced protection was dependent on the CDG receptor STING and required CD4 + T cells but was independent of secretory IgA. These findings demonstrate that MOF-based nanovaccines incorporating a cyclic dinucleotide represent an effective platform for inducing protective mucosal immunity against giardiasis. More broadly, this approach offers a versatile strategy for delivering hydrophilic adjuvants and multivalent antigens for vaccination against mucosal pathogens of the gastrointestinal tract.