Engineering an Effective Immune Adjuvant by Designed Control of Shape and Crystallinity of Aluminum Oxyhydroxide Nanoparticles

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Abstract

Adjuvants based on aluminum salts (Alum) are commonly used in vaccines to boost the immune response against infectious agents. However, the detailed mechanism of how Alum enhances adaptive immunity and exerts its adjuvant immune effect remains unclear. Other than being comprised of micrometer-sized aggregates that include nanoscale particulates, Alum lacks specific physicochemical properties to explain activation of the innate immune system, including the mechanism by which aluminum-based adjuvants engage the NLRP3 inflammasome and IL-1β production. This is putatively one of the major mechanisms required for an adjuvant effect. Because we know that long aspect ratio nanomaterials trigger the NLRP3 inflammasome, we synthesized a library of aluminum oxyhydroxide (AlOOH) nanorods to determine whether control of the material shape and crystalline properties could be used to quantitatively assess NLRP3 inflammasome activation and linkage of the cellular response to the material's adjuvant activities in vivo. Using comparison to commercial Alum, we demonstrate that the crystallinity and surface hydroxyl group display of AlOOH nanoparticles quantitatively impact the activation of the NLRP3 inflammasome in human THP-1 myeloid cells or murine bone marrow-derived dendritic cells (BMDCs). Moreover, these in vitro effects were correlated with the immunopotentiation capabilities of the AlOOH nanorods in a murine OVA immunization model. These results demonstrate that shape, crystallinity, and hydroxyl content play an important role in NLRP3 inflammasome activation and are therefore useful for quantitative boosting of antigen-specific immune responses. These results show that the engineered design of aluminum-based adjuvants in combination with dendritic cell property-activity analysis can be used to design more potent aluminum-based adjuvants.

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