Chiral-Structured Aluminum Oxyhydroxide Nanoadjuvants for Prophylactic Vaccines

The chirality of biomaterials plays a critical role in biological interactions, such as cellular uptake, receptor binding, and immune activation. Despite the widespread use of aluminum-based adjuvants in vaccines and significant advances in optimizing their physicochemical properties, the impact of chirality on immunological performance remains poorly understood. Here, we present a chiral engineering strategy for chiral aluminum oxyhydroxide (l-/d-AlOOH) nanoadjuvants using enantiomeric l- or d-lysine hydrochloride as the structure-directing agents. Both enantiomers modulate crystal growth by introducing anisotropic atomic arrangements. Owing to its stronger interaction with aluminum, l-lysine inhibits longitudinal growth of l-AlOOH and induces chiral structure formation with a lower aspect ratio. Adsorption studies reveal that l-AlOOH exhibits a lower adsorption coefficient for human papillomavirus antigen (HPV) type 18 L1 virus-like particles (VLPs), the antigen particles with spatial chirality, which was attributed to the intrinsic chirality mismatch between l-AlOOH and HPV 18 L1 VLPs. Correspondingly, l-AlOOH facilitates accelerated antigen release from the injection site and trafficking into the lymph nodes. Additionally, l-AlOOH significantly enhances antigen uptake by dendritic cells in vitro compared with achiral and d-lysine-induced AlOOH. In HPV and hepatitis B surface antigen (HBsAg) vaccination models, l-AlOOH boosts antigen-specific antibody titers, indicating chirality-controlled humoral immunity. These findings demonstrate that the chiral configuration of AlOOH modulates its adjuvanticity through chirality-driven antigen delivery, providing a blueprint for the rational design of next-generation vaccine adjuvants.