Mannose-grafted polyaspartic acid-functionalized dual-ion nanoadjuvants trigger cGAS-STING-mediated immune responses...

Calcium phosphate (CaP) nanoparticles are limited as vaccine adjuvants by their inherent weak immunogenicity and colloidal instability. To address this, we developed mannose-grafted polyaspartic acid-functionalized calcium-manganese phosphate hybrid nanoparticles (Man@CaMnP NPs) via a facile assembly strategy. The resulting nanoplatform exhibited excellent colloidal stability and high antigen encapsulation efficiency (>90%). In vitro, surface mannosylation significantly enhanced antigen uptake by antigen-presenting cells (APCs). Following intracellular degradation, the co-released Mn²⁺ and Ca²⁺ synergistically drove innate immunity by activating the cGAS-STING pathway, with Mn²⁺ directly engaging the axis and Ca²⁺ amplifying downstream inflammatory signaling. In vivo, the nanovaccine formed a local depot for prolonged antigen retention. Compared to commercial alum, Man@CaMnP NPs overcame the inherent Th2 bias, eliciting broader and more robust immune responses, characterized by elevated antigen-specific IgG titers, robust CD4⁺/CD8⁺ T cell activation, and strong Th1-associated cellular immunity. With no observable organ toxicity, this dual-ion system provides a safe and highly effective nanoadjuvant strategy for vaccines requiring robust cellular immune responses.