Metalloparticle‐Engineered Pickering Emulsion Displaying AAV‐Vectored Vaccine for Enhancing Antigen Expression and Immunogenicity Against Pathogens

Recombinant adeno-associated viruses (rAAVs) have emerged as promising vaccine vectors due to their enduring efficacy with a single dose. However, insufficient cellular immune responses and the random and non-specific distribution of AAVs post-injection may hinder the development of AAV vaccines. Here, a novel Pickering emulsion platform stabilized by biomineralized manganese nanoparticles and aluminum hydroxide, which can rapidly and efficiently load AAVs, is reported. This platform confers AAVs with favorable in vivo distribution kinetics, diversifying AAV endocytic pathways with reduced dependency on the sialic acid receptor-mediated route, and ultimately enhancing AAV infection efficiency in antigen present cells (APCs). Concurrently, the Pickering emulsion substantially boosts endogenous 2'3'-cGAMP production, further activating the cGAS-STING pathway for stronger immune responses and improving protective efficacy in bacterial infection models. The STING pathway activation also increases AAV target gene expression, potently augmenting the cross-protective potential of AAV vaccines for COVID-19. These synergistic effects ensure that effective immune responses are induced even at one-fifth of the AAV vaccination dose, while the Pickering emulsion further reduces the accumulation of AAV in the liver, thereby improving their safety. The findings highlight the potential of Pickering emulsions as valuable enhancers for viral vectors, providing insights for their broader clinical applicability.