Double-metal ion adjuvant stabilized Pickering emulsion to amplify humoral and cellular immune responses

Metal ions play critical roles in many immune processes, and their modulation may open up new forms of vaccine adjuvants. Current vaccines predominantly utilize aluminum salts as adjuvants, but alum has poor ability to induce cellular immunity. Manganese (Mn²⁺) can activate cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway for amplifying cellular immune responses, but free Mn²⁺ may cause certain neurotoxicity due to its random in vivo distribution. Herein, Mn²⁺ is initially biomineralized into human serum albumin nanoparticles (HSA-Mn) to improve the biocompatibility of Mn adjuvants. Then HSA-Mn and alum adjuvants are co-dispersed at the squalene/water interphase, resulting in a bimetallic adjuvant co-stabilized Pickering nanoemulsion (HMANE). Compared to lecithin-stabilized emulsion, HMANE increased the surface roughness by approximately 6-fold and significantly improved its interactions with antigen-presenting cells (APCs). After vaccination, HMANE-adjuvanted inactivated SARS-CoV-2 virus (CorV-HMANE) rapidly induced antibody generation and efficiently activated the STING pathway to produce a stronger cellular immune response. In addition, the abundant memory B and T cells induced by the CorV-HMANE further ensured its long-term protective efficacy for at least 4 months. In conclusion, our study highlights the great potential of Pickering emulsions as metal adjuvant platforms, providing new insight for further adjuvant development.