AMnESTI reverses age-associated lung immune decline to drive heterosubtypic protection by inactivated influenza vaccines

Existing influenza vaccines fail to elicit heterosubtypic immunity and have limited efficacy in the elderly. We developed AMnESTI (AEC-targeting MN Encapsulated STING agonist), an alveolar epithelial cell (AEC)–targeting manganese-complexed liposome encapsulating the stimulator of interferon genes (STING) agonist ADU-S100. Intranasal administration activated the cyclic GMP-AMP synthase–STING pathway in AECs, robustly expanding plasmacytoid dendritic cells, monocyte-derived dendritic cells, and inflammatory monocytes while reducing regulatory T cells (T reg cells) and immunosuppressive cDC2β + cells and promoting M1 macrophage polarization. Single-cell RNA sequencing and flow cytometry established that the adjuvant sufficiently revived the aged lung immunity in mice to a proimmune state at the cellular, molecular, and functional levels, consistent with immune responses in younger mice. A single intranasal dose of AMnESTI-adjuvanted influenza vaccine conferred complete heterosubtypic protection in aged mice against representative influenza strains. These findings demonstrate that transient reprogramming of aged lung immunity facilitates robust vaccine responses and identify AECs as a potential mucosal adjuvant target for broadly protective influenza vaccines in the elderly.