A nano-adjuvant platform potentiates immunity for potent mucosal and systemic defense against influenza.

Vaccines against respiratory viruses such as influenza require adjuvant platforms capable of simultaneously inducing robust mucosal and systemic immunity. Here, we report a PEGylated aluminum-manganese oxide hybrid nano-adjuvant (Al-Mn-PEG) as an efficient mucosal vaccine delivery system. Al-Mn-PEG exhibits high stability and biocompatibility, enhancing antigen uptake, activation, and lysosomal escape in antigen-presenting cells, thus promoting cross-presentation. In vivo, intranasal immunization with Al-Mn-PEG loaded with hemagglutinin from influenza A or B viruses induces strong mucosal sIgA and systemic IgG responses, drives a mixed Th1/Th2 immune profile with systemic Th1 skewing, and activates CD8+ T cells, resulting in comprehensive immune protection. Mechanistically, Al-Mn-PEG engages both the STING/TBK1/IRF3 and NLRP3 pathways, which potentiate the immune system and drive coordinated innate and adaptive immune responses. This work establishes Al-Mn-PEG as a versatile adjuvant platform, offering a strategy for next-generation respiratory vaccines.