Trained immunity driven by Enterococcus faecalis ribosomal protein S11 enhances antigen presentation and boosts...

The limited availability of adjuvants poses a significant challenge in modern vaccine development, as they play a crucial role in enhancing vaccine efficacy. Trained immunity, driven by metabolic and epigenetic reprogramming of innate immune cells, offers a novel platform for adjuvant discovery. However, current studies predominantly focus on classical inducers such as β-glucan and BCG, limiting the exploration of key genes underlying trained immune responses. Here, we introduce a phenotypic evaluation model using Galleria mellonella larvae, identifying the gut commensal Enterococcus faecalis as a potent inducer of trained immunity. Through bioactivity-guided fractionation, we identified ribosomal protein S11 (RPS11) as the active agonist. Mechanistically, RPS11 induces trained immunity through TLR4-TET2 signaling-mediated ribosomal biogenesis inhibition, thereby shaping the enhanced MHC molecule expression phenotype in trained antigen-presenting cells. Notably, RPS11 conjugated with superparamagnetic iron oxide nanoparticles (RSNPs) significantly boosted the efficacy of an influenza vaccine. These findings highlight that harnessing the synergistic effects of innate and adaptive immune memory, combined with nanoparticle-based delivery of trained immunity agonists, presents a promising strategy for advancing next-generation vaccines against infectious diseases.