Morphology-Engineered Bioparticles Drive Trained Immunity via TLR1/MAPK/mTOR–Redox–Methylation Hub for Broad-Spectrum Protection against MDR Pathogens

The global spread of multidrug-resistant bacteria and cross-infection among pathogens presents significant threats to public health. Conventional antibiotics and vaccines have proven inadequate against rapidly mutating pathogens and synergistic infections caused by multidrug-resistant bacteria. Immunotherapies based on trained immunity offer promise in addressing these challenges by rapidly enhancing host immune responses and providing broad protection without reliance on specific antigens. Previous studies have demonstrated that filamentous bio-particles, engineered from microbial morphology, significantly enhance vaccine efficacy as delivery carriers. However, the impact of these particles on innate immunity remains poorly understood. Experimental evidence indicates that filamentous bio-particles (fBLP) can induce moderate inflammation and balance oxidative stress, providing broad-spectrum protection against multidrug-resistant infections lasting up to 21 days. Further studies provide evidence supporting the hypothesis that fBLP triggers a trained immune-like phenotype in vitro and in vivo, independent of antigen specificity. This includes an increase in macrophage phagocytosis, moderate secretion of pro-inflammatory cytokines, and alterations in metabolic pathways. fBLP-triggered trained immunity alters receptor activation via the TLR1/MAPK/mTOR signaling pathway, promoting metabolic reprogramming, as evidenced by enhanced glycolysis, increased accumulation of TCA cycle metabolites, and alterations in amino acid and lipid metabolism. These processes involve epigenetic modifications, such as deacetylation and demethylation, which selectively amplify MAPK pathway activation and induce unique metabolic changes. Collectively, these alterations establish an immune memory state. This study pioneers the integration of morphology engineering and trained immunity, offering an innovative strategy to disease prevention and the design of anti-infective vaccines.