Mechanoimmuno‐Engineered Dendritic Cell Membrane Nanodiscs Presenting Diverse Antigens for Potent Antibacterial Vaccination

ABSTRACT Conventional antibacterial vaccines often fail to elicit robust immunity against multifaceted virulence factors, including bacterial surface antigens and secreted toxins, particularly lacking the strong T‐cell responses essential for effective infection prevention. To overcome this limitation, we engineered dendritic cell (DC) membrane‐derived nanodiscs (aDCNDs) with stiffness‐tuned topology as a mechanoimmunological antibacterial nanovaccine. aDCNDs uniquely co‐present multi‐antigens from bacterial membranes and secreted toxins alongside upregulated immune‐stimulatory molecules, eliciting potent adaptive immunity that simultaneously targets Pseudomonas aeruginosa cells and neutralizes cytotoxic exotoxins for dual protection. Their precisely controlled sub‐50 nm size enables superior lymph node accumulation versus larger nanovesicles. Importantly, aDCNDs engage T cell mechanotransduction to promote TAZ nuclear translocation, augmenting T cell activation and the secretion of IFN‐γ, IL‐17A, and IL‐4, an effect not observed with conventional soft nanovesicles. The increased stiffness of aDCNDs represents an important and likely contributor to this mechano‐stimulatory effect. In lethal murine models of septicemia and pneumonia, aDCNDs vaccination achieved profound reductions in bacterial burdens (up to 99.99%) and markedly improved survival without systemic toxicity. This work establishes the aDCND platform as a safe and effective antibacterial strategy, highlighting mechano‐immunology as a critical design principle for next‐generation antibacterial vaccines.