Engineered bacterial outer membrane vesicle vaccine prevents T cell exhaustion for antibacterial immunotherapy.

Gram-negative pathogens evade immune clearance and promote chronic infections by residing intracellularly. While outer membrane vesicles (OMVs) hold promise as antibacterial vaccine platforms, their clinical potential is limited by lysosomal entrapment of antigens and endotoxin-induced toxicity. Herein, we present an innovative nano-encapsulation strategy to engineer OMVs and overcome these two obstacles. We engineered Porphyromonas gingivalis (P. gingivalis) OMVs by incorporating metal ion adjuvants, coordinated with phenolic ligands, to form a rigid, acid-responsive nanoshell. This shell enhances dendritic cell uptake and promotes lysosomal escape, redirecting antigens to cytosolic cross-presentation and reprogramming CD8+ T cell responses through STING signaling. Nano-encapsulation also attenuates endotoxin-induced systemic cytokine storms, reducing lethality. In murine periodontitis, the engineered OMV vaccine lowers P. gingivalis burden, prevents T cell exhaustion, and mitigates inflammatory tissue damage. These findings provide a safe and effective strategy to counteract immune evasion by intracellular pathogens, with promising potential for immunotherapy against chronic bacterial infections.