Bacteria-inspired mechano-chemical nanovaccines enable multi-activation of dendritic cells for potent antitumor immunity

Constructed a novel bacteria-inspired mechano-chemical dual-adjuvant nanovaccine (F-PEI/Si@TEV). • Biomimetic stiff surface activates YAP/TAZ mechanotransduction to boost DC phagocytosis and metabolic reprogramming. • F-PEI triggers TLR4 chemical signaling and facilitate lysosomal escape for efficient antigen cross-presentation. • Combined mechano-chemical cues co-orchestrate multiple signaling axes for enhanced antitumor immunity. Despite dendritic cell (DC)-centered antitumor vaccines hold great promise, conventional nanovaccines severely suffer from the uncoupled mechanical and chemical cues, which leads to insufficient DC phagocytosis, suboptimal DC activation, and compromised antigen cross-presentation, thereby limiting their therapeutic efficacy. Herein, we engineer a bacteria-inspired mechano-chemical dual-adjuvant nanovaccine (F-PEI/Si@TEV) via cryogenic silicification of thermal-shocked tumor-derived extracellular vesicles (TEVs), which encapsulates full tumor antigens within silica shells and is surface-modified with fluorinated polyethyleneimine (F-PEI). The nanovaccine possesses a stiff and rough surface mimicking bacterial physical characteristics, promoting DC phagocytosis and metabolic reprogramming through YAP/TAZ-mediated mechanotransduction. Meanwhile, the F-PEI layer serves as a pathogen-mimetic biochemical agonist to trigger TLR4 signaling and enable lysosomal escape for enhanced antigen cross-presentation. Notably, the integrated nanovaccine further orchestrates the TNF, PI3K-Akt, and NF-κB signaling networks to achieve full-scale DC maturation and T-cell activation. In vivo, F-PEI/Si@TEV elicits robust and systemic antitumor immunity, effectively suppressing tumor growth and lung metastasis in both prophylactic and therapeutic tumor models. This work establishes an integrated mechano-chemical immunomodulatory platform for synchronous DC activation and antigen delivery, offering a universal and translatable strategy for next-generation potent cancer nanovaccines.