Acoustic cavitation-enhanced lymphatic trafficking of inhaled bacterial-sourced biohybrid vaccines for antitumor immunity.

The clinical translation of personalized cancer vaccines is currently impeded by the dual challenges of rapid antigen manufacturing and inefficient delivery to lymphoid tissues. In this study, we present a biohybrid nanovaccine platform that bridges synthetic biology and acoustic engineering to enable a noninvasive airway-to-lymph-node vaccination strategy. Leveraging an engineered nonpathogenic Escherichia coli TOP10 strain as living antigen factories, we construct ultrasound-responsive, manganese-chelated bacterial membrane nanovesicles that encapsulate biosynthesized tumor antigens. Following nebulized inhalation, low-intensity ultrasound triggers the acoustic droplet vaporization of these nanovesicles. This process induces cavitation-enhanced lymphatic trafficking, which actively overcomes pulmonary physiological barriers to promote deep tissue penetration and efficient antigen drainage to pulmonary lymph nodes. The spatiotemporally controlled co-delivery of antigenic proteins, innate bacterial adjuvants, and Mn2+ orchestrates a potent immune cascade, driving robust dendritic cell maturation and antigen cross-presentation. Consequently, this 'inhale-and-act' strategy elicits strong systemic antitumor immunity for next-generation personalized immunotherapy.