Construction and evaluation of an engineered autonomously lysing Salmonella system coupled with self-assembled nanoparticles as a vaccine platform for antigen delivery

regulated by Mg²⁺ concentration, and Streptococcus pneumoniae (S. pneumoniae) antigen PspA was used to evaluate this system, which was fused with ferritin (FR) or dihydrolipoyl acetyltransferase (E2p) to self-assembled nanoparticles. The results confirmed Mg²⁺-responsive programmed lysis both in vitro and in vivo and the successful synthesis and assembly of antigen-displaying nanoparticles in S. Typhimurium. Animal studies demonstrated that all engineered autonomously lysing Salmonella strains colonized gut-associated lymphoid tissues equivalently to the control. Notably, this Salmonella vaccine platform showed no significant histopathological signs of virulence in liver or spleen tissues relative to PBS-treated controls. Immunization with the control and this Salmonella vaccine platform elicited robust anti-PspA IgG responses and conferred significant protection against challenge with wild-type S. pneumoniae. Moreover, the nanoparticle-fused constructs (FR and E2p) also induced significant mucosal IgA responses, and the anti-PspA-specific IgG response induced by this Salmonella vaccine platform was significantly higher than that elicited by the non-nanoparticle controls in long-term immune responses. Collectively, our findings establish a programmable lysis-based Salmonella vaccine platform that achieves an optimal balance between the biosafety of attenuated Salmonella and the efficacy of antigen delivery, providing a versatile strategy for next-generation live vector vaccines.