DNA-Based Immunostimulatory Hydrogel Loaded with Nanoparticle-Detained Toxins as a Toxoid Vaccine against Bacterial Infection

Vaccines have been highly successful in protecting against many different types of infections. Unfortunately, there are still many high-priority pathogens for which there are no clinically approved formulations. Recently, nanoparticle-based strategies have been explored for more effective antigen delivery to the immune system. Nanotoxoids are an emerging platform that leverages cell membrane coating technology to safely deliver toxic bacterial antigens in their native form for antivirulence vaccination. In order to further boost their immunogenicity, we have formulated nanotoxoids against staphylococcal α-hemolysin by embedding them into a DNA-based hydrogel with immunostimulatory CpG motifs. The resulting nanoparticle–hydrogel composite is injectable and improves the in vivo delivery of the bacterial toxin while stimulating nearby immune cells. This resulting in elevated antibody production and stronger antigen-specific cellular immune responses. In mouse models of pneumonia and skin infection caused by methicillin-resistant <i>Staphylococcus aureus</i>, mice that are vaccinated with our new hybrid vaccine formulation are better protected. Our work highlights the benefits of combining nanovaccines with immunostimulatory hydrogels into a single platform. We believe that the approach can be readily generalized to a range of infectious diseases.