An Inorganic Stimulator of Interferon Genes Sensitizer for the Metalloimmunotherapy of Intracellular Bacterial Infections

Bone infections associated with the formation of intracellular bacterial niches in macrophages and bone cells play an important role in the long-lasting nature of chronic infections. One major mechanism of intracellular bacterial persistence lies in the low antibiotic permeability and subverted immune responses. It is now increasingly apparent that metal elements such as Mn, Zn, and Se exploit the stimulator of interferon genes (STING) pathway in immune cells to combat invading pathogens and intrinsic aberrant cells. Here, we report a prototype of bacterial metalloimmunotherapy using a synthetic inorganic STING sensitizer (SSZ), which comprises Se-loaded mesoporous silica nanoparticles and ZnO quantum dot lids. Mechanistically, the inorganic STING sensitizer could restore the bactericidal activity of lysosomes in macrophages and generate type I interferons, achieving effective intracellular bacterial clearance. Topical application of the inorganic STING sensitizer initiated robust antibacterial immunity, leading to obvious therapeutic efficacy toward both intracellular bacteria and biofilms in a mouse osteomyelitis model. Rechallenging the SSZ-cured mice with bacteria led to effective inhibition of bacterial growth, suggesting the generation of long-term antibacterial memory responses. This antibacterial strategy was also proven effective in a rabbit knee prosthetic infection model. Overall, the inorganic STING sensitizer offers an alternative approach for intracellular bacterial treatments, and this underscores the great potential of metalloimmunotherapy for infectious diseases.