Inactivated and attenuated meningitis bacteria intracellularly loaded with nanoagents cross blood-brain barrier for glioblastoma immunotherapy

Glioblastoma (GBM) treatment faces a significant challenge due to the blood-brain barrier (BBB) restricting therapeutic delivery. In this study, we found that inactivated and attenuated meningitis bacteria (e.g., Escherichia coli K1) intracellularly loaded with nanoagents could safely and effectively bypass the BBB even when injected intravenously into mice at a dose of ~ 10⁷ colony forming units (CFU) since the vehicles preserved the bacteria’s structure and chemotaxis while removing their pathogenicity. We demonstrated that bacteria could internalize glucose polymer, indocyanine green and stimulator of interferon genes (STING) agonists (e.g., SR717)-modified silica nanoparticles through the bacteria-specific adenosine-triphosphate (ATP)-binding cassette sugar transporter pathway. As a result, the developed system could deliver approximately five times more nanoagents to the brain than free nanoagents. Upon 808-nm irradiation, the indocyanine green induced photothermal effects that destroyed the bacteria, releasing the SR717, which triggered adaptive antitumor immunity, and the bacterial remnants further induced innate antitumor immunity. Our findings demonstrate that this inactivated nanobacteria system effectively treats GBM in mice, suggesting potential for broader applications in central nervous system disorders.