Nose-to-brain delivery of gold nanozyme with cascade effect for bacterial meningitis therapy

The presence of the blood–brain barrier limits the drug concentration in the brain, while low concentrations of antibiotics make it difficult to kill infecting bacteria and tends to induce drug resistance, making the clinical treatment of bacterial meningitis challenging. Herein, a nose-to-brain delivery strategy of small-sized nanozyme has been fabricated for combating bacterial meningitis, to overcome the low drug concentration and drug resistance. This strategy was achieved by a protein-supported Au nanozyme (ANZ). With a particle size of less than 10 nm, it possesses both glucose oxidase-like and peroxidase-like activities and can generate large amounts of reactive oxygen species through a cascade effect without the addition of external H₂O₂. Benefiting from the cascade catalytic amplification effect generated by its dual enzyme-like activities, ANZ shows significant broad-spectrum antibacterial activity without inducing bacterial resistance in vitro. Notably, small-sized ANZ exhibits higher brain entry efficiency and greater accumulation after intranasal administration compared to oral or intravenous administration. In a mouse model of bacterial meningitis, the mice treated with ANZ had lower bacterial loads in the brain and higher survival and clinical behavior scores compared to the classical antibiotic ceftriaxone. Additionally, the meningitis mice exhibited undamaged cognitive and behavioral abilities, indicating the excellent biocompatibility of ANZ. The above results demonstrate that nose-to-brain delivery of ANZ exhibits high intracerebral accumulation, strong antibacterial efficacy and does not lead to bacterial resistance. It holds broad prospects for the treatment of bacterial meningitis.

Graphical abstract