Targeted nanotheranostics for the treatment of epilepsy through in vivo hijacking of locally activated macrophages

Abstract

Epilepsy refers to a disabling neurological disorder featured by the long-term and unpredictable occurrence of seizures owing to abnormal excessive neuronal electrical activity and is closely linked to unresolved inflammation, oxidative stress, and hypoxia. The difficulty of accurate localization and targeted drug delivery to the lesion hinders the effective treatment of this disease. The locally activated inflammatory cells in the epileptogenic region offer a new opportunity for drug delivery to the lesion. In this work, CD163-positive macrophages in the epileptogenic region were first harnessed as Trojan horses after being hijacked by targeted albumin manganese dioxide nanoparticles, which effectively penetrated the brain endothelial barrier and delivered multifunctional nanomedicines to the epileptic foci. Hence, accumulative nanoparticles empowered the visualization of the epileptogenic lesion through microenvironment-responsive MR T1-weight imaging of manganese dioxide. Besides, these manganese-based nanomaterials played a pivotal role in shielding neurons from cell apoptosis mediated by oxidative stress and hypoxia. Taken together, the present study provides an up-to-date approach for integrated diagnosis and treatment of epilepsy and other hypoxia-associated inflammatory diseases. STATEMENT OF SIGNIFICANCE: The therapeutic effects of antiepileptic drugs (AEDs) are hindered by insufficient drug accumulation in the epileptic site. Herein, we report an efficient strategy to use locally activated macrophages as carriers to deliver multifunctional nanoparticles to the brain lesion. As MR-responsive T1 contrast agents, multifunctional BMC nanoparticles can be harnessed to accurately localize the epileptogenic region with high sensitivity and specificity. Meanwhile, catalytic nanoparticles BMC can synergistically scavenge ROS, generate O₂ and regulate neuroinflammation for the protection of neurons in the brain.

Keywords: CD163+ macrophages; Epilepsy; Neuroprotection; Responsive magnetic resonance imaging; Theranostics.