Gadolinium-ceria hybrid system enables synergistic alleviation of oxidative stress and metabolic thrombo-inflammation for efficient ischemic stroke treatment

Abstract

Ischemic stroke is a primary cause of global death and long-term disability. However, current neuroprotective drugs are far from satisfactory in clinical practice. Compelling evidence has emerged that targeting conjoined multiple factors can bring comprehensive treatment. Herein, we report an image-guided gadolinium-ceria nanoparticle-immobilized small therapeutic molecules (ML265) hybrid system for targeted mitigation of oxidative stress and disruption of metabolic reprogramming in cerebral thrombo-inflammation post ischemic stroke. Sub-10 nm hybrid nanotherapeutics sufficiently extravasate through the blood brain barrier (BBB) to pathological brain area. ML265 effectively obstructs the dimerization of metabolic enzyme (pyruvate kinase muscle 2, PKM2) via NF-κB signaling pathway, thus resulting in a significant reduction in the infiltration of neutrophils, monocytes and macrophages companied with declined production of inflammatory cytokines. Concomitantly, the incorporation of gadolinium into ceria nanoparticles allows enhanced antioxidant capability in alleviation of overproduced radicals, and also confers magnetic resonance imaging (MRI) of the injured brain tissue. The therapy is shown to substantially improve the brain recovery in murine ischemic stroke model. Complemented with great tolerance, this strategy offers a safe and effective strategy for ischemic stroke treatment.