Self-Assembled Quercetin–Mecobalamin Nanoparticles Mitigate Ischemic Stroke Injury via Enhanced Neuroprotection and Microglial Modulation

Ischemic stroke is the key cause of increased disability and mortality in society. Quercetin (Qu), a natural compound with neuroprotective effects, shows promise for treating ischemic stroke. However, Qu's hydrophobicity may be an important factor limiting its therapeutic efficacy. Here, a novel quercetin nanodrug (Qu-Me NPs) is constructed by a facile self-assembly with mecobalamin (a FDA-approved drug for peripheral neuropathy), aiming to overcome the hydrophobicity and improve the bioavailability of Qu. Qu-Me NPs exhibits excellent dispersibility, uniform particle size, and stability in physiological media. Qu-Me NPs markedly attenuated infarct size, reduced neuroinflammation, and improved functional recovery at a 1/10 dose of free quercetin in the mouse middle cerebral artery occlusion (MCAO) model. Mechanistically, Qu-Me NPs modulated anti-inflammatory and antioxidative stress pathways, including suppression of microglial M1 polarization by the downregulation of Panx1 and attenuation of pro-inflammatory cytokine production (IL-1β, IL-6). These findings suggest that Qu-Me NPs is a new formulation of Qu, safe, and efficient therapeutic nanodrug for treating MCAO with a ready-to-be-clinically translated potential.