A DNA Nanostructure-Based Neuroprotectant against Neuronal Apoptosis via Inhibiting Toll-like Receptor 2 Signaling Pathway in Acute Ischemic Stroke

Ischemic stroke is a main cause of cognitive neurological deficits and disability worldwide due to a plethora of neuronal apoptosis. Unfortunately, numerous neuroprotectants for neurons have failed because of biological toxicity, severe side effects, and poor efficacy. Tetrahedral framework nucleic acids (tFNAs) possess excellent biocompatibility and various biological functions. Here, we tested the efficacy of a tFNA for providing neuroprotection against neuronal apoptosis in ischemic stroke. The tFNA prevented apoptosis of neurons (SHSY-5Y cells) caused by oxygen-glucose deprivation/reoxygenation through interfering with ischemia cascades (excitotoxicity and oxidative stress) in vitro. It effectively ameliorated the microenvironment of the ischemic hemisphere by upregulating expression of erythropoietin and inhibiting inflammation, which reversed neuronal loss, alleviated cell apoptosis, significantly shrank the infarction volume from 33.9% to 2.7%, and attenuated neurological deficits in transient middle cerebral artery occlusion (tMCAo) rat models in vivo. In addition, blocking the TLR2-MyD88-NF-κB signaling pathway is a potential mechanism of the neuroprotection by tFNA in ischemic stroke. These findings indicate that tFNA is a safe pleiotropic nanoneuroprotectant and a promising therapeutic strategy for ischemic stroke.