Delivery of miRNAs through Metal-Organic Framework Nanoparticles for Assisting Neural Stem Cell Therapy for Ischemic Stroke.

Abstract

Stroke is the most common cause of disability globally. Neural stem cell (NSC) therapy, which can replace lost and damaged neurons, has been proposed as a potential treatment for stroke. The therapeutic efficacy of NSC therapy is hindered by the fact that only a small number of NSCs undergo neuronal differentiation. Neuron-specific miR-124, which promotes the differentiation of NSCs into mature neurons, can be combined with NSC therapy to cure ischemic stroke. However, the instability and poor internalization of miR-124 seriously hamper its broad clinical application. Herein, an innovative strategy involving delivery of miR-124 via a Ca-MOF@miR-124 nanodelivery system, which effectively prevents the degradation of miR-124 by nucleases and promotes the internalization of miR-124 by NSCs, is presented. The effect of accelerated neuronal directed differentiation of NSCs was assessed through <i>in vitro</i> cell experiments, and the clinical application potential of this nanodelivery system for the treatment of ischemic stroke was assessed through <i>in vivo</i> experiments involving the combination of NSC therapy and Ca-MOF@miR-124 nanoparticles. The results indicate that Ca-MOF@miR-124 nanoparticles can promote the differentiation of NSCs into mature neurons with electrophysiological function within 5 days. The differentiation rate of cells treated with Ca-MOF@miR-124 nanoparticles was at least 5 days faster than that of untreated cells. Moreover, Ca-MOF@miR-124 nanoparticles decreased the ischemic area to almost normal levels by day 7. The combination of Ca-MOF@miR-124 nanoparticles and NSC therapy will enhance the treatment of traumatic nerve injury and neurodegenerative diseases.