| Description |
The transcription factor Olig2 is highly expressed throughout oligodendroglial development and is required for the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and remyelination. Although Olig2 overexpression in OPCs is a possible therapeutic target for enhancing myelin repair in ischemic stroke, strategies for expressing Olig2 in vivo remain technologically challenging. Lipid nanoparticle (LNP)-delivered synthetic modified messenger RNA (mRNA) is considered a reasonable tool for in vivo protein expression. Thus, CD140a-targeted LNPs loaded with Olig2 mRNA (C-Olig2) was created to achieve specific Olig2 protein expression in PDGFRα+/CD140a OPCs for ischemic stroke therapy. We show that C-Olig2 promotes the differentiation of PDGFRα+ OPCs derived from mouse neural stem cells into mature, functional oligodendrocytes in vitro, suggesting that mRNA-LNP-mediated Olig2 overexpression is a rational approach to promoting oligodendrocyte differentiation and myelin regeneration. Furthermore, injection of C-Olig2 into a murine model of ischemic stroke improved blood brain barrier (BBB) integrity, enhanced remyelination and rescued learning and cognitive decline. Bulk RNA sequencing (RNA-seq) and single-nucleus RNA-seq (snRNA-seq) revealed upregulated learning- and memory-related biological processes in brains from mice treated with C-Olig2 vs. empty LNPs (Mock). Collectively, our results indicate that multifunctional nanomedicine targeting mRNA expression has therapeutic potential in ischemic stroke and may become a promising strategy for many brain diseases. |
