Nanochannel‐Based Poration Drives Benign and Effective Nonviral Gene Delivery to Peripheral Nerve Tissue

Abstract

While gene and cell therapies have emerged as promising treatment strategies for various neurological conditions, heavy reliance on viral vectors can hamper widespread clinical implementation. Here, the use of tissue nanotransfection as a platform nanotechnology to drive nonviral gene delivery to nerve tissue via nanochannels, in an effective, controlled, and benign manner is explored. TNT facilitates plasmid DNA delivery to the sciatic nerve of mice in a voltage‐dependent manner. Compared to standard bulk electroporation (BEP), impairment in toe‐spread and pinprick response is not caused by TNT, and has limited to no impact on electrophysiological parameters. BEP, however, induces significant nerve damage and increases macrophage immunoreactivity. TNT is subsequently used to deliver vasculogenic cell therapies to crushed nerves via delivery of reprogramming factor genes Etv2, Foxc2, and Fli1 (EFF). The results indicate the TNT‐based delivery of EFF in a sciatic nerve crush model leads to increased vascularity, reduced macrophage infiltration, and improved recovery in electrophysiological parameters compared to crushed nerves that are TNT‐treated with sham/empty plasmids. Altogether, the results indicate that TNT can be a powerful platform nanotechnology for localized nonviral gene delivery to nerve tissue, in vivo, and the deployment of reprogramming‐based cell therapies for nerve repair/regeneration.

Applications of Tissue Nano-Transfection Technology (TNT): A Systematic Review

“…TNT is used to treat ischemic stroke in mice by delivering reprogramming factors (Etv2, Foxc2, and Fli1 (EFF)) which are vasculogenic cell therapies. These treatment methods lead to increased vascularity and revealed infract resolution, indicating that TNT is a particularly promising future approach to treat ischemic stroke [10].…”

Nanotransfection-based vasculogenic cell reprogramming drives functional recovery in a mouse model of ischemic stroke

“…Nonviral approaches to gene/cargo delivery have the potential to facilitate the development of highly translational cell therapies for a wide variety of conditions ( 18 , 19 , 41 – 45 ). Here, we showed that nonviral nanotransfection of Etv2 , Foxc2 , and Fli1 ( EFF ) into fibroblasts can drive reprogramming-based vasculogenic cell therapies of relevance to ischemic stroke when deployed intracranially.…”

Applications of Tissue Nano-Transfection Technology (TNT): a systematic review

“…TNT can be used to deliver reprogramming factors genes Etv2, Foxc2, and Fli1 (EFF) to crushed nerves, which results in increased vascularity and better recovery. Tissue Nano transfection, when compared to Bulk Electroporation (BEP), does not hinder toe-spread and pinprick response and does not affect electrophysiological parameters, whereas BEP can cause nerve damage and increase macrophage overexpression (10).…”