Strategies for enhanced gene delivery to the central nervous system

The delivery of genes to the central nervous system (CNS) has been a persistent challenge due to various biological barriers. The blood-brain barrier (BBB), in particular, hampers the access of systemically injected drugs to parenchymal cells, allowing only a minimal percentage (<1%) to pass through. Recent scientific insights highlight the crucial role of the extracellular space (ECS) in governing drug diffusion. Taking into account advancements in vectors, techniques, and knowledge, the discussion will center on the most notable vectors utilized for gene delivery to the CNS. This review will explore the influence of the ECS - a dynamically regulated barrier-on drug diffusion. Furthermore, we will underscore the significance of employing remote-control technologies to facilitate BBB traversal and modulate the ECS. Given the rapid progress in gene editing, our discussion will also encompass the latest advances focused on delivering therapeutic editing in vivo to the CNS tissue. In the end, a brief summary on the impact of Artificial Intelligence (AI)/Machine Learning (ML), ultrasmall, soft endovascular robots, and high-resolution endovascular cameras on improving the gene delivery to the CNS will be provided.