Abstract: Central nervous system (CNS) diseases are a global public health concern, exacerbated by the aging population. Nucleic acid drugs have shown great potential in this field. They target specific gene sequences through the principle of complementary base pairing, allowing intervention before protein expression. These drugs offer high specificity, good safety profiles, and relatively short development cycles. However, the presence of the blood-brain barrier (BBB) and the complexity of CNS pathologies restrict drug delivery, making effective delivery systems crucial for the therapeutic effect of nucleic acid drugs. This review introduces nucleic acid drugs developed for CNS disease treatment in recent years, along with their mechanisms of action. It analyzes the obstacles encountered in brain-targeted delivery of nucleic acid drugs, focusing on the physiological structure and function of the BBB, as well as potential pathways and associated mechanisms for achieving delivery. It details the mechanisms of utilizing viral vectors, nucleic acid drug modification techniques, lipid nanoparticles, polymeric nanoparticles, and exosomes to penetrate the blood-brain barrier, as well as their applications in the delivery of nucleic acid drugs. The aim of this review is to compile and analyze current strategies for enabling nucleic acid drugs to cross the BBB while improving targeting and stability. It explores methods to enhance delivery efficiency and provides guidance for future research and clinical application, ultimately promoting the development of nucleic acid therapeutics for CNS disease treatment.