Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.

核酸药物具有靶点选择丰富、设计简单、疗效良好且持久的优点。它们已被证明在脑部疾病治疗中具有不可替代的优越性，而载体是治疗效果的决定性因素。严格的生理屏障，如循环中的降解和清除、血脑屏障、细胞摄取、内体/溶酶体屏障、释放等，阻碍载体将核酸药物递送至大脑。针对单一靶点的核酸药物对于治疗发病机制复杂的脑部疾病效果不佳。患者个体差异导致核酸药物治疗脑部疾病存在严重的不确定性。在这篇综述中，我们简要总结了核酸药物的分类。接下来，我们讨论药物递送过程中的生理障碍和通用应对策略，并介绍这些通用策略在核酸药物载体上的应用方法。随后，我们探索了基于核酸药物的脑部疾病联合治疗的多药方案以及相应载体的构建。接下来，我们通过医学成像的诊断信息以及将造影剂引入载体的方式来解决患者分层和个性化治疗的可行性。最后，我们展望了基于载体的脑部疾病综合诊断和基因治疗的未来可行性和仍然面临的挑战。