Stroke is a major cause of disability and mortality globally and is typically divided into ischemic and hemorrhagic stroke. When a stroke occurs, either blockage or rupture of cerebral blood vessels results in rapid neurological dysfunction because of ischemia or hemorrhage in the cerebral parenchyma. Although current treatment methods, such as intravascular thrombolysis, surgical hematoma evacuation, and neuroprotection, can partially alleviate symptoms, these strategies often fail to fully restore functional impairments resulting from brain injury. Nucleic acid-based therapy is an emerging treatment modality aimed at modulating the expression of disease-associated genes by introducing exogenous nucleic acids that exert therapeutic effects at the genetic level. However, the inherent properties of naked RNA dictate the necessity for carriermediated delivery in vivo. With the development of biomedical engineering and nanotechnology, nucleic acid-based delivery systems have shown promise for the clinical translation of stroke therapies owing to their excellent biocompatibility and efficient delivery capability. This review emphasizes the advancements in nucleic acid-based delivery systems for stroke therapy and anticipates their future prospective potential to provide new insights and directions for precise stroke therapy.