Adeno-associated virus (AAV) vectors have emerged as a leading platform for gene therapy targeting central nervous system (CNS) disorders; however, efficient, safe, and scalable delivery across the blood-brain barrier (BBB) remains a central challenge for clinical translation. This review provides a comprehensive and forward-looking synthesis of recent advances in AAV-based CNS gene therapy, focusing on delivery strategies, disease applications, and genome editing technologies, while highlighting key translational factors influencing clinical outcomes. We first outline the biological properties of AAV vectors, including capsid diversity, genome packaging constraints, and regulatory elements that govern transgene expression and durability. We then compare major routes of administration—direct intracranial delivery, cerebrospinal fluid (CSF)-mediated approaches, and systemic intravenous injection—highlighting their advantages and limitations in achieving brain-wide versus region-specific transduction. In addition, we discuss key parameters affecting in vivo performance, including dose, distribution, and tissue tropism. Special emphasis is placed on recent advances in capsid engineering, including in vivo directed evolution, receptor-guided rational design, and cross-species validation strategies that aim to bridge long-standing translational gaps between rodent models and nonhuman primates or humans. We next summarize therapeutic progress across major CNS disorders, including neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease, as well as monogenic neurodevelopmental and lysosomal storage disorders exemplified by Rett syndrome and mucopolysaccharidosis, together with emerging clinical insights from ongoing trials. In parallel, we describe the integration of AAV delivery with genome editing modalities—particularly base and prime editing—which offer precise and potentially safer alternatives to conventional gene replacement strategies, especially for diseases driven by defined genetic variants. Finally, we outline key translational bottlenecks, including host immune responses, dose-dependent toxicity, limited packaging capacity, and the need for improved cell-type specificity and regulatory control. We propose a framework for next-generation CNS gene therapy centered on “human receptor-guided capsid design, multi-layered transcriptional regulation, and precision genome editing”. Together with advances in scalable manufacturing, quality control, and regulatory standardization, these developments are expected to improve safety, enhance delivery efficiency, and support more durable therapeutic outcomes. This review provides an integrated perspective to guide future research and facilitate clinical translation of AAV-based therapeutics for CNS disorders.
Han et al. (Mon,) studied this question.