Liang Fuming, Cui Shizhen, Yang Jing, He Zhaohui, Zhu Ling
CAS Key Laboratory of Standardization and Measurement for Nanotechnology National Center for Nanoscience and Technology Beijing 100190 P. R. China.
Department of Neurosurgery The First Affiliated Hospital of Chongqing Medical University 1 Friendship Road Chongqing 400016 P. R. China.
Adv Genet (Hoboken). 2025 Jun 24;6(2):e00010. doi: 10.1002/ggn2.202500010. eCollection 2025 Jun.
Central nervous system (CNS) disorders are driven by complex genetic and epigenetic factors. While gene-based interventions (siRNA, mRNA, CRISPR systems, etc.) hold transformative potential, their clinical application is severely constrained by inefficient delivery, especially across the blood-brain barrier. Nanocarriers have emerged as transformative platforms that overcome these challenges by enabling efficient BBB penetration while ensuring precise biodistribution control and enhanced therapeutic payload protection. This review explores recent advances in nanoplatform-enabled genetic intervention that overcome the delivery challenges through innovative engineering approaches. We discuss the genetic and epigenetic mechanisms underlying major CNS pathologies, the current limitations of free nucleic acid therapeutics, the development of advanced nanoplatforms that achieve blood-brain barrier penetration and targeted delivery. We further also evaluate therapeutic prospects across disease models while addressing translational challenges in stability, targeting specificity, and manufacturing scalability. By integrating fundamental research with preclinical applications, this review provides both a theoretical framework and practical roadmap for developing next-generation nanotherapeutics for CNS genetic medicine.
中枢神经系统（CNS）疾病由复杂的遗传和表观遗传因素驱动。虽然基于基因的干预措施（小干扰RNA、信使核糖核酸、CRISPR系统等）具有变革潜力，但其临床应用受到递送效率低下的严重限制，尤其是在穿越血脑屏障方面。纳米载体已成为变革性平台，通过实现高效的血脑屏障穿透，同时确保精确的生物分布控制和增强治疗载荷保护，克服了这些挑战。本综述探讨了纳米平台介导的基因干预的最新进展，这些进展通过创新的工程方法克服了递送挑战。我们讨论了主要中枢神经系统病理学背后的遗传和表观遗传机制、游离核酸疗法的当前局限性、实现血脑屏障穿透和靶向递送的先进纳米平台的开发。我们还进一步评估了跨疾病模型的治疗前景，同时解决了稳定性、靶向特异性和制造可扩展性方面的转化挑战。通过将基础研究与临床前应用相结合，本综述为开发用于中枢神经系统基因医学的下一代纳米疗法提供了理论框架和实践路线图。
